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Keir, Stephen Thomas

Positions:

Professor in Neurosurgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.P.H. 2001

M.P.H. — University of North Carolina at Chapel Hill

DrPH 2004

DrPH — University of North Carolina at Chapel Hill

Grants:

Pediatric Brain Tumor Consortium

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Jude Children's Research Hospital
Role
Collaborator
Start Date
April 01, 2014
End Date
March 31, 2017

Truncated GLI1 In Glioblastoma

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 15, 2014
End Date
June 30, 2014

Regional AGT Depletion of CNS and Leptomeningeal Tumors

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Research Analyst
Start Date
February 01, 2002
End Date
January 31, 2006

Publications:

Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program.

CBL0137 is a novel drug that modulates FAcilitates Chromatin Transcription (FACT), resulting in simultaneous nuclear factor-κB suppression, heat shock factor 1 suppression and p53 activation. CBL0137 has demonstrated antitumor effects in animal models of several adult cancers and neuroblastoma.CBL0137 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations ranging from 1.0 nM to 10.0 μM and against the PPTP in vivo solid tumor xenograft and acute lymphocytic leukemia (ALL) panels at 50 mg/kg administered intravenously weekly for 4 weeks.The median relative IC50 (rIC50 ) value for the PPTP cell lines was 0.28 μM (range: 0.13-0.80 μM). There were no significant differences in rIC50 values by histotype. CBL0137 induced significant differences in event-free survival (EFS) distribution compared to control in 10 of 31 (32%) evaluable solid tumor xenografts and in eight of eight (100%) evaluable ALL xenografts. Significance differences in EFS distribution were observed in four of six osteosarcoma lines, three of three rhabdoid tumor lines and two of six rhabdomyosarcoma lines. No objective responses were observed among the solid tumor xenografts. For the ALL panel, one xenograft achieved complete response and four achieved partial response.The most consistent in vivo activity for CBL0137 was observed against ALL xenografts, with some solid tumor xenograft lines showing tumor growth delay. It will be important to relate the drug levels in mice at 50 mg/kg to those in humans at the recommended phase 2 dose.

Authors
Lock, R; Carol, H; Maris, JM; Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Keir, ST; Wu, J; Purmal, A; Gudkov, A; Kurmashev, D; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Lock, R, Carol, H, Maris, JM, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Keir, ST, Wu, J, Purmal, A, Gudkov, A, Kurmashev, D, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program." Pediatric blood & cancer 64.4 (April 2017).
PMID
27650817
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
64
Issue
4
Publish Date
2017
DOI
10.1002/pbc.26263

Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program.

VS-4718, a novel inhibitor of focal adhesion kinase (FAK), was tested against the Pediatric Preclinical Testing Program's (PPTP's) in vitro cell line panel and showed a median relative IC50 of 1.22 μM. VS-4718 was tested in vivo against the PPTP xenograft models using a dose of 50 mg/kg administered by the oral route twice daily for 21 days. VS-4718 induced significant differences in an event-free survival distribution compared with control in 18 of 36 of the evaluable solid tumor xenografts and in 0 of 8 acute lymphoblastic leukemia (ALL) xenografts, but no xenograft lines showed tumor regression. Future plans include further evaluation of the role of FAK inhibition in combination with ABL kinase inhibitors for Ph+ ALL.

Authors
Kurmasheva, RT; Gorlick, R; Kolb, EA; Keir, ST; Maris, JM; Lock, RB; Carol, H; Kang, M; Reynolds, CP; Wu, J; Houghton, PJ; Smith, MA
MLA Citation
Kurmasheva, RT, Gorlick, R, Kolb, EA, Keir, ST, Maris, JM, Lock, RB, Carol, H, Kang, M, Reynolds, CP, Wu, J, Houghton, PJ, and Smith, MA. "Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program." Pediatric blood & cancer 64.4 (April 2017).
PMID
27786412
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
64
Issue
4
Publish Date
2017
DOI
10.1002/pbc.26304

Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program.

MK-8242 is an inhibitor of MDM2 that stabilizes the tumor suppressor TP53 and induces growth arrest or apoptosis downstream of TP53 induction.MK-8242 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10.0 μM and against the PPTP in vivo xenograft panels using oral gavage on Days 1-5 and Day 15-19 at a dose of 125 mg/kg (solid tumors) or 75 mg/kg (acute lymphoblastic leukemia [ALL] models).The median IC50 for MK-8242 was 0.07 μM for TP53 wild-type cell lines versus >10 μM for TP53 mutant cell lines. MK-8242 induced a twofold or greater delay in time to event in 10 of 17 (59%) of TP53 wild-type solid tumor xenografts, excluding osteosarcoma xenografts that have very low TP53 expression. Objective responses were observed in seven solid tumor xenografts representing multiple histotypes. For the systemic-disease ALL panel, among eight xenografts there were two complete responses (CRs) and six partial responses (PRs). Two additional MLL-rearranged xenografts (MV4;11 and RS4;11) grown subcutaneously showed maintained CR and PR, respectively. The expected pharmacodynamic responses to TP53 activation were observed in TP53 wild-type models treated with MK-8242. Pharmacokinetic analysis showed that MK-8242 drug exposure in SCID mice appears to exceed that was observed in adult phase 1 trials.MK-8242-induced tumor regressions across multiple solid tumor histotypes and induced CRs or PRs for most ALL xenografts. This activity was observed at MK-8242 drug exposures that appear to exceed those observed in human phase 1 trials.

Authors
Kang, MH; Reynolds, CP; Kolb, EA; Gorlick, R; Carol, H; Lock, R; Keir, ST; Maris, JM; Wu, J; Lyalin, D; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Kang, MH, Reynolds, CP, Kolb, EA, Gorlick, R, Carol, H, Lock, R, Keir, ST, Maris, JM, Wu, J, Lyalin, D, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program." Pediatric blood & cancer 63.10 (October 2016): 1744-1752.
PMID
27238606
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
63
Issue
10
Publish Date
2016
Start Page
1744
End Page
1752
DOI
10.1002/pbc.26064

Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis.

Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%-87.5%). Allowing for misprediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798-809. ©2016 AACR.

Authors
Murphy, B; Yin, H; Maris, JM; Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Keir, ST; Kurmasheva, RT; Dvorchik, I; Wu, J; Billups, CA; Boateng, N; Smith, MA; Lock, RB; Houghton, PJ
MLA Citation
Murphy, B, Yin, H, Maris, JM, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Keir, ST, Kurmasheva, RT, Dvorchik, I, Wu, J, Billups, CA, Boateng, N, Smith, MA, Lock, RB, and Houghton, PJ. "Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis." Cancer research 76.19 (October 2016): 5798-5809.
PMID
27496711
Source
epmc
Published In
Cancer Research
Volume
76
Issue
19
Publish Date
2016
Start Page
5798
End Page
5809

A Therapeutic Antibody for Cancer, Derived from Single Human B Cells.

Some patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery.

Authors
Bushey, RT; Moody, MA; Nicely, NL; Haynes, BF; Alam, SM; Keir, ST; Bentley, RC; Roy Choudhury, K; Gottlin, EB; Campa, MJ; Liao, H-X; Patz, EF
MLA Citation
Bushey, RT, Moody, MA, Nicely, NL, Haynes, BF, Alam, SM, Keir, ST, Bentley, RC, Roy Choudhury, K, Gottlin, EB, Campa, MJ, Liao, H-X, and Patz, EF. "A Therapeutic Antibody for Cancer, Derived from Single Human B Cells." Cell reports 15.7 (May 4, 2016): 1505-1513.
Website
http://hdl.handle.net/10161/12221
PMID
27160908
Source
epmc
Published In
Cell Reports
Volume
15
Issue
7
Publish Date
2016
Start Page
1505
End Page
1513
DOI
10.1016/j.celrep.2016.04.038

Initial Testing of NSC 750854, a Novel Purine Analog, Against Pediatric Tumor Models by the Pediatric Preclinical Testing Program.

NSC 750854 is a purine analog with an antitumor activity profile distinctive from that of other anticancer purines. It has shown significant activity against adult cancer preclinical models.NSC 750854 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered intraperitoneally at a dose of 5 mg/kg daily for 5 days repeated at day 15.The median relative IC50 (rIC50 ) value for the PPTP cell lines was 32 nM (range from 11 to 124 nM), with consistent cytotoxicity across all cell lines. Acute lymphoblastic leukemia (ALL) cell lines were more sensitive to NSC 750854 than non-ALL cell lines. NSC 750854 induced significant differences in EFS distribution compared to control in 31 of 35 (89%) solid tumor xenografts. It induced tumor growth inhibition meeting criteria for intermediate or high event free survival (EFS) T/C activity in 17 of 32 (53%) evaluable solid tumor xenografts (most consistently in the rhabdomyosarcoma panel). Objective responses were observed in 15 of 37 (41%) solid tumor xenografts and in all eight leukemia models with complete response (CR) or maintained complete response (MCR) in seven of eight leukemia models.NSC 750854 has a unique spectrum of antitumor activity compared with other agents tested by the PPTP as it induces regression in tumor models with limited sensitivity to most agents tested to date. Given the promising level of activity observed for NSC 750854 against PPTP preclinical models, further exploration of its mechanism of action is warranted.

Authors
Gorlick, R; Kolb, EA; Keir, ST; Maris, JM; Lock, RB; Carol, H; Reynolds, CP; Kang, MH; Billups, CA; Collins, J; Kurmashev, D; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Gorlick, R, Kolb, EA, Keir, ST, Maris, JM, Lock, RB, Carol, H, Reynolds, CP, Kang, MH, Billups, CA, Collins, J, Kurmashev, D, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial Testing of NSC 750854, a Novel Purine Analog, Against Pediatric Tumor Models by the Pediatric Preclinical Testing Program." Pediatric blood & cancer 63.3 (March 2016): 443-450.
PMID
26797892
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
63
Issue
3
Publish Date
2016
Start Page
443
End Page
450
DOI
10.1002/pbc.25826

Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program.

Selinexor (KPT-330) is an inhibitor of the major nuclear export receptor, exportin 1 (XPO1, also termed chromosome region maintenance 1, CRM1) that has demonstrated activity in preclinical models and clinical activity against several solid and hematological cancers.Selinexor was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered orally at a dose of 10 mg/kg thrice weekly for 4 weeks.Selinexor demonstrated cytotoxic activity in vitro, with a median relative IC50 value of 123 nM (range 13.0 nM to >10 μM). Selinexor induced significant differences in event-free survival (EFS) distribution in 29 of 38 (76%) of the evaluable solid tumor xenografts and in five of eight (63%) of the evaluable ALL xenografts. Objective responses (partial or complete responses, PR/CR) were observed for 4 of 38 solid tumor xenografts including Wilms tumor, medulloblastoma (n = 2), and ependymoma models. For the ALL panel, two of eight (25%) xenografts achieved either CR or maintained CR. Two responding xenografts had FBXW7 mutations at R465 and two had SMARCA4 mutations. Selinexor induced p53, p21, and cleaved PARP in several solid tumor models.Selinexor induced regression against several solid tumor and ALL xenografts and slowed tumor growth in a larger number of models. Pharmacodynamic effects for XPO1 inhibition were noted. Defining the relationship between selinexor systemic exposures in mice and humans will be important in assessing the clinical relevance of these results.

Authors
Attiyeh, EF; Maris, JM; Lock, R; Reynolds, CP; Kang, MH; Carol, H; Gorlick, R; Kolb, EA; Keir, ST; Wu, J; Landesman, Y; Shacham, S; Lyalin, D; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Attiyeh, EF, Maris, JM, Lock, R, Reynolds, CP, Kang, MH, Carol, H, Gorlick, R, Kolb, EA, Keir, ST, Wu, J, Landesman, Y, Shacham, S, Lyalin, D, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program." Pediatric blood & cancer 63.2 (February 2016): 276-286.
PMID
26398108
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
63
Issue
2
Publish Date
2016
Start Page
276
End Page
286
DOI
10.1002/pbc.25727

MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B.

The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

Authors
Hu, J; Sun, T; Wang, H; Chen, Z; Wang, S; Yuan, L; Liu, T; Li, H-R; Wang, P; Feng, Y; Wang, Q; McLendon, RE; Friedman, AH; Keir, ST; Bigner, DD; Rathmell, J; Fu, X-D; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Hu, J, Sun, T, Wang, H, Chen, Z, Wang, S, Yuan, L, Liu, T, Li, H-R, Wang, P, Feng, Y, Wang, Q, McLendon, RE, Friedman, AH, Keir, ST, Bigner, DD, Rathmell, J, Fu, X-D, Li, Q-J, Wang, H, and Wang, X-F. "MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B." Cancer cell 29.1 (January 2016): 49-60.
Website
http://hdl.handle.net/10161/11667
PMID
26766590
Source
epmc
Published In
Cancer Cell
Volume
29
Issue
1
Publish Date
2016
Start Page
49
End Page
60
DOI
10.1016/j.ccell.2015.12.005

Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells.

Under normal physiologic conditions, the glutathione S-transferase P1 (GSTP1) protein exists intracellularly as a dimer in reversible equilibrium with its monomeric subunits. In the latter form, GSTP1 binds to the mitogen-activated protein kinase, JNK, and inhibits JNK downstream signaling. In tumor cells, which frequently are characterized by constitutively high GSTP1 expression, GSTP1 undergoes phosphorylation by epidermal growth factor receptor (EGFR) at tyrosine residues 3, 7, and 198. Here we report on the effect of this EGFR-dependent GSTP1 tyrosine phosphorylation on the interaction of GSTP1 with JNK, on the regulation of JNK downstream signaling by GSTP1, and on tumor cell survival. Using in vitro and in vivo growing human brain tumors, we show that tyrosine phosphorylation shifts the GSTP1 dimer-monomer equilibrium to the monomeric state and facilitates the formation of the GSTP1-JNK complex, in which JNK is functionally inhibited. Targeted mutagenesis and functional analysis demonstrated that the increased GSTP1 binding to JNK results from phosphorylation of the GSTP1 C-terminal Tyr-198 by EGFR and is associated with a >2.5-fold decrease in JNK downstream signaling and a significant suppression of both spontaneous and drug-induced apoptosis in the tumor cells. The findings define a novel mechanism of regulatory control of JNK signaling that is mediated by the EGFR/GSTP1 cross-talk and provides a survival advantage for tumors with activated EGFR and high GSTP1 expression. The results lay the foundation for a novel strategy of dual EGFR/GSTP1 for treating EGFR+ve, GSTP1 expressing GBMs.

Authors
Okamura, T; Antoun, G; Keir, ST; Friedman, H; Bigner, DD; Ali-Osman, F
MLA Citation
Okamura, T, Antoun, G, Keir, ST, Friedman, H, Bigner, DD, and Ali-Osman, F. "Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells." The Journal of biological chemistry 290.52 (December 2015): 30866-30878.
PMID
26429914
Source
epmc
Published In
The Journal of biological chemistry
Volume
290
Issue
52
Publish Date
2015
Start Page
30866
End Page
30878
DOI
10.1074/jbc.m115.656140

Initial testing (stage 1) of BAL101553, a novel tubulin binding agent, by the pediatric preclinical testing program.

BAL101553 is a highly water soluble prodrug of BAL27862 that arrests tumor cell proliferation and induces cell death in cancer cells through disruption of the microtubule network. In vitro BAL27862 demonstrated potent activity, with the median relative IC50 (rIC50 ) of 13.8 nM (range 5.4-25.2 nM). The in vitro activity of BAL27862 against the PPTP cell lines is distinctive from that previously described for vincristine. BAL101553 induced significant differences in EFS distribution compared to control in 16 of 30 (53%) solid tumor xenografts and in two of four (67%) of the evaluable ALL xenografts. No objective responses were observed.

Authors
Kolb, EA; Gorlick, R; Keir, ST; Maris, JM; Kang, MH; Reynolds, CP; Lock, RB; Carol, H; Wu, J; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Kolb, EA, Gorlick, R, Keir, ST, Maris, JM, Kang, MH, Reynolds, CP, Lock, RB, Carol, H, Wu, J, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of BAL101553, a novel tubulin binding agent, by the pediatric preclinical testing program." Pediatric blood & cancer 62.6 (June 2015): 1106-1109.
PMID
25407467
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
62
Issue
6
Publish Date
2015
Start Page
1106
End Page
1109
DOI
10.1002/pbc.25329

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

Authors
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; Mclendon, R; Ali-Osman, F; Bigner, DD; Sampson, JH; Kwatra, MM
MLA Citation
Brown, KE, Chagoya, G, Kwatra, SG, Yen, T, Keir, ST, Cooter, M, Hoadley, KA, Rasheed, A, Lipp, ES, Mclendon, R, Ali-Osman, F, Bigner, DD, Sampson, JH, and Kwatra, MM. "Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development." Journal of neurochemistry 133.5 (June 2015): 730-738.
PMID
25598002
Source
epmc
Published In
Journal of Neurochemistry
Volume
133
Issue
5
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1111/jnc.13032

Dynamic treatment effect (DTE) curves reveal the mode of action for standard and experimental cancer therapies.

We present a method for estimating the empirical dynamic treatment effect (DTE) curves from tumor growth delay (TGD) studies. This improves on current common methods of TGD analysis, such as T/C ratio and doubling times, by providing a more detailed treatment effect and overcomes their lack of reproducibility. The methodology doesn't presuppose any prior form for the treatment effect dynamics and is shown to give consistent estimates with missing data. The method is illustrated by application to real data from TGD studies involving three types of therapy. Firstly, we demonstrate that radiotherapy induces a sharp peak in inhibition in a FaDu model. The height, duration and timing of the peak increase linearly with radiation dose. Second, we demonstrate that a combination of temozolomide and an experimental therapy in a glioma PDX model yields an effect, similar to an additive version of the DTE curves for the mono-therapies, except that there is a 30 day delay in peak inhibition. In the third study, we consider the DTE of anti-angiogenic therapy in glioma. We show that resulting DTE curves are flat. We discuss how features of the DTE curves should be interpreted and potentially used to improve therapy.

Authors
Choudhury, KR; Keir, ST; Ashcraft, KA; Boss, M-K; Dewhirst, MW
MLA Citation
Choudhury, KR, Keir, ST, Ashcraft, KA, Boss, M-K, and Dewhirst, MW. "Dynamic treatment effect (DTE) curves reveal the mode of action for standard and experimental cancer therapies." Oncotarget 6.16 (June 2015): 14656-14668.
PMID
25986925
Source
epmc
Published In
Oncotarget
Volume
6
Issue
16
Publish Date
2015
Start Page
14656
End Page
14668

Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program.

Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan.Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 μmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment.In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide.The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation.

Authors
Smith, MA; Reynolds, CP; Kang, MH; Kolb, EA; Gorlick, R; Carol, H; Lock, RB; Keir, ST; Maris, JM; Billups, CA; Lyalin, D; Kurmasheva, RT; Houghton, PJ
MLA Citation
Smith, MA, Reynolds, CP, Kang, MH, Kolb, EA, Gorlick, R, Carol, H, Lock, RB, Keir, ST, Maris, JM, Billups, CA, Lyalin, D, Kurmasheva, RT, and Houghton, PJ. "Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program." Clinical cancer research : an official journal of the American Association for Cancer Research 21.4 (February 2015): 819-832.
PMID
25500058
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
4
Publish Date
2015
Start Page
819
End Page
832
DOI
10.1158/1078-0432.ccr-14-2572

Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673.

BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks.BMN 673 was tested in vitro at concentrations ranging from 0.1 nM to 1 μM and in vivo at a daily dose of 0.33 mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days.The median relative IC50 (rIC50 ) concentration against the PPTP cell lines was 25.8 nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 vs. 31.1 nM, respectively). In vivo BMN 673 induced statistically significant differences in EFS distribution in 17/43 (39.5%) xenograft models. Three objective regressions were observed: a complete response (CR) in a medulloblastoma line (BT-45), a maintained CR in a Wilms tumor line (KT-10), and a maintained CR in an ependymoma line (BT-41). BMN 673 maintained its high level of activity against KT-10 with a threefold reduction in dose. KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair.The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers. Single agent activity is more likely for patients whose tumors have defects in HR repair.

Authors
Smith, MA; Hampton, OA; Reynolds, CP; Kang, MH; Maris, JM; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Wu, J; Kurmasheva, RT; Wheeler, DA; Houghton, PJ
MLA Citation
Smith, MA, Hampton, OA, Reynolds, CP, Kang, MH, Maris, JM, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Keir, ST, Wu, J, Kurmasheva, RT, Wheeler, DA, and Houghton, PJ. "Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673." Pediatric blood & cancer 62.1 (January 2015): 91-98.
PMID
25263539
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
62
Issue
1
Publish Date
2015
Start Page
91
End Page
98
DOI
10.1002/pbc.25201

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development

© 2015 International Society for Neurochemistry.The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR.

Authors
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; McLendon, R; Ali-Osman, F; Bigner, DD; Sampson, JH; Kwatra, MM
MLA Citation
Brown, KE, Chagoya, G, Kwatra, SG, Yen, T, Keir, ST, Cooter, M, Hoadley, KA, Rasheed, A, Lipp, ES, McLendon, R, Ali-Osman, F, Bigner, DD, Sampson, JH, and Kwatra, MM. "Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development." Journal of Neurochemistry 133.5 (2015): 730-738.
Source
scival
Published In
Journal of Neurochemistry
Volume
133
Issue
5
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1111/jnc.13032

Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models.

Retaspimycin hydrochloride (IPI-504), an Hsp90 (heat shock protein 90) inhibitor, has shown activity in multiple preclinical cancer models, such as lung, breast and ovarian cancers. However, its biological effects in gliomas and normal brain derived cellular populations remain unknown. In this study, we profiled the expression pattern of Hsp90α/β mRNA in stable glioma cell lines, multiple glioma-derived primary cultures and human neural stem/progenitor cells. The effects of IPI-504 on cell proliferation, apoptosis, motility and expression of Hsp90 client proteins were evaluated in glioma cell lines. In vivo activity of IPI-504 was investigated in subcutaneous glioma xenografts. Our results showed Hsp90α and Hsp90β expression levels to be patient-specific, higher in high-grade glioma-derived primary cells than in low-grade glioma-derived primary cells, and strongly correlated with CD133 expression and differentiation status of cells. Hsp90 inhibition by IPI-504 induced apoptosis, blocked migration and invasion, and significantly decreased epidermal growth factor receptor levels, mitogen-activated protein kinase and/or Akt activities, and secretion of vascular endothelial growth factor in glioma cell lines. In vivo study showed that IPI-504 could mildly attenuate tumor growth in immunocompromised mice. These findings suggest that targeting Hsp90 by IPI-504 has the potential to become an active therapeutic strategy in gliomas in a selective group of patients, but further research into combination therapies is still needed.

Authors
Di, K; Keir, ST; Alexandru-Abrams, D; Gong, X; Nguyen, H; Friedman, HS; Bota, DA
MLA Citation
Di, K, Keir, ST, Alexandru-Abrams, D, Gong, X, Nguyen, H, Friedman, HS, and Bota, DA. "Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models." Journal of neuro-oncology 120.3 (December 2014): 473-481.
PMID
25115740
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
120
Issue
3
Publish Date
2014
Start Page
473
End Page
481
DOI
10.1007/s11060-014-1579-y

Initial solid tumor testing (stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program.

AZD1480 is an ATP competitive inhibitor of Janus kinases 1 and 2 (JAK1, 2) that has been shown to inhibit the growth of solid tumor models. This agent was selected for testing the putative role of JAK/STAT signaling in the standard PPTP solid tumor models.AZD1480 was tested against the PPTP in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo solid tumor xenograft panels at (60 mg/kg once daily (SID) × 5) for three consecutive weeks. Additional studies evaluated 5 to 20 mg/kg BID × 5 with SID dosing at 7-30 mg/kg at weekends for three consecutive weeks.In vitro the median relative IC50 (rIC50 ) for the PPTP cell lines was 1.5 µM, with a range from 0.3 µM to 5.9 µM. The two cell lines with rIC50 values of 0.3 µM both had ALK activating genomic alterations. AZD1480 demonstrated statistically significant differences (P < 0.05) in EFS distribution compared to control in 89% of the solid tumor xenografts. AZD1480 induced intermediate (EFS T/C > 2) or high-level growth inhibition in 15 of 30 (50%) solid tumor xenografts. Tumor regressions were observed in three of six Wilms tumor models at doses that induced inhibition of Stat3(Y705) phosphorylation.AZD1480 demonstrated significant tumor growth inhibition against most PPTP solid tumor xenografts, similar to that observed for antiangiogenic agents tested by the PPTP. Tumor regressing activity was noted for Wilms tumor xenografts.

Authors
Houghton, PJ; Kurmasheva, RT; Lyalin, D; Maris, JM; Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Keir, ST; Wu, J; Smith, MA
MLA Citation
Houghton, PJ, Kurmasheva, RT, Lyalin, D, Maris, JM, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Keir, ST, Wu, J, and Smith, MA. "Initial solid tumor testing (stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program." Pediatric blood & cancer 61.11 (November 2014): 1972-1979.
PMID
25131802
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
61
Issue
11
Publish Date
2014
Start Page
1972
End Page
1979
DOI
10.1002/pbc.25175

miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways.

Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell-associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance-associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a-dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a-centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.

Authors
Wang, H; Sun, T; Hu, J; Zhang, R; Rao, Y; Wang, S; Chen, R; McLendon, RE; Friedman, AH; Keir, ST; Bigner, DD; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Wang, H, Sun, T, Hu, J, Zhang, R, Rao, Y, Wang, S, Chen, R, McLendon, RE, Friedman, AH, Keir, ST, Bigner, DD, Li, Q-J, Wang, H, and Wang, X-F. "miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways." The Journal of clinical investigation 124.10 (October 2014): 4489-4502.
PMID
25202981
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
10
Publish Date
2014
Start Page
4489
End Page
4502
DOI
10.1172/jci75284

Initial Testing (Stage 1) of the Notch Inhibitor PF-03084014, by the Pediatric Preclinical Testing Program (vol 61, pg 1493, 2014)

Authors
Carol, H; Maris, JM; Kang, MH; Reynolds, CP; Kolb, EA; Gorlick, R; Keir, ST; Wu, J; Lyalin, D; Kurmasheva, RT; Houghton, PJ; Smith, MA; Lock, RB
MLA Citation
Carol, H, Maris, JM, Kang, MH, Reynolds, CP, Kolb, EA, Gorlick, R, Keir, ST, Wu, J, Lyalin, D, Kurmasheva, RT, Houghton, PJ, Smith, MA, and Lock, RB. "Initial Testing (Stage 1) of the Notch Inhibitor PF-03084014, by the Pediatric Preclinical Testing Program (vol 61, pg 1493, 2014)." PEDIATRIC BLOOD & CANCER 61.9 (September 2014): 1716-1716.
Source
wos-lite
Published In
Pediatric Blood & Cancer
Volume
61
Issue
9
Publish Date
2014
Start Page
1716
End Page
1716
DOI
10.1002/pbc.25186

Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program.

MLN0128 is an investigational small molecule ATP-competitive inhibitor of the serine/threonine kinase mTOR. MLN0128 was tested against the in vitro panel at concentrations ranging from 0.1 nM to 1 μM and against the PPTP in vivo panels at a dose of 1 mg/kg administered orally daily × 28. In vitro the median relative IC(50) concentration was 19 nM. In vivo MLN0128 induced significant differences in EFS in 24/31 (77%) solid tumor models, but 0/7 ALL xenografts. The modest activity observed for MLN0128 against the PPTP preclinical models is similar to that previously reported for another TOR kinase inhibitor.

Authors
Kang, MH; Reynolds, CP; Maris, JM; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Wu, J; Lyalin, D; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Kang, MH, Reynolds, CP, Maris, JM, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Keir, ST, Wu, J, Lyalin, D, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program." Pediatric blood & cancer 61.8 (August 2014): 1486-1489.
PMID
24623675
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
61
Issue
8
Publish Date
2014
Start Page
1486
End Page
1489
DOI
10.1002/pbc.24989

Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program.

PF-03084014, a γ-secretase inhibitor, was tested against the PPTP in vitro cell line panel (1.0 nM to 10 μM) and against the in vivo xenograft panels (administered orally twice daily on Days 1-7 and 15-21). PF-03084014 demonstrated limited in vitro activity, with no cell line achieving ≥50% inhibition. PF-03084014 induced significant differences in EFS distribution in 14 of 35 (40%) solid tumor xenografts, and 1 of 9 ALL xenografts (which lacked a NOTCH1 mutation), but objective responses were not observed. PF-03084014 demonstrated limited single agent activity in vitro and in vivo against the pediatric preclinical models studied.

Authors
Carol, H; Maris, JM; Kang, MH; Reynolds, CP; Kolb, EA; Gorlick, R; Keir, ST; Wu, J; Kurmasheva, RT; Houghton, PJ; Smith, MA; Lock, RB; Lyalin, D
MLA Citation
Carol, H, Maris, JM, Kang, MH, Reynolds, CP, Kolb, EA, Gorlick, R, Keir, ST, Wu, J, Kurmasheva, RT, Houghton, PJ, Smith, MA, Lock, RB, and Lyalin, D. "Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program." Pediatric blood & cancer 61.8 (August 2014): 1493-1496.
PMID
24664981
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
61
Issue
8
Publish Date
2014
Start Page
1493
End Page
1496
DOI
10.1002/pbc.25026

Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.

Frequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.

Authors
Killela, PJ; Pirozzi, CJ; Healy, P; Reitman, ZJ; Lipp, E; Rasheed, BA; Yang, R; Diplas, BH; Wang, Z; Greer, PK; Zhu, H; Wang, CY; Carpenter, AB; Friedman, H; Friedman, AH; Keir, ST; He, J; He, Y; McLendon, RE; Herndon, JE; Yan, H; Bigner, DD
MLA Citation
Killela, PJ, Pirozzi, CJ, Healy, P, Reitman, ZJ, Lipp, E, Rasheed, BA, Yang, R, Diplas, BH, Wang, Z, Greer, PK, Zhu, H, Wang, CY, Carpenter, AB, Friedman, H, Friedman, AH, Keir, ST, He, J, He, Y, McLendon, RE, Herndon, JE, Yan, H, and Bigner, DD. "Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas." Oncotarget 5.6 (March 2014): 1515-1525.
PMID
24722048
Source
epmc
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1515
End Page
1525

Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program

Background: Quisinostat (JNJ-26481585) is a second-generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards Class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs. Procedures: Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.0nM to 10μM and was tested against the PPTP in vivo panels at a dose of 5mg/kg (solid tumors) or 2.5mg/kg (ALL models) administered intraperitoneally daily×21. Results: In vitro quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC50 value for the PPTP cell lines was 2.2nM (range <1-19nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease. Conclusions: Quisinostat demonstrated broad activity in vitro, and retarded growth in the majority of solid tumor xenografts studied. The most consistent in vivo activity signals observed were for the glioblastoma xenografts and T-cell ALL xenografts. © 2013 Wiley Periodicals, Inc.

Authors
Carol, H; Gorlick, R; Kolb, EA; Morton, CL; Manesh, DM; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Wozniak, A; Hickson, I; Lyalin, D; Kurmasheva, RT; Houghton, PJ; Smith, MA; Lock, R
MLA Citation
Carol, H, Gorlick, R, Kolb, EA, Morton, CL, Manesh, DM, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Wozniak, A, Hickson, I, Lyalin, D, Kurmasheva, RT, Houghton, PJ, Smith, MA, and Lock, R. "Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program." Pediatric Blood and Cancer 61.2 (February 1, 2014): 245-252.
Source
scopus
Published In
Pediatric Blood & Cancer
Volume
61
Issue
2
Publish Date
2014
Start Page
245
End Page
252
DOI
10.1002/pbc.24724

Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program.

BACKGROUND: Quisinostat (JNJ-26481585) is a second-generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards Class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs. PROCEDURES: Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 μM and was tested against the PPTP in vivo panels at a dose of 5 mg/kg (solid tumors) or 2.5 mg/kg (ALL models) administered intraperitoneally daily × 21. RESULTS: In vitro quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC50 value for the PPTP cell lines was 2.2 nM (range <1-19 nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease. CONCLUSIONS: Quisinostat demonstrated broad activity in vitro, and retarded growth in the majority of solid tumor xenografts studied. The most consistent in vivo activity signals observed were for the glioblastoma xenografts and T-cell ALL xenografts.

Authors
Carol, H; Gorlick, R; Kolb, EA; Morton, CL; Manesh, DM; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Wozniak, A; Hickson, I; Lyalin, D; Kurmasheva, RT; Houghton, PJ; Smith, MA; Lock, R
MLA Citation
Carol, H, Gorlick, R, Kolb, EA, Morton, CL, Manesh, DM, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Wozniak, A, Hickson, I, Lyalin, D, Kurmasheva, RT, Houghton, PJ, Smith, MA, and Lock, R. "Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 61.2 (February 2014): 245-252.
PMID
24038993
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
61
Issue
2
Publish Date
2014
Start Page
245
End Page
252
DOI
10.1002/pbc.24724

Initial testing (stage 1) of the Polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical Testing Program.

BACKGROUND: Volasertib (BI 6727) is a potent inhibitor of Polo-like kinase 1 (Plk1), that is overexpressed in several childhood cancers and cell lines. Because of its novel mechanism of action, volasertib was evaluated through the PPTP. PROCEDURES: Volasertib was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels administered IV at a dose of 30 mg/kg (solid tumors) or 15 mg/kg (ALL models) using a q7dx3 schedule. RESULTS: In vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1 nM, (range 6.0-135 nM). Volasertib induced significant differences in EFS in 19 of 32 (59%) of the evaluable solid tumor xenografts and in 2 of 4 (50%) of the evaluable ALL xenografts. Volasertib induced tumor growth inhibition meeting criteria for intermediate EFS T/C (>2) activity in 11 of 30 (37%) evaluable solid tumor xenografts, including neuroblastoma (4 of 6) and glioblastoma (2 of 3) panels, and 2 of 4 ALL models. Objective responses (CR's) were observed for 4 of 32 solid tumor (two neuroblastoma, one glioblastoma, and one rhabdomyosarcoma) and one of four ALL xenografts. CONCLUSIONS: Volasertib shows potent in vitro activity against the PPTP cell lines with no histotype selectivity. In vivo, volasertib induced regressions in several xenograft models. However, pharmacokinetic data suggest that mice tolerate higher systemic exposure to volasertib than humans, suggesting that the current results may over-estimate potential clinical efficacy against the childhood cancers studied.

Authors
Gorlick, R; Kolb, EA; Keir, ST; Maris, JM; Reynolds, CP; Kang, MH; Carol, H; Lock, R; Billups, CA; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Gorlick, R, Kolb, EA, Keir, ST, Maris, JM, Reynolds, CP, Kang, MH, Carol, H, Lock, R, Billups, CA, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of the Polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 61.1 (January 2014): 158-164.
PMID
23956067
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
61
Issue
1
Publish Date
2014
Start Page
158
End Page
164
DOI
10.1002/pbc.24616

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation.

KMT2D (lysine (K)-specific methyltransferase 2D), formerly named MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2, also known as ALR/MLL4), is a histone methyltransferase that plays an important role in regulating gene transcription. In particular, it targets histone H3 lysine 4 (H3K4), whose methylations serve as a gene activation mark. Recently, KMT2D has emerged as one of the most frequently mutated genes in a variety of cancers and in other human diseases, including lymphoma, medulloblastoma, gastric cancer, and Kabuki syndrome. Mutations in KMT2D identified thus far point to its loss-of-function in pathogenesis and suggest its role as a tumor suppressor in various tissues. To determine the effect of a KMT2D deficiency on neoplastic cells, we used homologous recombination- and nuclease-mediated gene editing approaches to generate a panel of isogenic colorectal and medulloblastoma cancer cell lines that differ with respect to their endogenous KMT2D status. We found that a KMT2D deficiency resulted in attenuated cancer cell proliferation and defective cell migration. Analysis of histone H3 modifications revealed that KMT2D was essential for maintaining the level of global H3K4 monomethylation and that its enzymatic SET domain was directly responsible for this function. Furthermore, we found that a majority of KMT2D binding sites are located in regions of potential enhancer elements. Together, these findings revealed the role of KMT2D in regulating enhancer elements in human cells and shed light on the tumorigenic role of its deficiency. Our study supports that KMT2D has distinct roles in neoplastic cells, as opposed to normal cells, and that inhibiting KMT2D may be a viable strategy for cancer therapeutics.

Authors
Guo, C; Chen, LH; Huang, Y; Chang, C-C; Wang, P; Pirozzi, CJ; Qin, X; Bao, X; Greer, PK; McLendon, RE; Yan, H; Keir, ST; Bigner, DD; He, Y
MLA Citation
Guo, C, Chen, LH, Huang, Y, Chang, C-C, Wang, P, Pirozzi, CJ, Qin, X, Bao, X, Greer, PK, McLendon, RE, Yan, H, Keir, ST, Bigner, DD, and He, Y. "KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation." Oncotarget 4.11 (November 2013): 2144-2153.
PMID
24240169
Source
pubmed
Published In
Oncotarget
Volume
4
Issue
11
Publish Date
2013
Start Page
2144
End Page
2153
DOI
10.18632/oncotarget.1555

Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program.

BACKGROUND: IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent). PROCEDURES: IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 µM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated. RESULTS: Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models. CONCLUSIONS: IMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined.

Authors
Wood, AC; Maris, JM; Gorlick, R; Kolb, EA; Keir, ST; Reynolds, CP; Kang, MH; Wu, J; Kurmasheva, RT; Whiteman, K; Houghton, PJ; Smith, MA
MLA Citation
Wood, AC, Maris, JM, Gorlick, R, Kolb, EA, Keir, ST, Reynolds, CP, Kang, MH, Wu, J, Kurmasheva, RT, Whiteman, K, Houghton, PJ, and Smith, MA. "Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program." Pediatr Blood Cancer 60.11 (November 2013): 1860-1867.
PMID
23798344
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
60
Issue
11
Publish Date
2013
Start Page
1860
End Page
1867
DOI
10.1002/pbc.24647

The integrated landscape of driver genomic alterations in glioblastoma.

Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.

Authors
Frattini, V; Trifonov, V; Chan, JM; Castano, A; Lia, M; Abate, F; Keir, ST; Ji, AX; Zoppoli, P; Niola, F; Danussi, C; Dolgalev, I; Porrati, P; Pellegatta, S; Heguy, A; Gupta, G; Pisapia, DJ; Canoll, P; Bruce, JN; McLendon, RE; Yan, H; Aldape, K; Finocchiaro, G; Mikkelsen, T; Privé, GG; Bigner, DD; Lasorella, A; Rabadan, R; Iavarone, A
MLA Citation
Frattini, V, Trifonov, V, Chan, JM, Castano, A, Lia, M, Abate, F, Keir, ST, Ji, AX, Zoppoli, P, Niola, F, Danussi, C, Dolgalev, I, Porrati, P, Pellegatta, S, Heguy, A, Gupta, G, Pisapia, DJ, Canoll, P, Bruce, JN, McLendon, RE, Yan, H, Aldape, K, Finocchiaro, G, Mikkelsen, T, Privé, GG, Bigner, DD, Lasorella, A, Rabadan, R, and Iavarone, A. "The integrated landscape of driver genomic alterations in glioblastoma." Nat Genet 45.10 (October 2013): 1141-1149.
PMID
23917401
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
10
Publish Date
2013
Start Page
1141
End Page
1149
DOI
10.1038/ng.2734

Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy.

PURPOSE: The EGF receptor gene (EGFR) is most frequently amplified and overexpressed, along with its deletion mutant, EGFRvIII, in glioblastoma. We tested the preclinical efficacy of the recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL, which is reactive with a 55-amino acid (AA) region present in the extracellular domain of both EGFRwt (583-637 AAs) and EGFRvIII (292-346 AAs) proteins. EXPERIMENTAL DESIGN: The binding affinity and specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII were measured by surface-plasmon resonance and flow cytometry. In vitro cytotoxicity of D2C7-(scdsFv)-PE38KDEL was measured by inhibition of protein synthesis in human EGFRwt-transfected NR6 (NR6W), human EGFRvIII-transfected NR6 (NR6M), EGFRwt-overexpressing A431-epidermoid-carcinoma, and glioblastoma xenograft cells (43, D08-0493MG, D2159MG, and D270MG). In vivo antitumor efficacy of D2C7-(scdsFv)-PE38KDEL was evaluated using 43, NR6M, and D270MG orthotopic tumor models. RESULTS: The KD of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII was 1.6×10(-9) mol/L and 1.3×10(-9) mol/L, respectively. Flow cytometry with NR6W and NR6M cells confirmed the specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII. The D2C7-(scdsFv)-PE38KDEL IC50 was 0.18 to 2.5 ng/mL on cells expressing EGFRwt (NR6W, A431, 43, and D08-0493MG). The D2C7-(scdsFv)-PE38KDEL IC50 was approximately 0.25 ng/mL on EGFRvIII-expressing cells (NR6M) and on EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells (D2159MG and D270MG). Significantly, in intracranial tumor models of 43, NR6M, and D270MG, treatment with D2C7-(scdsFv)-PE38KDEL by convection-enhanced delivery prolonged survival by 310% (P=0.006), 28% (P=0.002), and 166% (P=0.001), respectively. CONCLUSIONS: In preclinical studies, the D2C7-(scdsFv)-PE38KDEL immunotoxin exhibited significant potential for treating brain tumors expressing EGFRwt, EGFRvIII, or both.

Authors
Chandramohan, V; Bao, X; Keir, ST; Pegram, CN; Szafranski, SE; Piao, H; Wikstrand, CJ; McLendon, RE; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, V, Bao, X, Keir, ST, Pegram, CN, Szafranski, SE, Piao, H, Wikstrand, CJ, McLendon, RE, Kuan, C-T, Pastan, IH, and Bigner, DD. "Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy." Clin Cancer Res 19.17 (September 1, 2013): 4717-4727.
PMID
23857604
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
17
Publish Date
2013
Start Page
4717
End Page
4727
DOI
10.1158/1078-0432.CCR-12-3891

Affinity-matured recombinant immunotoxin targeting gangliosides 3'-isoLM1 and 3',6'-isoLD1 on malignant gliomas.

About 60 percent of glioblastomas highly express the gangliosides 3'-isoLM1 and 3',6'-isoLD1 on the cell surface, providing ideal targets for brain tumor immunotherapy. A novel recombinant immunotoxin, DmAb14m-(scFv)-PE38KDEL (DmAb14m-IT), specific for the gangliosides 3'-isoLM1 and 3',6'-isoLD1, was constructed with improved affinity and increased cytotoxicity for immunotherapeutic targeting of glioblastoma. We isolated an scFv parental clone from a previously established murine hybridoma, DmAb14, that is specific to both 3'-isoLM1 and 3',6'-isoLD1. We then performed in vitro affinity maturation by CDR hotspot random mutagenesis. The binding affinity and specificity of affinity-matured DmAb14m-IT were measured by surface-plasmon resonance, flow cytometry, and immunohistochemical analysis. In vitro cytotoxicity of DmAb14m-IT was measured by protein synthesis inhibition and cell death assays in human cell lines expressing gangliosides 3'-isoLM1 and 3',6'-isoLD1 (D54MG and D336MG) and xenograft-derived cells (D2224MG). As a result, the KD of DmAb14m-IT for gangliosides 3'-isoLM1 and 3',6'-isoLD1 was 2.6 × 10(-9)M. Also, DmAb14m-IT showed a significantly higher internalization rate in cells expressing 3'-isoLM1 and 3',6'-isoLD1. The DmAb14m-IT IC 50 was 80 ng/mL (1194 pM) on the D54MG cell line, 5 ng/ml (75 pM) on the D336MG cell line, and 0.5 ng/ml (7.5 pM) on the D2224MG xenograft-derived cells. There was no cytotoxicity on ganglioside-negative HEK293 cells. Immunohistochemical analysis confirmed the specific apparent affinity of DmAb14m-IT with 3'-isoLM1 and 3',6'-isoLD1. In conclusion, DmAb14m-IT showed specific binding affinity, a significantly high internalization rate, and selective cytotoxicity on glioma cell lines and xenograft-derived cells expressing 3'-isoLM1 and 3',6'-isoLD1, thereby displaying robust therapeutic potential for testing the antitumor efficacy of DmAb14m-IT at the preclinical level and eventually in the clinical setting.

Authors
Piao, H; Kuan, C-T; Chandramohan, V; Keir, ST; Pegram, CN; Bao, X; Månsson, J-E; Pastan, IH; Bigner, DD
MLA Citation
Piao, H, Kuan, C-T, Chandramohan, V, Keir, ST, Pegram, CN, Bao, X, Månsson, J-E, Pastan, IH, and Bigner, DD. "Affinity-matured recombinant immunotoxin targeting gangliosides 3'-isoLM1 and 3',6'-isoLD1 on malignant gliomas." MAbs 5.5 (September 2013): 748-762.
PMID
23924792
Source
pubmed
Published In
mAbs
Volume
5
Issue
5
Publish Date
2013
Start Page
748
End Page
762
DOI
10.4161/mabs.25860

Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program.

BACKGROUND: Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers. PROCEDURES: Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21. RESULTS: In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1-14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR. CONCLUSIONS: The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine.

Authors
Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Carol, H; Lock, R; Keir, ST; Maris, JM; Billups, CA; Desjardins, C; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Carol, H, Lock, R, Keir, ST, Maris, JM, Billups, CA, Desjardins, C, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program." Pediatr Blood Cancer 60.8 (August 2013): 1325-1332.
PMID
23553917
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
60
Issue
8
Publish Date
2013
Start Page
1325
End Page
1332
DOI
10.1002/pbc.24517

Initial testing (stage 1) of ganetespib, an Hsp90 inhibitor, by the Pediatric Preclinical Testing Program.

Ganetespib, an Hsp90 inhibitor, was tested against the PPTP in vitro cell line panel and selected xenografts in vivo, including JAK2- and BRAF-mutated models. Ganetespib demonstrated potent in vitro cytotoxic activity (median rIC50 8.8 nM, range 4.4-27.1 nM). In vivo, ganetespib induced significant differences in EFS distribution for 4 of 11 xenografts. Intermediate activity (EFS T/C > 2) was noted only for the MV4;11 xenograft, and there were no objective responses. Administered as single agents, Hsp90 inhibitors examined by the PPTP have shown limited evidence for a therapeutic window against both solid tumor and leukemia pediatric preclinical models.

Authors
Lock, RB; Carol, H; Maris, JM; Kang, MH; Reynolds, CP; Kolb, EA; Gorlick, R; Keir, ST; Billups, CA; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Lock, RB, Carol, H, Maris, JM, Kang, MH, Reynolds, CP, Kolb, EA, Gorlick, R, Keir, ST, Billups, CA, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of ganetespib, an Hsp90 inhibitor, by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 60.7 (July 2013): E42-E45.
PMID
23303741
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
60
Issue
7
Publish Date
2013
Start Page
E42
End Page
E45
DOI
10.1002/pbc.24451

Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors.

Our study demonstrates the glioma tumor antigen podoplanin to be present at very high levels (>90%) in both glioblastoma (D2159MG, D08-0308MG and D08-0493MG) and medulloblastoma (D283MED, D425MED and DAOY) xenografts and cell line. We constructed a novel recombinant single-chain antibody variable region fragment (scFv), NZ-1, specific for podoplanin from the NZ-1 hybridoma. NZ-1-scFv was then fused to Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide (NZ-1-PE38KDEL). The immunotoxin (IT) was further stabilized by a disulfide (ds) bond between the heavy-chain and light-chain variable regions as the construct NZ-1-(scdsFv)-PE38KDEL. NZ-1-(scdsFv)-PE38KDEL exhibited significant reactivity to glioblastoma and medulloblastoma cells. The affinity of NZ-1-(scdsFv), NZ-1-(scdsFv)-PE38KDEL and NZ-1 antibody for podoplanin peptide was 2.1 × 10(-8) M, 8.0 × 10(-8) M and 3.9 × 10(-10) M, respectively. In a protein stability assay, NZ-1-(scdsFv)-PE38KDEL retained 33-98% of its activity, whereas that of NZ-1-PE38KDEL declined to 13% of its initial levels after incubation at 37°C for 3 days. In vitro cytotoxicity of the NZ-1-(scdsFv)-PE38KDEL was measured in cells isolated from glioblastoma xenografts, D2159MG, D08-0308MG and D08-0493MG, and in the medulloblastoma D283MED, D425MED and DOAY xenografts and cell line. The NZ-1-(scdsFv)-PE38KDEL IT was highly cytotoxic, with an 50% inhibitory concentration in the range of 1.6-29 ng/ml. Significantly, NZ-1-(scdsFv)-PE38KDEL demonstrated tumor growth delay, averaging 24 days (p < 0.001) and 21 days (p < 0.001) in D2159MG and D283MED in vivo tumor models, respectively. Crucially, in the D425MED intracranial tumor model, NZ-1-(scdsFv)-PE38KDEL caused a 41% increase in survival (p ≤ 0.001). In preclinical studies, NZ-1-(scdsFv)-PE38KDEL exhibited significant potential as a targeting agent for malignant brain tumors.

Authors
Chandramohan, V; Bao, X; Kato Kaneko, M; Kato, Y; Keir, ST; Szafranski, SE; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, V, Bao, X, Kato Kaneko, M, Kato, Y, Keir, ST, Szafranski, SE, Kuan, C-T, Pastan, IH, and Bigner, DD. "Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors." Int J Cancer 132.10 (May 15, 2013): 2339-2348.
PMID
23115013
Source
pubmed
Published In
International Journal of Cancer
Volume
132
Issue
10
Publish Date
2013
Start Page
2339
End Page
2348
DOI
10.1002/ijc.27919

Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program.

BACKGROUND: The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models. PROCEDURES: Temozolomide was tested against the PPTP in vitro panel at concentrations ranging from 0.1 to 1,000 µM and was tested against the PPTP in vivo panels at doses from 22 to 100 mg/kg administered orally daily for 5 days, repeated at day 21. RESULTS: In vitro temozolomide showed cytotoxicity with a median relative IC50 (rIC50 ) value of 380 µM against the PPTP cell lines (range 1 to > 1,000 µM). The three lines with rIC50 values lesser than 10 µM had low MGMT expression compared to the remaining cell lines. In vivo temozolomide demonstrated significant toxicity at 100 mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR [MCR], 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66 mg/kg temozolomide and with tumor regressions at 22 and 44 mg/kg restricted to models with low MGMT expression. CONCLUSIONS: Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression.

Authors
Keir, ST; Maris, JM; Reynolds, CP; Kang, MH; Kolb, EA; Gorlick, R; Lock, R; Carol, H; Morton, CL; Wu, J; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Keir, ST, Maris, JM, Reynolds, CP, Kang, MH, Kolb, EA, Gorlick, R, Lock, R, Carol, H, Morton, CL, Wu, J, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program." Pediatr Blood Cancer 60.5 (May 2013): 783-790.
PMID
23335050
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
60
Issue
5
Publish Date
2013
Start Page
783
End Page
790
DOI
10.1002/pbc.24368

Initial testing (stage 1) of the phosphatidylinositol 3' kinase inhibitor, SAR245408 (XL147) by the pediatric preclinical testing program.

BACKGROUND: Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. However, less is known regarding the relevance of this pathway in pediatric cancers. Here we have evaluated SAR245408, a novel small molecule PI3K inhibitor, against childhood cancer cell lines and xenografts. PROCEDURES: SAR245408 was tested against the PPTP in vitro cell line panel at concentrations from 10 to 100 µM and against the PPTP in vivo xenograft panels at a dose of 100 mg/kg administered orally daily × 14. RESULTS: In vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 µM (range 2.7-24.5 µM). SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for two of seven (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts. CONCLUSIONS: Under the conditions evaluated in this study, SAR245408 achieved modest single-agent activity against most PPTP preclinical models. Further exploration of SAR245408 in combination with standard agents or with other signaling inhibitors could be considered.

Authors
Reynolds, CP; Kang, MH; Carol, H; Lock, R; Gorlick, R; Kolb, EA; Kurmasheva, RT; Keir, ST; Maris, JM; Billups, CA; Houghton, PJ; Smith, MA
MLA Citation
Reynolds, CP, Kang, MH, Carol, H, Lock, R, Gorlick, R, Kolb, EA, Kurmasheva, RT, Keir, ST, Maris, JM, Billups, CA, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of the phosphatidylinositol 3' kinase inhibitor, SAR245408 (XL147) by the pediatric preclinical testing program." Pediatr Blood Cancer 60.5 (May 2013): 791-798.
PMID
23002019
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
60
Issue
5
Publish Date
2013
Start Page
791
End Page
798
DOI
10.1002/pbc.24301

Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program.

BACKGROUND: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. PROCEDURES: RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hours exposure (1 nM to 10 µM). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100 mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html). RESULTS: RG7112 demonstrated cytotoxic activity with a lower median IC(50) for p53 WT versus p53 mutant cell lines (approximately 0.4 µM vs. >10 µM, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C > 2) in 10 of 26 (38%) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was one partial response, five complete responses and one maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels. CONCLUSIONS: RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation.

Authors
Carol, H; Reynolds, CP; Kang, MH; Keir, ST; Maris, JM; Gorlick, R; Kolb, EA; Billups, CA; Geier, B; Kurmasheva, RT; Houghton, PJ; Smith, MA; Lock, RB
MLA Citation
Carol, H, Reynolds, CP, Kang, MH, Keir, ST, Maris, JM, Gorlick, R, Kolb, EA, Billups, CA, Geier, B, Kurmasheva, RT, Houghton, PJ, Smith, MA, and Lock, RB. "Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 60.4 (April 2013): 633-641.
PMID
22753001
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
60
Issue
4
Publish Date
2013
Start Page
633
End Page
641
DOI
10.1002/pbc.24235

Exomic Sequencing of Four Rare Central Nervous System Tumor Types

Authors
Bettegowda, C; Agrawal, N; Jiao, Y; Wang, Y; Wood, LD; Rodriguez, FJ; Hruban, RH; Gallia, GL; Binder, ZA; Riggins, CJ; Salmasi, V; Riggins, GJ; Reitman, ZJ; Rasheed, A; Keir, S; Shinjo, S; Marie, S; McLendon, R; Jallo, G; Vogelstein, B; Bigner, D; Yan, H; Kinzler, KW; Papadopoulos, N
MLA Citation
Bettegowda, C, Agrawal, N, Jiao, Y, Wang, Y, Wood, LD, Rodriguez, FJ, Hruban, RH, Gallia, GL, Binder, ZA, Riggins, CJ, Salmasi, V, Riggins, GJ, Reitman, ZJ, Rasheed, A, Keir, S, Shinjo, S, Marie, S, McLendon, R, Jallo, G, Vogelstein, B, Bigner, D, Yan, H, Kinzler, KW, and Papadopoulos, N. "Exomic Sequencing of Four Rare Central Nervous System Tumor Types." ONCOTARGET 4.4 (April 2013): 572-583.
PMID
23592488
Source
wos-lite
Published In
Oncotarget
Volume
4
Issue
4
Publish Date
2013
Start Page
572
End Page
583

Reversing the Warburg effect as a treatment for glioblastoma.

Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase. Through activation of AMP-activated protein kinase, MB inactivates downstream acetyl-CoA carboxylase and decreases cyclin expression. Structure-activity relationship analysis demonstrated that toluidine blue O, an MB derivative with similar bioenergetic actions, exerts similar action in GBM cell proliferation. In contrast, two other MB derivatives, 2-chlorophenothiazine and promethazine, exert no effect on cellular bioenergetics and do not inhibit GBM cell proliferation. MB inhibits cell proliferation in both temozolomide-sensitive and -insensitive GBM cell lines. In a human GBM xenograft model, a single daily dosage of MB does not activate AMP-activated protein kinase signaling, and no tumor regression was observed. In summary, the current study provides the first in vitro proof of concept that reversal of Warburg effect might be a novel therapy for GBM.

Authors
Poteet, E; Choudhury, GR; Winters, A; Li, W; Ryou, M-G; Liu, R; Tang, L; Ghorpade, A; Wen, Y; Yuan, F; Keir, ST; Yan, H; Bigner, DD; Simpkins, JW; Yang, S-H
MLA Citation
Poteet, E, Choudhury, GR, Winters, A, Li, W, Ryou, M-G, Liu, R, Tang, L, Ghorpade, A, Wen, Y, Yuan, F, Keir, ST, Yan, H, Bigner, DD, Simpkins, JW, and Yang, S-H. "Reversing the Warburg effect as a treatment for glioblastoma." J Biol Chem 288.13 (March 29, 2013): 9153-9164.
PMID
23408428
Source
pubmed
Published In
The Journal of biological chemistry
Volume
288
Issue
13
Publish Date
2013
Start Page
9153
End Page
9164
DOI
10.1074/jbc.M112.440354

Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model.

Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy.

Authors
Keir, ST; Friedman, HS; Reardon, DA; Bigner, DD; Gray, LA
MLA Citation
Keir, ST, Friedman, HS, Reardon, DA, Bigner, DD, and Gray, LA. "Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model." J Neurooncol 111.2 (January 2013): 97-102.
PMID
23086436
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
111
Issue
2
Publish Date
2013
Start Page
97
End Page
102
DOI
10.1007/s11060-012-0995-0

The integrated landscape of driver genomic alterations in glioblastoma

Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention. © 2013 Nature America, Inc. All rights reserved.

Authors
Frattini, V; Trifonov, V; Chan, JM; Castano, A; Lia, M; Abate, F; Keir, ST; Ji, AX; Zoppoli, P; Niola, F; al, E
MLA Citation
Frattini, V, Trifonov, V, Chan, JM, Castano, A, Lia, M, Abate, F, Keir, ST, Ji, AX, Zoppoli, P, Niola, F, and al, E. "The integrated landscape of driver genomic alterations in glioblastoma." Nature Genetics 45.10 (2013): 1141-1149.
Source
scival
Published In
Nature Genetics
Volume
45
Issue
10
Publish Date
2013
Start Page
1141
End Page
1149
DOI
10.1038/ng.2734

Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors

Our study demonstrates the glioma tumor antigen podoplanin to be present at very high levels (>90%) in both glioblastoma (D2159MG, D08-0308MG and D08-0493MG) and medulloblastoma (D283MED, D425MED and DAOY) xenografts and cell line. We constructed a novel recombinant single-chain antibody variable region fragment (scFv), NZ-1, specific for podoplanin from the NZ-1 hybridoma. NZ-1-scFv was then fused to Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide (NZ-1-PE38KDEL). The immunotoxin (IT) was further stabilized by a disulfide (ds) bond between the heavy-chain and light-chain variable regions as the construct NZ-1-(scdsFv)-PE38KDEL. NZ-1-(scdsFv)-PE38KDEL exhibited significant reactivity to glioblastoma and medulloblastoma cells. The affinity of NZ-1-(scdsFv), NZ-1-(scdsFv)-PE38KDEL and NZ-1 antibody for podoplanin peptide was 2.1 × 10-8 M, 8.0 × 10-8 M and 3.9 × 10-10 M, respectively. In a protein stability assay, NZ-1-(scdsFv)-PE38KDEL retained 33-98% of its activity, whereas that of NZ-1-PE38KDEL declined to 13% of its initial levels after incubation at 37°C for 3 days. In vitro cytotoxicity of the NZ-1-(scdsFv)-PE38KDEL was measured in cells isolated from glioblastoma xenografts, D2159MG, D08-0308MG and D08-0493MG, and in the medulloblastoma D283MED, D425MED and DOAY xenografts and cell line. The NZ-1-(scdsFv)-PE38KDEL IT was highly cytotoxic, with an 50% inhibitory concentration in the range of 1.6-29 ng/ml. Significantly, NZ-1-(scdsFv)-PE38KDEL demonstrated tumor growth delay, averaging 24 days (p < 0.001) and 21 days (p < 0.001) in D2159MG and D283MED in vivo tumor models, respectively. Crucially, in the D425MED intracranial tumor model, NZ-1-(scdsFv)-PE38KDEL caused a 41% increase in survival (p ≤ 0.001). In preclinical studies, NZ-1-(scdsFv)-PE38KDEL exhibited significant potential as a targeting agent for malignant brain tumors. What's new? Podoplanin is a glycoprotein that is overexpressed in several types of malignant tumor, including glioblastoma, medulloblastoma, mesothelioma, and germ-cell tumors. In this study, the authors constructed a novel immunotoxin to target podoplanin, by fusing a monoclonal antibody fragment to exotoxin A from Pseudomonas. In preclinical studies, this immunotoxin, called NZ-1-(scdsFv)-PE38KDEL, increased survival by 41%. Its specificity and high binding affinity allow for specific targeting of tumor cells while avoiding adjacent normal tissue, thereby having the potential to improve survival of patients with brain tumors. Copyright © 2012 UICC.

Authors
Chandramohan, V; Bao, X; Kaneko, MK; Kato, Y; Keir, ST; Szafranski, SE; Kuan, CT; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, V, Bao, X, Kaneko, MK, Kato, Y, Keir, ST, Szafranski, SE, Kuan, CT, Pastan, IH, and Bigner, DD. "Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors." International Journal of Cancer 132.10 (2013): 2339-2348.
Source
scival
Published In
International Journal of Cancer
Volume
132
Issue
10
Publish Date
2013
Start Page
2339
End Page
2348
DOI
10.1002/ijc.27919

Mibefradil, a novel therapy for glioblastoma multiforme: Cell cycle synchronization and interlaced therapy in a murine model

Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy. © 2012 Springer Science+Business Media New York.

Authors
Keir, ST; Friedman, HS; Reardon, DA; Bigner, DD; Gray, LA
MLA Citation
Keir, ST, Friedman, HS, Reardon, DA, Bigner, DD, and Gray, LA. "Mibefradil, a novel therapy for glioblastoma multiforme: Cell cycle synchronization and interlaced therapy in a murine model." Journal of Neuro-Oncology 111.2 (2013): 97-102.
Source
scival
Published In
Journal of Neuro-Oncology
Volume
111
Issue
2
Publish Date
2013
Start Page
97
End Page
102
DOI
10.1007/s11060-012-0995-0

Initial testing (stage 1) of the cyclin dependent kinase inhibitor SCH 727965 (dinaciclib) by the pediatric preclinical testing program.

BACKGROUND: SCH 727965 is a novel drug in clinical development that potently and selectively inhibits CDK1, CDK2, CDK5, and CDK9. The activity of SCH 727965 was evaluated against the PPTP's in vitro and in vivo panels. PROCEDURES: SCH 727965 was tested against the PPTP in vitro panel using 96 hours exposure at concentrations ranging from 0.1 nM to 1.0 µM. It was tested against the PPTP in vivo panels at a dose of 40 mg/kg administered intraperitoneally twice weekly for 2 weeks and repeated at Day 21 with a total observation period of 6 weeks. RESULTS: The median IC(50) value for the cell lines was 7.5 nM, with less than fourfold range between the minimum (3.4 nM) and maximum (11.2 nM) IC(50) values. SCH 727965 demonstrated an activity pattern consistent with cytotoxicity for most of the cell lines. Forty-three xenograft models were studied and SCH 727965 induced significant delays in event free survival distribution compared to control in 23 of 36 (64%) evaluable solid tumor xenografts and in 3 of 7 ALL xenografts. SCH 727965 did not induce objective responses in the solid tumor panels and the best response observed was stable disease for one osteosarcoma xenograft. In the leukemia panel, there were two objective responses with a complete response observed in a single xenograft. CONCLUSIONS: SCH 727965 shows an interesting pattern of activity suggesting its potential applicability against selected childhood cancers, particularly leukemias.

Authors
Gorlick, R; Kolb, EA; Houghton, PJ; Morton, CL; Neale, G; Keir, ST; Carol, H; Lock, R; Phelps, D; Kang, MH; Reynolds, CP; Maris, JM; Billups, C; Smith, MA
MLA Citation
Gorlick, R, Kolb, EA, Houghton, PJ, Morton, CL, Neale, G, Keir, ST, Carol, H, Lock, R, Phelps, D, Kang, MH, Reynolds, CP, Maris, JM, Billups, C, and Smith, MA. "Initial testing (stage 1) of the cyclin dependent kinase inhibitor SCH 727965 (dinaciclib) by the pediatric preclinical testing program." Pediatr Blood Cancer 59.7 (December 15, 2012): 1266-1274.
PMID
22315240
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
59
Issue
7
Publish Date
2012
Start Page
1266
End Page
1274
DOI
10.1002/pbc.24073

Pilot study of the impact of massage therapy on sources and levels of distress in brain tumour patients.

BACKGROUND: Patients with brain tumours report elevated levels of distress across the disease course. Massage therapy is a commonly used complementary therapy and is employed in cancer care to reduce psychological stress and to improve quality of life (QoL). The purpose of this pilot study was to obtain a preliminary assessment of the effect of massage therapy on patient-reported psychological outcomes and QoL. MATERIALS AND METHODS: This study was a prospective, single-arm intervention. Participants were newly diagnosed primary brain tumour patients who reported experiencing distress and who received a total of eight massages over a period of 4 weeks. Participants completed the National Comprehensive Cancer Network's Distress Thermometer (DT) six times over a 5-week period. RESULTS: As a group, levels of distress dropped significantly between baseline and week 3 (mean 4.19, SD 1.481, p≤0.025), with a further significant reduction in distress between week 3 and week 4 (p≤0.001). At the end of week 4, the DT scores of all participants were below the threshold for being considered distressed. By the end of the intervention, participants reported significant improvements in one test domain focused on emotional well-being. CONCLUSIONS: This study further documents that brain tumour patients report high levels of distress across the disease course. However, participants in this study reported improvements in distress level and total number of sources of distress while receiving massage therapy.

Authors
Keir, ST; Saling, JR
MLA Citation
Keir, ST, and Saling, JR. "Pilot study of the impact of massage therapy on sources and levels of distress in brain tumour patients." BMJ supportive & palliative care 2.4 (December 2012): 363-366.
PMID
24654222
Source
epmc
Published In
BMJ Supportive and Palliative Care
Volume
2
Issue
4
Publish Date
2012
Start Page
363
End Page
366
DOI
10.1136/bmjspcare-2012-000224

Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233.

Glioblastoma multiforme (GBM) is the most common and devastating form of primary central nervous system malignancy. The prognosis for patients diagnosed with GBM is poor, having a median survival rate of 12-15 months. Despite modern advances in the development of antineoplastic agents, the efficacy of newer anti-cancer agents in the treatment of GBM is yet to be determined. Thus, there remains a significant unmet need for new therapeutic strategies against GBM. A promising chemotherapeutic intervention has emerged from studies of cannabinoid receptor agonists wherein tetrahydrocannabinol has been the most extensively studied. The novel cannabinoid ligand KM-233 was developed as a lead platform for future optimization of biopharmaceutical properties of classical based cannabinoid ligands. Treatment of U87MG human GBM cells with KM-233 caused a time dependent change in the phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3, and p70S6K. Almost complete mitochondrial depolarization was observed 6 h post-treatment followed by a rapid increase in cleaved caspase 3 and significant cytoskeletal contractions. Treatment with KM-233 also resulted in a redistribution of the Golgi-endoplasmic reticulum structures. Dose escalation studies in the orthotopic model using U87MG cells revealed an 80 % reduction in tumor size after 12 mg/kg daily dosing for 20 days. The evaluation of KM-233 against primary tumor tissue in the side flank model revealed a significant decrease in the rate of tumor growth. These findings indicate that structural refinement of KM-233 to improve its biopharmaceutical properties may lead to a novel and efficacious treatment for GBM.

Authors
Gurley, SN; Abidi, AH; Allison, P; Guan, P; Duntsch, C; Robertson, JH; Kosanke, SD; Keir, ST; Bigner, DD; Elberger, AJ; Moore, BM
MLA Citation
Gurley, SN, Abidi, AH, Allison, P, Guan, P, Duntsch, C, Robertson, JH, Kosanke, SD, Keir, ST, Bigner, DD, Elberger, AJ, and Moore, BM. "Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233." J Neurooncol 110.2 (November 2012): 163-177.
PMID
22875710
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
110
Issue
2
Publish Date
2012
Start Page
163
End Page
177
DOI
10.1007/s11060-012-0958-5

Initial testing (stage 1) of SGI-1776, a PIM1 kinase inhibitor, by the pediatric preclinical testing program.

The PIM kinase inhibitor, SGI-1776, was tested against the PPTP in vitro (1.0 nM-10 µM) and in vivo panels (148 mg/kg daily × 5 days for 3 weeks). SGI-1776 exhibited cytotoxic activity in vitro with a median relative IC(50) of 3.1 µM. SGI-1776 induced significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. SGI-1776 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induced complete responses of subcutaneous MV4;11 (B myeloid leukemia).

Authors
Batra, V; Maris, JM; Kang, MH; Reynolds, CP; Houghton, PJ; Alexander, D; Kolb, EA; Gorlick, R; Keir, ST; Carol, H; Lock, R; Billups, CA; Smith, MA
MLA Citation
Batra, V, Maris, JM, Kang, MH, Reynolds, CP, Houghton, PJ, Alexander, D, Kolb, EA, Gorlick, R, Keir, ST, Carol, H, Lock, R, Billups, CA, and Smith, MA. "Initial testing (stage 1) of SGI-1776, a PIM1 kinase inhibitor, by the pediatric preclinical testing program." Pediatr Blood Cancer 59.4 (October 2012): 749-752.
PMID
22052829
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
59
Issue
4
Publish Date
2012
Start Page
749
End Page
752
DOI
10.1002/pbc.23364

Initial testing of the multitargeted kinase inhibitor pazopanib by the Pediatric Preclinical Testing Program.

Pazopanib is an oral angiogenesis inhibitor targeting vascular growth factor receptor-1, -2, and -3, platelet derived growth factor receptor-α, platelet derived growth factor receptor-β, and KIT that has demonstrated activity against a variety of adult cancer xenografts. Pazopanib was tested against a panel of pediatric rhabdomyosarcoma and Ewing sarcoma xenografts at a dose of 108 mg/kg/day or 100 mg/kg twice daily, administered orally for 28 days. While no objective responses were observed, pazopanib induced statistically significant differences in event-free survival compared to controls in approximately one-half of the sarcoma xenograft models tested. Though well tolerated, pazopanib showed limited activity against the sarcoma models evaluated, with the best tumor responses being growth delay.

Authors
Keir, ST; Morton, CL; Wu, J; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Keir, ST, Morton, CL, Wu, J, Kurmasheva, RT, Houghton, PJ, and Smith, MA. "Initial testing of the multitargeted kinase inhibitor pazopanib by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 59.3 (September 2012): 586-588.
PMID
22190407
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
59
Issue
3
Publish Date
2012
Start Page
586
End Page
588
DOI
10.1002/pbc.24016

Testing of the Akt/PKB inhibitor MK-2206 by the Pediatric Preclinical Testing Program.

BACKGROUND: MK-2206 is a small molecule allosteric inhibitor of Akt/PKB that is undergoing clinical trials for treatment of cancer. PROCEDURES: MK-2206 was tested against the PPTP in vitro panel using a 96-hour exposure (1.0 nM-10 µM), and in vivo using thrice weekly dosing for a planned 4 weeks at its maximum tolerated dose (MTD) of 180 mg/kg. RESULTS: In vitro, the median relative IC(50) value for MK-2206 was 2.2 µM. Four cell lines with IC(50) values < 200 nM included two ALL cell lines (COG-LL-317 and RS4;11), an AML cell line with an activating KIT mutation (Kasumi-1), and a Ewing sarcoma cell line (CHLA-10). In vivo, MK-2206 induced significant differences in EFS distribution compared to control in 12 of 29 (41%) of the evaluable solid tumor xenografts and in 2 of 8 (25%) of the evaluable ALL xenografts. Significant differences in EFS distribution were most frequently noted in the osteosarcoma panel (6 of 6). A single solid tumor xenograft (OS-31) had a greater than twofold increase in time to event compared to control animals, with all other solid tumor xenografts showing lesser degrees of tumor growth inhibition. Objective responses were not observed for either the solid tumor or ALL xenografts. CONCLUSIONS: MK-2206 showed its most consistent activity in vitro against ALL cell lines and in vivo against osteosarcoma xenografts. However, no objective responses were observed in solid tumor or ALL xenografts. Further preclinical work evaluating MK-2206 in pediatric models in the combination therapy setting may contribute to its pediatric development.

Authors
Gorlick, R; Maris, JM; Houghton, PJ; Lock, R; Carol, H; Kurmasheva, RT; Kolb, EA; Keir, ST; Reynolds, CP; Kang, MH; Billups, CA; Smith, MA
MLA Citation
Gorlick, R, Maris, JM, Houghton, PJ, Lock, R, Carol, H, Kurmasheva, RT, Kolb, EA, Keir, ST, Reynolds, CP, Kang, MH, Billups, CA, and Smith, MA. "Testing of the Akt/PKB inhibitor MK-2206 by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 59.3 (September 2012): 518-524.
PMID
22102563
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
59
Issue
3
Publish Date
2012
Start Page
518
End Page
524
DOI
10.1002/pbc.23412

Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program.

JNJ-26854165 was originally developed as an activator of p53 capable of inducing apoptosis in cancer cell lines. In vitro, JNJ-26854165 demonstrated cytotoxic activity. The ALL cell line panel had a significantly lower median IC(50) (0.85 µM) than the remaining cell lines. In vivo JNJ-26854165 induced significant differences in EFS distribution compared to control in 18 of 37 solid tumors and in 5 of 7 of the evaluable ALL xenografts. Objective responses were observed in 4 of 37 solid tumor xenografts, and 2 of 7 ALL xenografts achieved PR or CR. Responses were noted in xenografts with both mutant and wild-type p53.

Authors
Smith, MA; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Maris, JM; Keir, ST; Morton, CL; Reynolds, CP; Kang, MH; Arts, J; Bashir, T; Janicot, M; Kurmasheva, RT; Houghton, PJ
MLA Citation
Smith, MA, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Maris, JM, Keir, ST, Morton, CL, Reynolds, CP, Kang, MH, Arts, J, Bashir, T, Janicot, M, Kurmasheva, RT, and Houghton, PJ. "Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program." Pediatr Blood Cancer 59.2 (August 2012): 329-332.
PMID
21922647
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
59
Issue
2
Publish Date
2012
Start Page
329
End Page
332
DOI
10.1002/pbc.23319

Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program.

BACKGROUND: MLN4924 is an investigational first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE). NAE is an essential component of the NEDD8 conjugation pathway, controlling the activity of a subset of ubiquitin-proteasome system (UPS) E3 ligases, multiprotein complexes that transfer ubiquitin molecules to substrate proteins. PROCEDURES: MLN4924 was tested against the PPTP in vitro panel using 96-hour exposure time at concentrations ranging from 1.0 nM to 10 µM. It was tested in vivo at a dose of 100 mg/kg [66 mg/kg for the acute lymphoblastic leukemia (ALL) xenografts] administered orally twice daily × 5 days. Treatment duration was 3 weeks. RESULTS: The median relative IC(50) for MLN4924 against the PPTP cell lines was 143 nM, (range: 15-678 nM) with that for the Ewing panel being significantly lower (31 nM). MLN4924 induced significant differences in EFS distribution compared to control in 20 of 34 (59%) evaluable solid tumor xenografts. MLN4924 induced intermediate activity (EFS T/C values >2) in 9 of the 33 evaluable xenografts (27%), including 4 of 4 glioblastoma xenografts, 2 of 3 Wilm's tumor xenografts, 2 of 5 rhabdomyosarcoma xenografts, and 1 of 4 neuroblastoma xenografts. For the ALL panel, 5 of 8 evaluable xenografts showed intermediate activity for the EFS T/C measure. MLN4924 did not induce objective responses in the PPTP solid tumor or ALL panels. CONCLUSIONS: MLN4924 showed potent activity in vitro and in vivo showed tumor growth inhibitory activity against a subset of the PPTP solid tumor and ALL xenografts.

Authors
Smith, MA; Maris, JM; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Reynolds, CP; Kang, MH; Morton, CL; Wu, J; Smith, PG; Yu, J; Houghton, PJ
MLA Citation
Smith, MA, Maris, JM, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Keir, ST, Reynolds, CP, Kang, MH, Morton, CL, Wu, J, Smith, PG, Yu, J, and Houghton, PJ. "Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program." Pediatr Blood Cancer 59.2 (August 2012): 246-253.
PMID
22012946
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
59
Issue
2
Publish Date
2012
Start Page
246
End Page
253
DOI
10.1002/pbc.23357

Initial testing (Stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program.

AT13387, a non-geldanamycin inhibitor of heat-shock protein 90 (HSP90), was tested against the PPTP in vitro panel (1.0 nM to 10 µM) and against the PPTP in vivo panels (40 or 60 mg/kg) administered orally twice weekly. In vitro AT13387 showed a median EC(50) value of 41 nM and exhibited activity consistent with a cytotoxic effect. In vivo AT13387 induced significant differences in EFS distribution compared to controls in 17% evaluable solid tumor xenografts, but in none of the ALL xenografts. No objective tumor responses were observed. In vivo AT13387 demonstrated only modest single agent activity.

Authors
Kang, MH; Reynolds, CP; Houghton, PJ; Alexander, D; Morton, CL; Kolb, EA; Gorlick, R; Keir, ST; Carol, H; Lock, R; Maris, JM; Wozniak, A; Smith, MA
MLA Citation
Kang, MH, Reynolds, CP, Houghton, PJ, Alexander, D, Morton, CL, Kolb, EA, Gorlick, R, Keir, ST, Carol, H, Lock, R, Maris, JM, Wozniak, A, and Smith, MA. "Initial testing (Stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program." Pediatr Blood Cancer 59.1 (July 15, 2012): 185-188.
PMID
21538821
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
59
Issue
1
Publish Date
2012
Start Page
185
End Page
188
DOI
10.1002/pbc.23154

Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program.

BACKGROUND: The centromere kinesin motor protein CENP-E plays a crucial role in mitosis, and is an appealing molecular target in cancer. GSK923295A is an allosteric inhibitor of CENP-E that is undergoing clinical evaluation. PROCEDURES: GSK923295A was evaluated against the 23 cell lines in the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposures to concentrations ranging from 1.0 nM to 10.0 µM. GSK923295A was also tested in vivo against the PPTP acute lymphoblastic leukemia (ALL) and solid tumor xenograft panels using a days 1-3 and 8-10 schedule that was repeated at day 21. The agent was administered via the intraperitoneal (i.p.) route at a daily dose of 125 mg/kg. RESULTS: The median IC(50) for all PPTP cell lines was 27 nM, with the median IC(50) for the ALL panel being the lowest (18 nM) and for the neuroblastoma panel the highest (39 nM). Excessive toxicity was observed for each of the 8 xenografts of the ALL panel in NOD/SCID mice. Thirty-five solid tumor xenograft models were considered evaluable. GSK923295A induced significant differences in event-free survival distribution compared to controls in 32 of 35 evaluable solid tumor xenografts tested. Objective responses were noted in 13 of 35 solid tumor xenografts, including 9 with maintained complete responses, and 3 with complete response (CR). CONCLUSIONS: GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts. These results suggest that CENP-E may be a valuable therapeutic target in pediatric cancer.

Authors
Lock, RB; Carol, H; Morton, CL; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Wozniak, AW; Gorlick, R; Kolb, EA; Houghton, PJ; Smith, MA
MLA Citation
Lock, RB, Carol, H, Morton, CL, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Wozniak, AW, Gorlick, R, Kolb, EA, Houghton, PJ, and Smith, MA. "Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program." Pediatr Blood Cancer 58.6 (June 2012): 916-923.
PMID
21584937
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
58
Issue
6
Publish Date
2012
Start Page
916
End Page
923
DOI
10.1002/pbc.23176

Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling.

RO4929097 is a potent and selective inhibitor of γ-secretase and as a result is able to inhibit Notch pathway signaling. The activity of RO4929097 was evaluated against the in vivo panels of the Pediatric Preclinical Testing Program (PPTP). RO4929097 induced significant differences in event-free survival (EFS) distribution compared to control in 6 of 26 (23%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The most consistent tumor growth delay effects were noted in the osteosarcoma panel. RO4929097 at the dose and schedule evaluated demonstrated little antitumor activity against childhood cancer xenografts.

Authors
Kolb, EA; Gorlick, R; Keir, ST; Maris, JM; Lock, R; Carol, H; Kurmasheva, RT; Reynolds, CP; Kang, MH; Wu, J; Houghton, PJ; Smith, MA
MLA Citation
Kolb, EA, Gorlick, R, Keir, ST, Maris, JM, Lock, R, Carol, H, Kurmasheva, RT, Reynolds, CP, Kang, MH, Wu, J, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling." Pediatr Blood Cancer 58.5 (May 2012): 815-818.
PMID
22052798
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
58
Issue
5
Publish Date
2012
Start Page
815
End Page
818
DOI
10.1002/pbc.23290

Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program.

BACKGROUND: IMC-A12, a fully human antibody that blocks ligand binding to the Type 1 insulin-like growth factor receptor, and rapamycin, a selective inhibitor of mTORC1 signaling, have both demonstrated significant antitumor activity against PPTP solid tumor models. Here we have evaluated antitumor activity of each agent individually and in combination against nine tumor models. PROCEDURES: IMC-A12 was administered twice weekly and rapamycin was administered daily for 5 days per week for a planned 4 weeks. The impact of combining IMC-A12 with rapamycin was evaluated using two measures: (1) the "therapeutic enhancement" measure, and (2) a linear regression model for time-to-event to formally evaluate for sub- and supra-additivity for the combination compared to the agents used alone. RESULTS: Two osteosarcomas, and one Ewing sarcoma of the nine xenografts tested showed therapeutic enhancement. The combination effect was most dramatic for EW-5 for which PD2 responses of short duration were observed for both single agents and a prolonged PR response was observed for the combination. Both OS-2 and OS-9 showed significantly longer times to progression with the combination compared to either of the single agents, although objective response criteria were not met. CONCLUSIONS: The combination of IMC-A12 with rapamycin was well tolerated, and induced tumor responses that were superior to either single agent alone in several models. These studies confirm reports using other antibodies that inhibit IGF-1 receptor-mediated signaling that indicate enhanced therapeutic effect for this combination, and extend the range of histotypes to encompass additional tumors expressing IGF-1R where this approach may be effective.

Authors
Kolb, EA; Gorlick, R; Maris, JM; Keir, ST; Morton, CL; Wu, J; Wozniak, AW; Smith, MA; Houghton, PJ
MLA Citation
Kolb, EA, Gorlick, R, Maris, JM, Keir, ST, Morton, CL, Wu, J, Wozniak, AW, Smith, MA, and Houghton, PJ. "Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program." Pediatr Blood Cancer 58.5 (May 2012): 729-735.
PMID
21630428
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
58
Issue
5
Publish Date
2012
Start Page
729
End Page
735
DOI
10.1002/pbc.23157

Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program.

LCL161, a SMAC mimetic, was tested against the PPTP in vitro panel (1.0 nM to 10.0 µM) and the PPTP in vivo panels (30 or 75 mg/kg [solid tumors] or 100 mg/kg [ALL]) administered orally twice in a week. LCL161 showed a median relative IC(50) value of >10 µM, being more potent against several leukemia and lymphoma lines. In vivo LCL161 induced significant differences in EFS distribution in approximately one-third of solid tumor xenografts (osteosarcoma and glioblastoma), but not in ALL xenografts. No objective tumor responses were observed. In vivo LCL161 demonstrated limited single agent activity against the pediatric preclinical models studied.

Authors
Houghton, PJ; Kang, MH; Reynolds, CP; Morton, CL; Kolb, EA; Gorlick, R; Keir, ST; Carol, H; Lock, R; Maris, JM; Billups, CA; Smith, MA
MLA Citation
Houghton, PJ, Kang, MH, Reynolds, CP, Morton, CL, Kolb, EA, Gorlick, R, Keir, ST, Carol, H, Lock, R, Maris, JM, Billups, CA, and Smith, MA. "Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 58.4 (April 2012): 636-639.
PMID
21681929
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
58
Issue
4
Publish Date
2012
Start Page
636
End Page
639
DOI
10.1002/pbc.23167

Combination testing of cediranib (AZD2171) against childhood cancer models by the pediatric preclinical testing program.

BACKGROUND: Cediranib (AZD2171) is a potent small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors. Cediranib has demonstrated single agent activity in several adult cancers and is being studied in combination with standard cytotoxic agents in multiple disease settings. PROCEDURES: Cediranib was tested in vivo against six childhood tumor xenograft models (four sarcomas, one glioblastoma, one neuroblastoma) alone or combined with cyclophosphamide (two models), vincristine (three models) or cisplatin (one model), each administered at its maximum tolerated dose, or rapamycin (six models). RESULTS: The combination of cediranib with standard cytotoxic agents was superior to the cytotoxic agent used alone for a single xenograft (one of the three xenografts evaluated for the vincristine-cediranib combination). The cediranib-cyclophosphamide combination was inferior to single agent cyclophosphamide in time to event for both models studied and was significantly inferior for one of the models. Cediranib combined with rapamycin was superior to each of the agents used alone in two of the six models and was determined to be additive or supra-additive with rapamycin in four models, although the effects were not large. CONCLUSIONS: Cediranib combined with cytotoxic chemotherapy agents demonstrated little or no benefit (and in one case was significantly inferior) compared to chemotherapy alone for the six pediatric cancer xenografts studied. By contrast, the combination of cediranib with rapamycin was additive or supra-additive in four of the six models in terms of prolongation of time to event, though tumor regressions were not observed for this combination.

Authors
Morton, CL; Maris, JM; Keir, ST; Gorlick, R; Kolb, EA; Billups, CA; Wu, J; Smith, MA; Houghton, PJ
MLA Citation
Morton, CL, Maris, JM, Keir, ST, Gorlick, R, Kolb, EA, Billups, CA, Wu, J, Smith, MA, and Houghton, PJ. "Combination testing of cediranib (AZD2171) against childhood cancer models by the pediatric preclinical testing program." Pediatr Blood Cancer 58.4 (April 2012): 566-571.
PMID
21538824
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
58
Issue
4
Publish Date
2012
Start Page
566
End Page
571
DOI
10.1002/pbc.23159

Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program.

BACKGROUND: AZD8055 is a small molecule ATP-competitive inhibitor of the serine/threonine kinase mTOR that regulates cap-dependent translation through the mTORC1 complex and Akt activation through the mTORC2 complex. Procedures AZD8055 was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 µM and against the PPTP in vivo panels at a dose of 20 mg/kg administered orally daily x 7 for 4 weeks. RESULTS: In vitro the median relative IC(50) for AZD8055 against the PPTP cell lines was 24.7 nM. Relative I/O values >0% (consistent with a cytostatic effect) were observed in 8 cell lines and 15 cell lines showed Relative I/O values ranging from -4.7 to -92.2% (consistent with varying degrees of cytotoxic activity). In vivo AZD8055 induced significant differences in EFS distribution compared to controls in 23 of 36 (64%) evaluable solid tumor xenografts, and 1 of 6 evaluable ALL xenografts. Intermediate activity for the time to event activity measure (EFS T/C >2) was observed in 5 of 32 (16%) solid tumor xenografts evaluable. The best response was stable disease. PD2 (progressive disease with growth delay) was observed in 20 of 36 (55.6%) evaluable solid tumor xenografts. AZD8055 significantly inhibited 4E-BP1, S6, and Akt phosphorylation following day 1 and day 4 dosing, but suppression of mTORC1 or mTORC2 signaling did not predict tumor sensitivity. CONCLUSIONS: AZD8055 demonstrated broad activity in vitro, but at the dose and schedule studied demonstrated limited activity in vivo against the PPTP solid tumor and ALL panels.

Authors
Houghton, PJ; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Morton, CL; Keir, ST; Reynolds, CP; Kang, MH; Phelps, D; Maris, JM; Billups, C; Smith, MA
MLA Citation
Houghton, PJ, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Morton, CL, Keir, ST, Reynolds, CP, Kang, MH, Phelps, D, Maris, JM, Billups, C, and Smith, MA. "Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program." Pediatr Blood Cancer 58.2 (February 2012): 191-199.
PMID
21337679
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
58
Issue
2
Publish Date
2012
Start Page
191
End Page
199
DOI
10.1002/pbc.22935

Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program.

BACKGROUND: Genz-644282 is a novel non-camptothecin topoisomerase I poison that is in clinical development. PROCEDURES: Genz-644282 was tested against the PPTP in vitro panel (0.1 nM to 1 µM), and in vivo using three times per week × 2 schedule repeated at day 21 at its maximum tolerated dose (MTD) of 4 mg/kg. Subsequently Genz-644282 was tested at 4, 3, 2, and 1 mg/kg in 3 models to assess the dose-response relationship. mRNA gene signatures predictive for Genz-644282 response in vitro were applied to select 15 tumor models that were evaluated prospectively. RESULTS: In vitro, Genz-644282 demonstrated potent cytotoxic activity with a median IC(50) of 1.2 nM (range 0.2-21.9 nM). In vivo, Genz-644282 at its MTD (4 mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid tumor models. At 2 mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models relatively insensitive to topotecan, but there were no objective responses at 1 mg/kg. Further testing at 2 mg/kg showed that Genz-644282 induced objective regressions in 7 of 17 (41%) models. There was a significant correlation between predictive response scores based on Affymetrix U133Plus2 baseline tumor expression profiles and the observed in vivo responses to Genz-644282. CONCLUSIONS: Genz-644282 was highly active within a narrow dose range (2-4 mg/kg), typical of other topoisomerase I poisons. As with other topoisomerase I poisons, how accurately these data will translate to clinical activity will depend upon the drug exposures that can be achieved in children treated with this agent.

Authors
Houghton, PJ; Lock, R; Carol, H; Morton, CL; Gorlick, R; Anders Kolb, E; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, CA; Zhang, MX; Madden, SL; Teicher, BA; Smith, MA
MLA Citation
Houghton, PJ, Lock, R, Carol, H, Morton, CL, Gorlick, R, Anders Kolb, E, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Billups, CA, Zhang, MX, Madden, SL, Teicher, BA, and Smith, MA. "Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program." Pediatr Blood Cancer 58.2 (February 2012): 200-209.
PMID
21548007
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
58
Issue
2
Publish Date
2012
Start Page
200
End Page
209
DOI
10.1002/pbc.23016

Malcolm A. Smith, John M. Maris, Richard Gorlick, E. Anders Kolb, Richard Lock, Hernan Carol, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, Christopher L. Morton, Jianrong Wu, Peter G. Smith, Jie Yu and Peter J. Houghton. Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Aug.; 59(2):246-253

Authors
Smith, MA; Maris, JM; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Reynolds, CP; Kang, MH; Morton, CL; Wu, J; Smith, PG; Yu, J; Houghton, PJ
MLA Citation
Smith, MA, Maris, JM, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Keir, ST, Reynolds, CP, Kang, MH, Morton, CL, Wu, J, Smith, PG, Yu, J, and Houghton, PJ. "Malcolm A. Smith, John M. Maris, Richard Gorlick, E. Anders Kolb, Richard Lock, Hernan Carol, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, Christopher L. Morton, Jianrong Wu, Peter G. Smith, Jie Yu and Peter J. Houghton. Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Aug.; 59(2):246-253." Pediatric Blood and Cancer 59.4 (2012): 772-772.
Source
scival
Published In
Pediatric Blood & Cancer
Volume
59
Issue
4
Publish Date
2012
Start Page
772
End Page
772
DOI
10.1002/pbc.24291

Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program

Authors
Morton, CL; Houghton, PJ; Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Maris, JM; Keir, ST; Wu, J; Smith, MA
MLA Citation
Morton, CL, Houghton, PJ, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Maris, JM, Keir, ST, Wu, J, and Smith, MA. "Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program." Pediatric Blood and Cancer 58.4 (2012): 652--.
Source
scival
Published In
Pediatric Blood & Cancer
Volume
58
Issue
4
Publish Date
2012
Start Page
652-
DOI
10.1002/pbc.24083

Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer.

PURPOSE: To gain a greater understanding of the potential of the Aurora kinase A inhibitor MLN8237 in the treatment of pediatric malignancies. METHODS: The activity of MLN8237 was evaluated against 28 neuroblastoma and Ewing sarcoma cell lines, and its in vivo efficacy was studied over a range of doses against 12 pediatric tumor xenograft models. Pharmacokinetic, pharmacodynamic, and genomic studies were undertaken. RESULTS: In vitro neuroblastoma cell lines were generally more sensitive to MLN8237 than Ewing sarcoma lines. MLN8237 demonstrated significant activity in vivo against solid tumor models at the maximum tolerated dose (MTD); however, only 2 of 6 neuroblastoma models had objective responses at 0.25MTD. In contrast, MLN8237 induced objective responses at its MTD and at 0.5MTD in three ALL models and in two out of three at 0.25MTD. Pharmacokinetic studies at 0.5MTD demonstrated a T (max) of 0.5 h, C (max) of 24.8 μM, AUC((0-24)) of 60.3 μM h, and 12 h trough level of 1.2 μM. Mitotic indices increased 6-12 h after MLN8237 administration. AURKA copy number variation was frequent in xenografts, and expression was highly correlated with copy number. CONCLUSIONS: Objective responses were more frequent in tumors with decreased AURKA copy number (5/8) compared to those with increased gene copy number (2/14). This report confirms the significant activity against both solid tumor and ALL xenografts at the MTD, with a steep dose response. These data support clinical development of MLN8237 in childhood cancer. Because of the steep dose-response relationship, such studies should target achieving trough levels of 1 μM or higher for sustained periods of treatment.

Authors
Carol, H; Boehm, I; Reynolds, CP; Kang, MH; Maris, JM; Morton, CL; Gorlick, R; Kolb, EA; Keir, ST; Wu, J; Wozniak, AE; Yang, Y; Manfredi, M; Ecsedy, J; Wang, J; Neale, G; Houghton, PJ; Smith, MA; Lock, RB
MLA Citation
Carol, H, Boehm, I, Reynolds, CP, Kang, MH, Maris, JM, Morton, CL, Gorlick, R, Kolb, EA, Keir, ST, Wu, J, Wozniak, AE, Yang, Y, Manfredi, M, Ecsedy, J, Wang, J, Neale, G, Houghton, PJ, Smith, MA, and Lock, RB. "Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer." Cancer Chemother Pharmacol 68.5 (November 2011): 1291-1304.
PMID
21448591
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
68
Issue
5
Publish Date
2011
Start Page
1291
End Page
1304
DOI
10.1007/s00280-011-1618-8

Initial testing of lenalidomide by the pediatric preclinical testing program.

BACKGROUND: Lenalidomide, a novel immunomodulatory agent, is reported to modulate stem cell differentiation, and have direct antiproliferative activity as well as inhibit inflammation and hyperalgesia. On the basis of this varied pharmacological profile, lenalidomide is under investigation as a treatment for a range of oncologic indications. PROCEDURES: Lenalidomide was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1 nM to 10 µM. It was tested against the PPTP in vivo panels at a dose of 30 mg/kg administered orally (PO) once daily for a planned for 6 weeks. RESULTS: In vitro activity was not observed at concentrations up to 10 µM. Lenalidomide was well tolerated, and induced significant differences in EFS distribution compared to control in 7 of 37 (18.9%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The best response in the solid tumor panel was PD2 [progressive disease with growth delay (EFS T/C > 1.5)], observed in 4 of 37 (10.8%) solid tumor xenografts. A single ALL xenograft showed a PD2 response. CONCLUSIONS: Direct antiproliferative effects of lenalidomide were not observed in vitro. In vivo lenalidomide demonstrated low activity against tumors in immune-deficient mice. Our results suggest that lenalidomide's utility in the pediatric clinical setting may depend upon its ability to induce antitumor activity through effects on host immune and stromal cells rather than through direct effects on tumor cells.

Authors
Reynolds, CP; Kang, MH; Keir, ST; Gorlick, R; Kolb, EA; Lock, R; Maris, JM; Carol, H; Morton, CL; Billups, CA; Smith, MA; Houghton, PJ
MLA Citation
Reynolds, CP, Kang, MH, Keir, ST, Gorlick, R, Kolb, EA, Lock, R, Maris, JM, Carol, H, Morton, CL, Billups, CA, Smith, MA, and Houghton, PJ. "Initial testing of lenalidomide by the pediatric preclinical testing program." Pediatr Blood Cancer 57.4 (October 2011): 606-611.
PMID
21360651
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
57
Issue
4
Publish Date
2011
Start Page
606
End Page
611
DOI
10.1002/pbc.22877

Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program.

BACKGROUND: PR-104 is rapidly hydrolyzed to PR-104A in vivo, which is activated by reduction to the corresponding 5-hydroxylamine (PR-104H) and amine (PR-104M) to produce DNA interstrand cross-links. PR-104 activation can occur via hypoxia-dependent reductases and also independently of hypoxia by aldo-keto reductase (AKR) 1C3. PROCEDURES: PR-104A was tested against the PPTP in vitro panel (10 nM to 100 µM), and PR-104 in vivo using a weekly × 6 schedule at its maximum tolerated dose (MTD) of 550 mg/kg. Subsequently PR-104 was tested at 270 and 110 mg/kg. Pharmacokinetics for PR-104 and its metabolites were determined, as were levels of AKR1C3 RNA and protein in xenografts. RESULTS: In vitro, the leukemia models were most sensitive to PR-104A. In vivo, PR-104 induced objective responses at its MTD in 21/34 solid tumor models and maintained complete responses against 7/7 acute lymphoblastic leukemia (ALL) models. At 270 mg/kg and lower dose levels, PR-104 did not induce solid tumor regressions, suggesting a steep dose-response relationship. Pharmacokinetic analysis suggests higher systemic exposures to PR-104A and its metabolites in mice compared to those achievable in patients. Levels of AKR1C3 protein did not correlate with tumor responsiveness. CONCLUSIONS: As monotherapy, PR-104 demonstrated a high level of activity against both solid tumor and ALL models at its MTD, but the activity was almost completely lost at half the MTD dose for solid tumors. Pharmacokinetic data at the PR-104 MTD from human trials suggest that PR-104 metabolites may not reach the plasma exposures in children that were associated with high-level preclinical activity.

Authors
Houghton, PJ; Lock, R; Carol, H; Morton, CL; Phelps, D; Gorlick, R; Kolb, EA; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Wozniak, AW; Gu, Y; Wilson, WR; Smith, MA
MLA Citation
Houghton, PJ, Lock, R, Carol, H, Morton, CL, Phelps, D, Gorlick, R, Kolb, EA, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Wozniak, AW, Gu, Y, Wilson, WR, and Smith, MA. "Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program." Pediatr Blood Cancer 57.3 (September 2011): 443-453.
PMID
21744473
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
57
Issue
3
Publish Date
2011
Start Page
443
End Page
453
DOI
10.1002/pbc.22921

Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program.

BACKGROUND: PG11047 is a novel conformationally restricted analog of the natural polyamine, spermine that lowers cellular endogenous polyamine levels and competitively inhibits natural polyamine functions leading to cancer cell growth inhibition. The activity of PG11047 was evaluated against the PPTP's in vitro and in vivo panels. PROCEDURES: PG11047 was evaluated against the PPTP in vitro panel using 96 hr exposure at concentrations ranging from 10 nM to 100 µM. It was tested against the PPTP in vivo panels at a dose of 100 mg/kg administered by the intraperitoneal route weekly for 6 weeks. RESULTS: In vitro PG11047 demonstrated a concentration-response pattern consistent with cytostatic activity. The median EC(50) for PG11047 was 71 nM. Cell lines of the Ewing sarcoma panel had a lower median EC(50) value compared to the remaining cell lines in the panel, while cell lines of the neuroblastoma panel had a higher median EC(50) value. In vivo PG11047 induced significant differences in EFS distribution compared to control in 5 of 32 (15.6%) of the evaluable solid tumor xenografts and in 0 of 7 (0%) of the evaluable ALL xenografts. The single case of tumor regression occurred in an ependymoma xenograft. CONCLUSIONS: Further pediatric development of PG11047 will require better defining a target population and identifying combinations for which there is a tumor-selective cytotoxic effect. The regression observed for an ependymoma xenograft and the exquisite sensitivity of some Ewing sarcoma cell lines to the antiproliferative effects of PG11047 provide leads for further preclinical investigations.

Authors
Smith, MA; Maris, JM; Lock, R; Kolb, EA; Gorlick, R; Keir, ST; Carol, H; Morton, CL; Reynolds, CP; Kang, MH; Houghton, PJ
MLA Citation
Smith, MA, Maris, JM, Lock, R, Kolb, EA, Gorlick, R, Keir, ST, Carol, H, Morton, CL, Reynolds, CP, Kang, MH, and Houghton, PJ. "Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program." Pediatr Blood Cancer 57.2 (August 2011): 268-274.
PMID
21360650
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
57
Issue
2
Publish Date
2011
Start Page
268
End Page
274
DOI
10.1002/pbc.22797

Affinity-matured anti-glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas.

Glycoprotein NMB (GPNMB), a transmembrane glycoprotein highly expressed in high-grade gliomas (HGGs), is an attractive target in cancer immunotherapy. We isolated a GPNMB-specific scFv clone, G49, from a human synthetic phage-display library. To obtain mutant single-chain variable-fragment antibodies (scFvs) with improved affinity and immunotoxins with increased activity, we subjected G49 to in vitro affinity maturation by a complementarity-determining-region (CDR) random-mutagenesis technique. Using light-chain CDR3 mutagenesis, cell-based panning by phage display, subsequent heavy-chain CDR1 mutagenesis, and flow-cytometric selection by yeast-surface display, we generated the mutant scFv clone 902V, with an overall 11-fold increase in affinity for GPNMB. Clone 902V was further randomized throughout the whole scFv by error-prone PCR, and one mutant, F6V, was selected by yeast-surface display. F6V scFv, differing from 902V by one amino-acid change in the light-chain CDR2, exhibited an affinity for GPNMB of 0.30 nM. The F6V mutant scFv clone was fused with a truncated form of Pseudomonas exotoxin A to form the immunotoxin F6V-PE38. F6V-PE38 demonstrated significant protein-synthesis-inhibition activity on GPNMB-expressing glioma and malignant melanoma cells (IC(50) = 0.5 ng/ml [8 pM]), a 60-fold improvement over G49 activity, but no cytotoxicity on GPNMB-negative cells. Furthermore, F6V-PE38 exhibited significant antitumor activity against subcutaneous malignant glioma xenografts in two nude-mouse models and a melanoma neoplastic meningitis model in athymic rats. These GPNMB-specific scFv antibodies and immunotoxins hold promise as reagents in targeted therapy for HGGs and other GPNMB-expressing malignancies.

Authors
Kuan, C-T; Wakiya, K; Keir, ST; Li, J; Herndon, JE; Pastan, I; Bigner, DD
MLA Citation
Kuan, C-T, Wakiya, K, Keir, ST, Li, J, Herndon, JE, Pastan, I, and Bigner, DD. "Affinity-matured anti-glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas." Int J Cancer 129.1 (July 1, 2011): 111-121.
PMID
20824708
Source
pubmed
Published In
International Journal of Cancer
Volume
129
Issue
1
Publish Date
2011
Start Page
111
End Page
121
DOI
10.1002/ijc.25645

Effect of massage therapy on stress levels and quality of life in brain tumor patients--observations from a pilot study.

BACKGROUND: Patients with brain tumors report experiencing elevated levels of stress across the disease continuum. Massage therapy is a commonly used complementary therapy and is employed in cancer care to reduce psychological stress and to improve quality of life (QoL). The purpose of this pilot study was to obtain a preliminary assessment of the efficacy of massage therapy on patient reported psychological outcomes and QoL. MATERIALS AND METHODS: The design of the study was a prospective, single-arm intervention. Participants were newly diagnosed primary brain tumor patients who reported experiencing stress and who received a total of eight massages over a period of 4 weeks. Participants completed the Perceived Stress Scale (PSS-10) and the Functional Assessment of Cancer Therapy-Brain to assess their stress level and QoL. RESULTS: As a group, levels of stress dropped significantly between weeks 2 and 3 (M = 12.3, SD = 3.09, P ≤ 0.010). A trend for the reduction in stress continued through week 4 (P ≤ 0.063). At the end of week 4, PSS-10 scores of all participants were below the threshold for being considered stressed. By the end of the intervention, participants reported significant improvements in three test domains, emotional well-being, additional brain tumor concerns, and social/family well-being. CONCLUSION: This study indicates that participation in a massage therapy program is both feasible and acceptable to newly diagnosed brain tumor patients experiencing stress. Furthermore, participants in this study reported improvements in stress and their QoL while receiving massage therapy.

Authors
Keir, ST
MLA Citation
Keir, ST. "Effect of massage therapy on stress levels and quality of life in brain tumor patients--observations from a pilot study." Support Care Cancer 19.5 (May 2011): 711-715.
PMID
21046417
Source
pubmed
Published In
Supportive Care in Cancer
Volume
19
Issue
5
Publish Date
2011
Start Page
711
End Page
715
DOI
10.1007/s00520-010-1032-5

Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program.

BACKGROUND: BMS-754807 is a small molecule ATP-competitive inhibitor of the type-1 insulin-like growth factor receptor currently in phase 1 clinical trials. PROCEDURES: BMS-754807 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 µM and was tested against the PPTP in vivo panels at a dose of 25 mg/kg administered orally BID for 6 days, repeated for 6 weeks. RESULTS: In vitro BMS-754807 showed a median EC(50) value of 0.62 µM against the PPTP cell lines. The median EC(50) for the four Ewing sarcoma cell lines was less than that for the remaining PPTP cell lines (0.19 µM vs. 0.78 µM, P = 0.0470). In vivo BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested, but in none of the ALL xenografts studied. Criteria for intermediate activity for the time to event activity measure (EFS T/C > 2) were met in 7 of 27 solid tumor xenografts evaluable for this measure. The best response was PD2 (progressive disease with growth delay), which was observed in 18 of 32 solid tumor xenografts. PD2 responses were most commonly observed in the rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and Wilms tumor panels. CONCLUSIONS: BMS-754807 activity in vitro is consistent with a specific IGF-1R effect that has half-maximal response in the 0.1 µM range and that is observed in a minority of the PPTP cell lines. In vivo intermediate activity was most commonly observed in the neuroblastoma and rhabdomyosarcoma panels.

Authors
Kolb, EA; Gorlick, R; Lock, R; Carol, H; Morton, CL; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, C; Smith, MA; Houghton, PJ
MLA Citation
Kolb, EA, Gorlick, R, Lock, R, Carol, H, Morton, CL, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Billups, C, Smith, MA, and Houghton, PJ. "Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program." Pediatr Blood Cancer 56.4 (April 2011): 595-603.
PMID
21298745
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
56
Issue
4
Publish Date
2011
Start Page
595
End Page
603
DOI
10.1002/pbc.22741

Cellular redox modulator, ortho Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) in the treatment of brain tumors.

Despite intensive efforts to improve multimodal treatment of brain tumor, survival remains limited. Current therapy consists of a combination of surgery, irradiation and chemotherapy with predisposition to long-term complications. Identifying novel targeted therapies is therefore at the forefront of brain tumor research. This study explores the utility of a manganese porphyrin in a brain tumor model. The compound used is ortho isomer, mangnese(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+). It is a powerful SOD mimic and peroxynitrite scavenger and a potent modulator of redox-based cellular transcriptional activity, able to suppress excessive immune and inflammatory responses and in turn proliferative pathways. It is further one of the most lipophilic compound among cationic Mn(III) N-alkylpyridylporphyrins, and thus accumulates predominantly in mitochondria relative to cytosol. In mitochondria, MnTnHex-2-PyP(5+) mimics our key antioxidant system, mitochondrial superoxide dismutase, MnSOD, whose overexpression has been widely shown to suppress tumor growth. Importantly, MnTnHex-2-PyP(5+) crosses blood brain barrier in sufficient amounts to demonstrate efficacy in treating CNS injuries. For those reasons we elected to test its effects in inhibiting brain tumor growth. This study is the first report of the antitumor properties of MnTnHex-2-PyP(5+) as a single agent in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D-456 MG) and pediatric medulloblastoma (D-341 MED), and is the first case where a redox-able metal complex has been used in glioma therapy. When given subcutaneously to mice bearing subcutaneous and intracranial xenografts, MnTnHex-2-PyP(5+) caused a significant (P ≤ 0.001) growth delay in D 245 MG, D-256 MG, D-341 MED, and D-456 MG tumors. Growth delay for mice bearing subcutaneous xenografts ranged from 3 days in D-54 MG to 34 days in D-341 MED. With mice bearing intracranial xenografts, MnTnHex-2-PyP(5+) increases median survival by 33% in adult glioblastoma multiforme (D-256 MG; p≤ 0.001) and 173% in pediatric medulloblastoma (D-341 MED, <0.001). The beneficial effects of MnTnHex-2-PyP(5+) are presumably achieved either (1) indirectly via elimination of signaling reactive oxygen and nitrogen species (in particular superoxide and peroxynitrite) which in turn would prevent activation of transcription factors; or (2) directly by coupling with cellular reductants and redox-sensitive signaling proteins. The former action is antioxidative while the latter action is presumably pro-oxidative in nature. Our findings suggest that the use of Mn porphyrin-based SOD mimics, and in particular lipophilic analogues such as MnTnHex-2-PyP(5+), is a promising approach for brain tumor therapy.

Authors
Keir, ST; Dewhirst, MW; Kirkpatrick, JP; Bigner, DD; Batinic-Haberle, I
MLA Citation
Keir, ST, Dewhirst, MW, Kirkpatrick, JP, Bigner, DD, and Batinic-Haberle, I. "Cellular redox modulator, ortho Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) in the treatment of brain tumors." Anticancer Agents Med Chem 11.2 (February 2011): 202-212.
PMID
21291403
Source
pubmed
Published In
Anti-Cancer Agents in Medicinal Chemistry
Volume
11
Issue
2
Publish Date
2011
Start Page
202
End Page
212

The genetic landscape of the childhood cancer medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Authors
Parsons, DW; Li, M; Zhang, X; Jones, S; Leary, RJ; Lin, JC-H; Boca, SM; Carter, H; Samayoa, J; Bettegowda, C; Gallia, GL; Jallo, GI; Binder, ZA; Nikolsky, Y; Hartigan, J; Smith, DR; Gerhard, DS; Fults, DW; VandenBerg, S; Berger, MS; Marie, SKN; Shinjo, SMO; Clara, C; Phillips, PC; Minturn, JE; Biegel, JA; Judkins, AR; Resnick, AC; Storm, PB; Curran, T; He, Y; Rasheed, BA; Friedman, HS; Keir, ST; McLendon, R; Northcott, PA; Taylor, MD; Burger, PC; Riggins, GJ; Karchin, R; Parmigiani, G et al.
MLA Citation
Parsons, DW, Li, M, Zhang, X, Jones, S, Leary, RJ, Lin, JC-H, Boca, SM, Carter, H, Samayoa, J, Bettegowda, C, Gallia, GL, Jallo, GI, Binder, ZA, Nikolsky, Y, Hartigan, J, Smith, DR, Gerhard, DS, Fults, DW, VandenBerg, S, Berger, MS, Marie, SKN, Shinjo, SMO, Clara, C, Phillips, PC, Minturn, JE, Biegel, JA, Judkins, AR, Resnick, AC, Storm, PB, Curran, T, He, Y, Rasheed, BA, Friedman, HS, Keir, ST, McLendon, R, Northcott, PA, Taylor, MD, Burger, PC, Riggins, GJ, Karchin, R, and Parmigiani, G et al. "The genetic landscape of the childhood cancer medulloblastoma." Science 331.6016 (January 28, 2011): 435-439.
PMID
21163964
Source
pubmed
Published In
Science
Volume
331
Issue
6016
Publish Date
2011
Start Page
435
End Page
439
DOI
10.1126/science.1198056

Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.

BACKGROUND: GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: GSK690693 was tested in vitro at concentrations from 1 nM to 10 µM, and against the in vivo panel of xenografts at a dose of 30 mg/kg daily × 5 for 6 consecutive weeks. Three measures of in vivo antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. RESULTS: GSK690693 inhibited cell growth in vitro with IC(50) values between 6.5 nM and >10 µM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity. CONCLUSIONS: GSK690693 demonstrated broad activity in vitro, however our results against both the solid tumor and ALL PPTP in vivo panels demonstrate that, as single agent at the dose and schedule used, GSK690693 has only modest antitumor activity.

Authors
Carol, H; Morton, CL; Gorlick, R; Kolb, EA; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, C; Smith, MA; Houghton, PJ; Lock, RB
MLA Citation
Carol, H, Morton, CL, Gorlick, R, Kolb, EA, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Billups, C, Smith, MA, Houghton, PJ, and Lock, RB. "Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program." Pediatr Blood Cancer 55.7 (December 15, 2010): 1329-1337.
PMID
20740623
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
55
Issue
7
Publish Date
2010
Start Page
1329
End Page
1337
DOI
10.1002/pbc.22710

Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program.

BACKGROUND: Sorafenib is an inhibitor of multiple kinases (e.g., VEGF receptors, PDGFR, FLT3, RET, BRAF, KIT) and is approved by FDA for treatment of two adult cancers. The activity of sorafenib was evaluated against the PPTP's in vitro and in vivo panels. PROCEDURES: Sorafenib was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1.0 nM to 10.0 µM. It was tested against the PPTP in vivo panels at a dose of 60 mg/kg administered by oral gavage daily for 5 days per week, repeated for 6 weeks. RESULTS: In vitro sorafenib demonstrated cytotoxic activity, with a median IC(50) value of 4.3 µM. Twenty of 23 cell lines had IC(50) values between 1.0 and 10.0 µM. A single cell line (Kasumi-1) with an activating KIT mutation had an IC(50) value < 1.0 µM (IC(50) = 0.02 µM). In vivo sorafenib induced significant differences in event-free survival (EFS) distribution compared to control in 27 of 36 (75%) of the evaluable solid tumor xenografts and in 1 of 8 (12.5%) of the evaluable ALL xenografts. Sorafenib induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C) in 15 of 34 (44%) evaluable solid tumor xenografts. No xenografts achieved an objective response. CONCLUSIONS: The primary in vitro activity of sorafenib was noted at concentrations above 1 µM, with the exception of a more sensitive cell line with an activating KIT mutation. The primary in vivo effect for sorafenib was tumor growth inhibition, which was observed across multiple histotypes.

Authors
Keir, ST; Maris, JM; Lock, R; Kolb, EA; Gorlick, R; Carol, H; Morton, CL; Reynolds, CP; Kang, MH; Watkins, A; Houghton, PJ; Smith, MA
MLA Citation
Keir, ST, Maris, JM, Lock, R, Kolb, EA, Gorlick, R, Carol, H, Morton, CL, Reynolds, CP, Kang, MH, Watkins, A, Houghton, PJ, and Smith, MA. "Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program." Pediatr Blood Cancer 55.6 (December 1, 2010): 1126-1133.
PMID
20672370
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
55
Issue
6
Publish Date
2010
Start Page
1126
End Page
1133
DOI
10.1002/pbc.22712

Corticorelin acetate, a synthetic corticotropin-releasing factor with preclinical antitumor activity, alone and with bevacizumab, against human brain tumor models.

BACKGROUND: Corticorelin acetate (CrA) is a synthetic form of corticotropin-releasing factor that is currently undergoing clinical trials in the treatment of peritumoral brain edema (PBE). This study preclinically investigated its potential as an antitumor agent against human brain tumor xenografts. MATERIALS AND METHODS: The in vivo efficacy of CrA as a single agent and in combination with the antiangiogenic agent, bevacizumab, was examined in three different patient-derived human brain tumor xenografts implanted orthotopically (intracranially) or subcutaneously in athymic mice. RESULTS: CrA significantly increased the lifespan of mice implanted orthotopically with two different pediatric brain tumor xenograft models. In one of these tumor models, the combination of CrA with bevacizumab produced a therapeutic outcome superior to that found using either of the two agents alone. CONCLUSION: The application of CrA for the treatment of PBE likely involves its activity as an anti-angiogenic agent, which may be one possible mechanism to explain its observed preclinical antitumor activity against orthotopic human brain tumor models. Additional studies to investigate other possible mechanisms of action are underway.

Authors
Gamez, I; Ryan, RP; Keir, ST
MLA Citation
Gamez, I, Ryan, RP, and Keir, ST. "Corticorelin acetate, a synthetic corticotropin-releasing factor with preclinical antitumor activity, alone and with bevacizumab, against human brain tumor models." Anticancer Res 30.12 (December 2010): 5037-5042.
PMID
21187487
Source
pubmed
Published In
Anticancer research
Volume
30
Issue
12
Publish Date
2010
Start Page
5037
End Page
5042

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas.

INTRODUCTION: Podoplanin/aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study was to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas. METHODS: The binding affinity of an anti-podoplanin antibody, NZ-1 (rat IgG(2a)), was determined by surface plasmon resonance and Scatchard analysis. NZ-1 was radioiodinated with (125)I using Iodogen [(125)I-NZ-1(Iodogen)] or N-succinimidyl 4-guanidinomethyl 3-[(131)I]iodobenzoate ([(131)I]SGMIB-NZ-1), and paired-label internalization assays of NZ-1 were performed. The tissue distribution of (125)I-NZ-1(Iodogen) and that of [(131)I]SGMIB-NZ-1 were then compared in athymic mice bearing glioblastoma xenografts. RESULTS: The dissociation constant (K(D)) of NZ-1 was determined to be 1.2 × 10(-10) M by surface plasmon resonance and 9.8 × 10(-10) M for D397MG glioblastoma cells by Scatchard analysis. Paired-label internalization assays in LN319 glioblastoma cells indicated that [(131)I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3 ± 0.8% of initially bound radioactivity at 8 h) compared to that from the (125)I-NZ-1(Iodogen) (10.0 ± 0.1% of initially bound radioactivity at 8 h). Likewise, tumor uptake of [(131)I]SGMIB-NZ-1 (39.9 ± 8.8 %ID/g at 24 h) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of (125)I-NZ-1(Iodogen) (29.7 ± 6.1 %ID/g at 24 h). CONCLUSIONS: The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma.

Authors
Kato, Y; Vaidyanathan, G; Kaneko, MK; Mishima, K; Srivastava, N; Chandramohan, V; Pegram, C; Keir, ST; Kuan, C-T; Bigner, DD; Zalutsky, MR
MLA Citation
Kato, Y, Vaidyanathan, G, Kaneko, MK, Mishima, K, Srivastava, N, Chandramohan, V, Pegram, C, Keir, ST, Kuan, C-T, Bigner, DD, and Zalutsky, MR. "Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas." Nucl Med Biol 37.7 (October 2010): 785-794.
PMID
20870153
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
37
Issue
7
Publish Date
2010
Start Page
785
End Page
794
DOI
10.1016/j.nucmedbio.2010.03.010

Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program.

BACKGROUND: AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development. PROCEDURES: AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10 microM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules. Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting. RESULTS: At the highest concentration used in vitro (10 microM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines. Against the in vivo tumor panels, AZD6244 induced significant differences in EFS distribution in 10 of 37 (27%) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no objective responses. Pharmacodynamic studies indicated at this dose and schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244 was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment. CONCLUSIONS: At the dose and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity. However, AZD6244 was highly active against BT-40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions.

Authors
Kolb, EA; Gorlick, R; Houghton, PJ; Morton, CL; Neale, G; Keir, ST; Carol, H; Lock, R; Phelps, D; Kang, MH; Reynolds, CP; Maris, JM; Billups, C; Smith, MA
MLA Citation
Kolb, EA, Gorlick, R, Houghton, PJ, Morton, CL, Neale, G, Keir, ST, Carol, H, Lock, R, Phelps, D, Kang, MH, Reynolds, CP, Maris, JM, Billups, C, and Smith, MA. "Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 55.4 (October 2010): 668-677.
PMID
20806365
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
55
Issue
4
Publish Date
2010
Start Page
668
End Page
677
DOI
10.1002/pbc.22576

HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.

Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.

Authors
Jin, G; Cook, S; Cui, B; Chen, WC; Keir, ST; Killela, P; Di, C; Payne, CA; Gregory, SG; McLendon, R; Bigner, DD; Yan, H
MLA Citation
Jin, G, Cook, S, Cui, B, Chen, WC, Keir, ST, Killela, P, Di, C, Payne, CA, Gregory, SG, McLendon, R, Bigner, DD, and Yan, H. "HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea." Neuro Oncol 12.9 (September 2010): 956-966.
PMID
20472715
Source
pubmed
Published In
Neuro-Oncology
Volume
12
Issue
9
Publish Date
2010
Start Page
956
End Page
966
DOI
10.1093/neuonc/noq045

EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity.

EGFR and its constitutively activated variant EGFRvIII are linked to glioblastoma resistance to therapy, the mechanisms underlying this association, however, are still unclear. We report that in glioblastoma, EGFR/EGFRvIII paradoxically co-expresses with p53-upregulated modulator of apoptosis (PUMA), a proapoptotic member of the Bcl-2 family of proteins primarily located on the mitochondria. EGFR/EGFRvIII binds to PUMA constitutively and under apoptotic stress, and subsequently sequesters PUMA in the cytoplasm. The EGFR-PUMA interaction is independent of EGFR activation and is sustained under EGFR inhibition. A Bcl-2/Bcl-xL inhibitor that mimics PUMA activity sensitizes EGFR/EGFRvIII-expressing glioblastoma cells to Iressa. Collectively, we uncovered a novel kinase-independent function of EGFR/EGFRvIII that leads to tumor drug resistance.

Authors
Zhu, H; Cao, X; Ali-Osman, F; Keir, S; Lo, H-W
MLA Citation
Zhu, H, Cao, X, Ali-Osman, F, Keir, S, and Lo, H-W. "EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity." Cancer Lett 294.1 (August 1, 2010): 101-110.
PMID
20153921
Source
pubmed
Published In
Cancer Letters
Volume
294
Issue
1
Publish Date
2010
Start Page
101
End Page
110
DOI
10.1016/j.canlet.2010.01.028

Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program.

BACKGROUND: Seneca Valley virus (NTX-010) is a non-recombinant, replication competent RNA virus that is undergoing phase 1 clinical trials in adults for tumors with neuroendocrine characteristics. Here we have evaluated the antitumor activity of NTX-010 administered systemically. PROCEDURES: In vitro NTX-010 was tested against 23 cell lines exposed for 96 hr at 1 x 10(-4) to 10(4) viral particles (vp)/cell. In vivo NTX-010 was administered intravenously once at 3 x 10(12) vp/kg. Three measures of antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event (fourfold increase in tumor volume for solid tumor models), measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. RESULTS: In vitro NTX-010 demonstrated a marked cytotoxic effect in a subset of the cell lines from the neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma panels. In vivo the most consistent activity was observed for the rhabdomyosarcoma and the neuroblastoma panels, with all four of the alveolar rhabdomyosarcoma xenografts and four of five neuroblastoma xenografts achieving CR or maintained CR. Objective responses were also observed in the rhabdoid tumor, Wilms tumor, and glioblastoma panels. CONCLUSIONS: NTX-010 demonstrated a high level of activity both in vitro and in vivo. Further analysis of existing testing and molecular characterization data may help define the biological characteristics of cancer cells that are associated with response to NTX-010.

Authors
Morton, CL; Houghton, PJ; Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Maris, JM; Keir, ST; Wu, J; Smith, MA
MLA Citation
Morton, CL, Houghton, PJ, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Maris, JM, Keir, ST, Wu, J, and Smith, MA. "Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program." Pediatr Blood Cancer 55.2 (August 2010): 295-303.
PMID
20582972
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
55
Issue
2
Publish Date
2010
Start Page
295
End Page
303
DOI
10.1002/pbc.22535

Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP).

BACKGROUND: MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis. PROCEDURES: MLN8237 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 microM and was tested against the PPTP in vivo panels at a dose of 20 mg/kg administered orally twice daily x 5 days. Treatment duration was 6 weeks for solid tumor xenografts and 3 weeks for ALL xenografts. RESULTS: MLN8237 had a median IC(50) of 61 nM against the PPTP in vitro panel. The ALL cell lines were more sensitive and the rhabdomyosarcoma cell lines less sensitive than the remaining PPTP cell lines. In vivo, MLN8237 induced significant differences in event-free survival (EFS) distributions compared to controls in 32/40 (80%) solid tumor models and all (6/6) ALL models. Maintained complete responses (CRs) were observed in 3 of 7 neuroblastoma xenografts, and all 6 evaluable ALL xenografts achieved CR (n = 4) or maintained CR (n = 2) status. Maintained CRs were observed among single xenografts in other panels, including the Wilms tumor, rhabdoid tumor, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and medulloblastoma. CONCLUSIONS: The in vivo activity observed against the neuroblastoma panel far exceeds that observed for standard agents evaluated against the panel by the PPTP. High levels of in vivo activity were also observed against the ALL xenograft panel. These data support expedited clinical development of MLN8237 in childhood cancer.

Authors
Maris, JM; Morton, CL; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Reynolds, CP; Kang, MH; Wu, J; Smith, MA; Houghton, PJ
MLA Citation
Maris, JM, Morton, CL, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Keir, ST, Reynolds, CP, Kang, MH, Wu, J, Smith, MA, and Houghton, PJ. "Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP)." Pediatr Blood Cancer 55.1 (July 15, 2010): 26-34.
PMID
20108338
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
55
Issue
1
Publish Date
2010
Start Page
26
End Page
34
DOI
10.1002/pbc.22430

[177Lu]-DOTA0-Tyr3-octreotate: A potential targeted radiotherapeutic for the treatment of Medulloblastoma

Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [177Lu-DOTA0,Tyr3]octreotate ([177Lu]DOTA- TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate this possibility in preclinical models of D341 MED human medulloblastoma by comparing the properties of [177Lu]DOTA-TATE to those of glucose-[125I-Tyr3]-octreotate ([125I]Gluc-TOCA), a radiopeptide previously shown to target this cell line. In vitro assays indicated that both labeled peptides exhibited similar cell-associated and in- ternalized radioactivity after a 30-min incubation at 37oC; however, at the end of the 4 h incubation period, the internal- ized radioactivity for [177Lu]DOTA-TATE (6.22 ± 0.75%) was nearly twice that for [125I]Gluc-TOCA (3.16 ± 0.27%), with similar differences seen in total cell-associated radioactivity levels. Consistent with the results from the internaliza- tion assays, results from paired-label tissue distribution studies in athymic mice with subcutaneous D341 MED medul- loblastoma xenografts showed a similar degree of tumor accumulation for [177Lu]DOTA-TATE and [125I]Gluc-TOCA at early time points but by 24 h, a more than 5-fold advantage was observed for the 177Lu-labeled peptide. Tumor-to-normal tissue ratios generally were more favorable for [177Lu]DOTA-TATE at all time points, due in part to its lower accumula- tion in normal tissues except kidneys. Taken together, these results suggest that [177Lu]DOTA-TATE warrants further in- vestigation as a targeted radiotherapeutic for medulloblastoma treatment. ©2010 Bentham Science Publishers Ltd.

Authors
Vaidyanathan, G; Affleck, DJ; Zhao, XG; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Zhao, XG, Keir, ST, and Zalutsky, MR. "[177Lu]-DOTA0-Tyr3-octreotate: A potential targeted radiotherapeutic for the treatment of Medulloblastoma." Current Radiopharmaceuticals 3.1 (July 12, 2010): 29-36.
Source
scopus
Published In
Current Radiopharmaceuticals
Volume
3
Issue
1
Publish Date
2010
Start Page
29
End Page
36
DOI
10.2174/1874471011003010029

Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program.

BACKGROUND: Many childhood malignancies including sarcomas, neuroblastoma, and Wilms tumor show the presence of both, active, type-1-insulin-like growth factor receptor (IGF-1R), and the autocrine production of its ligands IGF-1/IGF-2. IMC-A12 is a fully human IgG1 antibody that prevents ligand binding to the IGF-1R. PROCEDURES: IMC-A12 was evaluated against the 23 cell lines of the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposure at concentrations ranging from 0.01 nM to 0.1 microM. IMC-A12 was tested in vivo at a dose of 1 mg/mouse administered intraperitoneally twice weekly for 6 weeks. RESULTS: In vitro, IMC-A12-induced T/C values <50% in only three cell lines, a rhabdomyosarcoma cell line (Rh41) and two Ewing sarcoma cell lines (TC-71 and CHLA-9). In vivo, IMC-A12 induced significant differences in EFS distribution compared to control in 24 of 34 (71%) evaluable solid tumor xenografts. Using the PPTP "time to event" activity measure, IMC-A12 induced intermediate (n = 13) or high (n = 1) activity in 33 xenografts evaluable for this activity measure, including 6 of 6 rhabdomyosarcoma xenografts, 3 of 5 osteosarcoma xenografts, 2 of 5 neuroblastoma xenografts, and 1 of 5 Ewing sarcoma xenografts. The only objective response observed was observed in a rhabdomyosarcoma xenograft (Rh28) that achieved a maintained complete response. CONCLUSIONS: IMC-A12 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels, with the activity primarily being tumor growth inhibition rather than tumor regression. IMC-A12 showed its greatest activity in vivo against the PPTP's rhabdomyosarcoma xenografts.

Authors
Houghton, PJ; Morton, CL; Gorlick, R; Kolb, EA; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Wu, J; Smith, MA
MLA Citation
Houghton, PJ, Morton, CL, Gorlick, R, Kolb, EA, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Wu, J, and Smith, MA. "Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program." Pediatr Blood Cancer 54.7 (July 1, 2010): 921-926.
PMID
20166202
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
54
Issue
7
Publish Date
2010
Start Page
921
End Page
926
DOI
10.1002/pbc.22367

Initial testing of topotecan by the pediatric preclinical testing program.

BACKGROUND: Topotecan is a small molecule DNA topoisomerase I poison, that has been successful in clinical trials against pediatric solid tumors and leukemias. Topotecan was evaluated against the Pediatric Preclinical Testing Program (PPTP) tumor panels as part of a validation process for these preclinical models. PROCEDURES: In vivo three measures of antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event (fourfold increase in tumor volume for solid tumor models, or > or =25% human CD45+ cells in the peripheral blood for acute lymphoblastic leukemia, ALL models) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. RESULTS: Topotecan inhibited cell growth in vitro with IC(50) values between 0.71 and 489 nM. Topotecan significantly increased EFS in 32 of 37 (87%) solid tumor xenografts and in all 8 of the ALL xenografts. Seventy-five percent of solid tumors met EFS T/C activity criteria for intermediate (n = 17) or high activity (n = 7). Objective responses were noted in eight solid tumor xenografts (Wilms, rhabdomyosarcoma, Ewing sarcoma, neuroblastoma). Among the six neuroblastomas, three achieved a PR. For the ALL panel, two maintained CRs, three CRs, and two PRs were observed. CONCLUSIONS: Topotecan demonstrated broad activity in vitro and in vivo against both the solid tumor and ALL panels, with significant tumor growth delay generated in all the panels. These results further demonstrate the validity of the PPTP panel for preclinical testing of new drugs.

Authors
Carol, H; Houghton, PJ; Morton, CL; Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Maris, JM; Keir, ST; Watkins, A; Smith, MA; Lock, RB
MLA Citation
Carol, H, Houghton, PJ, Morton, CL, Kolb, EA, Gorlick, R, Reynolds, CP, Kang, MH, Maris, JM, Keir, ST, Watkins, A, Smith, MA, and Lock, RB. "Initial testing of topotecan by the pediatric preclinical testing program." Pediatr Blood Cancer 54.5 (May 2010): 707-715.
PMID
20017204
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
54
Issue
5
Publish Date
2010
Start Page
707
End Page
715
DOI
10.1002/pbc.22352

Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer.

Recent epidemiologic studies report that regular exercise may be associated with substantial reductions in cancer-specific and all-cause mortality following a breast cancer diagnosis. The mechanisms underlying this relationship have not been identified. We investigated the effects of long-term voluntary wheel running on growth and progression using an animal model of human breast cancer. We also examined effects on the central features of tumor physiology, including markers of tumor blood perfusion/vascularization, hypoxia, angiogenesis, and metabolism. Athymic female mice fed a high-fat diet were orthotopically (direct into the mammary fat pad) implanted with human breast cancer cells (MDA-MB-231 at 1 x 10(6)) into the right dorsal mammary fat pad and randomly assigned (1:1) to voluntary wheel running (n = 25) or a nonintervention (sedentary) control group (n = 25). Tumor volume was measured every three days using digital calipers. All experimental animals were killed when tumor volume reached > or = 1,500 mm(3). Kaplan-Meier (KM) analysis indicated that tumor growth (survival) was comparable between the experimental groups (exercise 44 days vs. control 48 days; KM proportional hazard ratio = 1.41, 95% confidence interval, 0.77-2.58, P = 0.14). However, tumors from exercising animals had significantly improved blood perfusion/vascularization relative to the sedentary control group (P < 0.05). Histological analyses indicated that intratumoral hypoxia levels (as assessed by hypoxia-inducible factor 1) were significantly higher in the exercise group relative to sedentary control (P < 0.05). Aerobic exercise can significantly increase intratumoral vascularization, leading to "normalization" of the tissue microenvironment in human breast tumors. Such findings may have important implications for inhibiting tumor metastasis and improving the efficacy of conventional cancer therapies.

Authors
Jones, LW; Viglianti, BL; Tashjian, JA; Kothadia, SM; Keir, ST; Freedland, SJ; Potter, MQ; Moon, EJ; Schroeder, T; Herndon, JE; Dewhirst, MW
MLA Citation
Jones, LW, Viglianti, BL, Tashjian, JA, Kothadia, SM, Keir, ST, Freedland, SJ, Potter, MQ, Moon, EJ, Schroeder, T, Herndon, JE, and Dewhirst, MW. "Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer." J Appl Physiol (1985) 108.2 (February 2010): 343-348.
PMID
19959769
Source
pubmed
Published In
Journal of applied physiology (Bethesda, Md. : 1985)
Volume
108
Issue
2
Publish Date
2010
Start Page
343
End Page
348
DOI
10.1152/japplphysiol.00424.2009

Initial testing (stage 1) of mapatumumab (HGS-ETR1) by the pediatric preclinical testing program.

Mapatumumab (HGS-ETR1) is a fully human IgG1 agonistic monoclonal antibody that exclusively targets and activates tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). It was tested in vitro at concentrations from 0.01 to 100 microg/ml and in vivo at a dose of 10 mg/kg administered intraperitoneally using a twice-weekly schedule. Mapatumumab demonstrated limited activity against the 23 cell lines of the PPTP in vitro panel with no lines achieving 50% growth inhibition. Mapatumumab induced significant differences in event-free survival distribution compared to controls in 9 of 37 evaluable solid tumor xenografts tested, but in none of the 8 ALL xenografts.

Authors
Smith, MA; Morton, CL; Kolb, EA; Gorlick, R; Keir, ST; Carol, H; Lock, R; Kang, MH; Reynolds, CP; Maris, JM; Watkins, AE; Houghton, PJ
MLA Citation
Smith, MA, Morton, CL, Kolb, EA, Gorlick, R, Keir, ST, Carol, H, Lock, R, Kang, MH, Reynolds, CP, Maris, JM, Watkins, AE, and Houghton, PJ. "Initial testing (stage 1) of mapatumumab (HGS-ETR1) by the pediatric preclinical testing program." Pediatr Blood Cancer 54.2 (February 2010): 307-310.
PMID
19856388
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
54
Issue
2
Publish Date
2010
Start Page
307
End Page
310
DOI
10.1002/pbc.22188

Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program.

Rapamycin demonstrated broad-spectrum tumor growth inhibition activity against the in vivo panels of childhood tumors used in the Pediatric Preclinical Testing Program (PPTP). Here we have evaluated rapamycin combined with agents used frequently in the treatment of childhood malignancies. Rapamycin was tested in vitro against 23 cell lines alone or in combination with melphalan, cisplatin, vincristine, or dexamethasone (leukemic models only). In vivo, the impact of combining rapamycin with a cytotoxic agent was evaluated using two measures: 1) the therapeutic enhancement measure, and 2) a linear regression model for time-to-event to formally evaluate for sub- and supraadditivity for the combination compared to the agents used alone. Combining rapamycin with cytotoxic agents in vitro gave predominantly subadditive or additive effects, except for dexamethasone in leukemia models for which supra-additive activity was observed. In vivo testing demonstrated that therapeutic enhancement was common for rapamycin in combination with cyclophosphamide and occurred for 4 of 11 evaluable xenografts for the rapamycin and vincristine combination. The combinations of rapamycin with either cyclophosphamide or vincristine were significantly more effective than the respective standard agents used alone at their maximum tolerated doses (MTD) for most evaluable xenografts. The combination of rapamycin and cisplatin produced excessive toxicity requiring cisplatin dose reductions, and therapeutic enhancement was not observed for this combination. Addition of rapamycin to either cyclophosphamide or vincristine at their respective MTDs appears promising, as these combinations are relatively well tolerated and as many of the pediatric preclinical models evaluated demonstrated therapeutic enhancement for these combinations.

Authors
Houghton, PJ; Morton, CL; Gorlick, R; Lock, RB; Carol, H; Reynolds, CP; Kang, MH; Maris, JM; Keir, ST; Kolb, EA; Wu, J; Wozniak, AW; Billups, CA; Rubinstein, L; Smith, MA
MLA Citation
Houghton, PJ, Morton, CL, Gorlick, R, Lock, RB, Carol, H, Reynolds, CP, Kang, MH, Maris, JM, Keir, ST, Kolb, EA, Wu, J, Wozniak, AW, Billups, CA, Rubinstein, L, and Smith, MA. "Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program." Mol Cancer Ther 9.1 (January 2010): 101-112.
PMID
20053767
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
9
Issue
1
Publish Date
2010
Start Page
101
End Page
112
DOI
10.1158/1535-7163.MCT-09-0952

[Lu]-DOTA-Tyr-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma.

Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [(177)Lu-DOTA(0),Tyr(3)]octreotate ([(177)Lu]DOTA-TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate this possibility in preclinical models of D341 MED human medulloblastoma by comparing the properties of [(177)Lu]DOTA-TATE to those of glucose-[(125)I-Tyr(3)]-octreotate ([(125)I]Gluc-TOCA), a radiopeptide previously shown to target this cell line. In vitro assays indicated that both labeled peptides exhibited similar cell-associated and internalized radioactivity after a 30-min incubation at 37°C; however, at the end of the 4 h incubation period, the internalized radioactivity for [(177)Lu]DOTA-TATE (6.22 " 0.75%) was nearly twice that for [(125)I]Gluc-TOCA (3.16 " 0.27%), with similar differences seen in total cell-associated radioactivity levels. Consistent with the results from the internalization assays, results from paired-label tissue distribution studies in athymic mice with subcutaneous D341 MED medulloblastoma xenografts showed a similar degree of tumor accumulation for [(177)Lu]DOTA-TATE and [(125)I]Gluc-TOCA at early time points but by 24 h, a more than 5-fold advantage was observed for the (177)Lu-labeled peptide. Tumor-to-normal tissue ratios generally were more favorable for [(177)Lu]DOTA-TATE at all time points, due in part to its lower accumulation in normal tissues except kidneys. Taken together, these results suggest that [(177)Lu]DOTA-TATE warrants further investigation as a targeted radiotherapeutic for medulloblastoma treatment.

Authors
Vaidyanathan, G; Affleck, DJ; Zhao, X-G; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Zhao, X-G, Keir, ST, and Zalutsky, MR. "[Lu]-DOTA-Tyr-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma." Curr Radiopharm 3.1 (2010): 29-36.
PMID
21243098
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
3
Issue
1
Publish Date
2010
Start Page
29
End Page
36
DOI
10.2174/1874471011003010029

Erratum: Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer (Journal of Applied Physiology (2010) 108: (343-348) DOI: 10.1152/japplphysiol.00424.2009)

Authors
Jones, LW; Viglianti, BL; Tashjian, JA; Kothadia, SM; Keir, ST; Freedland, SJ; Potter, MQ; Moon, EJ; Schroeder, T; Herndon, JE; Dewhirst, MW
MLA Citation
Jones, LW, Viglianti, BL, Tashjian, JA, Kothadia, SM, Keir, ST, Freedland, SJ, Potter, MQ, Moon, EJ, Schroeder, T, Herndon, JE, and Dewhirst, MW. "Erratum: Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer (Journal of Applied Physiology (2010) 108: (343-348) DOI: 10.1152/japplphysiol.00424.2009)." Journal of Applied Physiology 108.4 (2010): 1021--.
Source
scival
Published In
Journal of applied physiology (Bethesda, Md. : 1985)
Volume
108
Issue
4
Publish Date
2010
Start Page
1021-
DOI
10.1152/japplphysiol.zdg-9024-corr.2010

Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program.

BACKGROUND: Ispinesib is a highly specific inhibitor of kinesin spindle protein (KSP, HsEg5), a mitotic kinesin required for separation of the spindle poles. Here we report the activity of ispinesib against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: Ispinesib was tested against the PPTP in vitro panel cell lines at concentrations from 0.1 nM to 1 microM and against the in vivo tumor panel xenografts by intraperitoneal administration (5 or 10 mg/kg) every 4 days for 3 doses repeated at day 21. RESULTS: Ispinesib was highly potent against the PPTP's in vitro cell lines with a median IC(50) of 4.1 nM. Ispinesib (10 mg/kg) induced unexplained toxicity in mice bearing osteosarcoma xenografts and exceeded the MTD in 12 of 40 non-osteosarcoma xenografts. Ispinesib induced significant tumor growth delay in 88% (23/26) of evaluable xenografts. Using a time to event measure of efficacy, ispinesib had intermediate and high levels of activity against 4 (21%) and 5 (26%) of the 19 evaluable solid tumor xenografts, respectively. Ispinesib induced maintained complete responses (CR) in a rhabdoid tumor, a Wilms tumor and a Ewing sarcoma xenograft. Ispinesib (5 mg/kg) produced 2 complete and 2 partial responses among 6 evaluable xenografts in the ALL panel. The in vivo pattern of activity was distinctive from that previously reported for vincristine. CONCLUSIONS: Ispinesib demonstrated broad in vivo antitumor activity, including maintained complete responses for several xenografts, although with high toxicity rates at the doses studied.

Authors
Carol, H; Lock, R; Houghton, PJ; Morton, CL; Kolb, EA; Gorlick, R; Reynolds, CP; Maris, JM; Keir, ST; Billups, CA; Smith, MA
MLA Citation
Carol, H, Lock, R, Houghton, PJ, Morton, CL, Kolb, EA, Gorlick, R, Reynolds, CP, Maris, JM, Keir, ST, Billups, CA, and Smith, MA. "Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program." Pediatr Blood Cancer 53.7 (December 15, 2009): 1255-1263.
PMID
19554570
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
53
Issue
7
Publish Date
2009
Start Page
1255
End Page
1263
DOI
10.1002/pbc.22056

Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program.

BACKGROUND: Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer. METHODS: Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 microM. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/day). Lapatinib pharmacokinetic parameters were determined in scid(-/-) mice. RESULTS: The median IC(50) value for lapatinib against the entire PPTP cell line panel was 6.84 microM (range, 2.08 to >10.0 microM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5% of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values. CONCLUSIONS: Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets.

Authors
Gorlick, R; Kolb, EA; Houghton, PJ; Morton, CL; Phelps, D; Schaiquevich, P; Stewart, C; Keir, ST; Lock, R; Carol, H; Reynolds, CP; Maris, JM; Wu, J; Smith, MA
MLA Citation
Gorlick, R, Kolb, EA, Houghton, PJ, Morton, CL, Phelps, D, Schaiquevich, P, Stewart, C, Keir, ST, Lock, R, Carol, H, Reynolds, CP, Maris, JM, Wu, J, and Smith, MA. "Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program." Pediatr Blood Cancer 53.4 (October 2009): 594-598.
PMID
19554571
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
53
Issue
4
Publish Date
2009
Start Page
594
End Page
598
DOI
10.1002/pbc.21989

Initial testing of aplidin by the pediatric pre-clinical testing program.

Aplidin was tested in vitro at concentrations ranging from from 0.1 nM to 1.0 microM and in vivo at a dose of 0.6 mg/kg administered intraperitoneally on an every 4 days x 3-schedule that was repeated at day 21. In vitro, Aplidin was most active against acute lymphoblastic leukemia (ALL) cell lines. In vivo, Aplidin induced significant differences in EFS distribution in 12 of 28 (43%) solid tumor models and 2 of 6 evaluable ALL models. Aplidin showed potent in vitro activity and induced significant in vivo tumor growth inhibition in some xenografts, but did not induce tumor regressions.

Authors
Morton, CL; Houghton, PJ; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, C; Smith, MA
MLA Citation
Morton, CL, Houghton, PJ, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Billups, C, and Smith, MA. "Initial testing of aplidin by the pediatric pre-clinical testing program." Pediatr Blood Cancer 53.3 (September 2009): 509-512.
PMID
19418543
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
53
Issue
3
Publish Date
2009
Start Page
509
End Page
512
DOI
10.1002/pbc.21976

Initial testing (stage 1) of vorinostat (SAHA) by the pediatric preclinical testing program.

Vorinostat, a histone deacetylase inhibitor, was evaluated against the in vitro and in vivo childhood solid tumor and leukemia models in the Pediatric Preclinical Testing Program (PPTP). In vitro testing was performed by the DIMSCAN cytotoxicity assay. In vivo, vorinostat was administered intraperitoneally to mice bearing xenografts. Vorinostat demonstrated 2-log cell growth inhibitory activity in vitro, but generally at concentrations not sustainable in the clinic. No objective responses were observed for any of the solid tumor or acute lymphoblastic leukemia xenografts. Preclinical studies with appropriate drug combinations may provide direction for further clinical evaluations of vorinostat against selected pediatric cancers.

Authors
Keshelava, N; Houghton, PJ; Morton, CL; Lock, RB; Carol, H; Keir, ST; Maris, JM; Reynolds, CP; Gorlick, R; Kolb, EA; Wu, J; Smith, MA
MLA Citation
Keshelava, N, Houghton, PJ, Morton, CL, Lock, RB, Carol, H, Keir, ST, Maris, JM, Reynolds, CP, Gorlick, R, Kolb, EA, Wu, J, and Smith, MA. "Initial testing (stage 1) of vorinostat (SAHA) by the pediatric preclinical testing program." Pediatr Blood Cancer 53.3 (September 2009): 505-508.
PMID
19418547
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
53
Issue
3
Publish Date
2009
Start Page
505
End Page
508
DOI
10.1002/pbc.21988

Family appraisal of caregiving in a brain cancer model

Caregivers of patients with brain tumors frequently provide care to a patient with a potentially short terminal disease trajectory. Understanding the impact of caregiving is important because caregivers are often called upon to make difficult decisions regarding the patient for whom they provide care. The goal of this study was to document caregiver appraisal of providing care to persons with brain tumors. Using 70 patient and caregiver dyads, levels of caregiver strain, distress, family well-being, and positive appraisal were assessed in caregivers of patients with brain cancer using the Family Appraisal of Caregiving Questionnaire for Palliative Care. Patient quality of life and stress were assessed using the Functional Assessment of Cancer Therapy-Brain and the Perceived Stress Scale. Participants indicated high levels of positive caregiver appraisal (mean [SD], 4.3 [0.53]) and low levels of strain (mean [SD], 2.72 [0.88]). Of the four domains assessed by the Family Appraisal of Caregiving Questionnaire for Palliative Care, only caregiver distress correlated (r = -0.245, P = .04) with patients' overall Functional Assessment of Cancer Therapy-Brain score. Higher patient Perceived Stress Scale scores were associated with caregiver strain and burden, whereas lower scores were associated with family well-being and positive caregiving appraisal. Despite the challenges that caregivers of patients with brain tumors must address, this study documented that respondents experienced higher levels of positive appraisal and family well-being over caregiver distress and strain. The data also indicated a clear relationship between caregiver appraisal and patient quality of life and more so regarding patient stress.

Authors
Keir, ST; Farland, MM; Lipp, ES; Friedman, HS
MLA Citation
Keir, ST, Farland, MM, Lipp, ES, and Friedman, HS. "Family appraisal of caregiving in a brain cancer model." Journal of Hospice and Palliative Nursing 11.1 (2009): 60-66.
Source
scival
Published In
Journal of Hospice and Palliative Nursing
Volume
11
Issue
1
Publish Date
2009
Start Page
60
End Page
66
DOI
10.1097/NJH.0b013e3181917e35

Distress persists in long-term brain tumor survivors with glioblastoma multiforme.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor. The prognosis for GBM patients is extremely poor with an estimated median survival of 12 months. Despite this statistic, a number of GBM patients are living longer than in the past as new detection and treatment approaches are used. However, little is known about the psychological correlates of this disease. To address this issue we investigated distress and its sources in long-term survivors (LTS) of this disease. MATERIALS AND METHODS: Participants were asked to complete the National Comprehensive Cancer Network's (NCCN) Distress Thermometer, a single-item rapid screening tool for distress. Participants were also asked to designate sources of distress from a 34-item list developed by the NCCN. Distress scores and sources of distress for long-term GBM survivors (>18 months) were compared to patients diagnosed within the last 18 months (<18 months). RESULTS: Eight-three brain tumor patients participated in this study. Fifty-nine percent of LTS met the > or = 4 cut-off score for distress (M = 4.61, SD 3.12) as compared to 49% of patients diagnosed less than 18 months (M = 3.93, SD = 2.21; x(2) = 0.406, NS), LTS reported fewer items of concern while more LTS reported being distressed. CONCLUSIONS: This study indicates that LTS of GBM report experiencing distress at similar levels to other brain tumor patients. Level of distress for LTS is directly related to the total number of concerns in both emotional and physical domains. IMPLICATIONS FOR CANCER SURVIVORS: Regardless of LTS status, distress continues to be a part of the disease trajectory for many GBM patients. As such, attention to distress in these survivors of a major life threatening disease is warranted in follow up surveillance visits.

Authors
Keir, ST; Farland, MM; Lipp, ES; Friedman, HS
MLA Citation
Keir, ST, Farland, MM, Lipp, ES, and Friedman, HS. "Distress persists in long-term brain tumor survivors with glioblastoma multiforme." J Cancer Surviv 2.4 (December 2008): 269-274.
PMID
18958627
Source
pubmed
Published In
Journal of Cancer Survivorship
Volume
2
Issue
4
Publish Date
2008
Start Page
269
End Page
274
DOI
10.1007/s11764-008-0069-7

An integrated genomic analysis of human glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

Authors
Parsons, DW; Jones, S; Zhang, X; Lin, JC-H; Leary, RJ; Angenendt, P; Mankoo, P; Carter, H; Siu, I-M; Gallia, GL; Olivi, A; McLendon, R; Rasheed, BA; Keir, S; Nikolskaya, T; Nikolsky, Y; Busam, DA; Tekleab, H; Diaz, LA; Hartigan, J; Smith, DR; Strausberg, RL; Marie, SKN; Shinjo, SMO; Yan, H; Riggins, GJ; Bigner, DD; Karchin, R; Papadopoulos, N; Parmigiani, G; Vogelstein, B; Velculescu, VE; Kinzler, KW
MLA Citation
Parsons, DW, Jones, S, Zhang, X, Lin, JC-H, Leary, RJ, Angenendt, P, Mankoo, P, Carter, H, Siu, I-M, Gallia, GL, Olivi, A, McLendon, R, Rasheed, BA, Keir, S, Nikolskaya, T, Nikolsky, Y, Busam, DA, Tekleab, H, Diaz, LA, Hartigan, J, Smith, DR, Strausberg, RL, Marie, SKN, Shinjo, SMO, Yan, H, Riggins, GJ, Bigner, DD, Karchin, R, Papadopoulos, N, Parmigiani, G, Vogelstein, B, Velculescu, VE, and Kinzler, KW. "An integrated genomic analysis of human glioblastoma multiforme." Science 321.5897 (September 26, 2008): 1807-1812.
PMID
18772396
Source
pubmed
Published In
Science
Volume
321
Issue
5897
Publish Date
2008
Start Page
1807
End Page
1812
DOI
10.1126/science.1164382

Initial testing of VNP40101M (Cloretazine) by the pediatric preclinical testing program.

VNP40101M is a novel alkylating agent that yields two reactive compounds (a chloroethylating species and methylisocyanate) and has demonstrated activity against a wide spectrum of tumor xenografts. VNP40101M was tested against an in vivo panel of five pediatric brain tumor xenografts at a dose of 18 mg/kg/day administered for 5 days. O-6-methylguanine-DNA methyltransferase (MGMT) levels of xenografts were assessed by Western blot analysis. Only one xenograft (GBM2), which lacked detectable MGMT expression, demonstrated an objective response to VNP40101M. VNP4010M antitumor activity was observed only in the absence of MGMT expression, with resistance to VNP4010M seen even with low MGMT expression.

Authors
Keir, ST; Morton, CL; Billups, C; Smith, MA; Houghton, PJ; Gururangan, S
MLA Citation
Keir, ST, Morton, CL, Billups, C, Smith, MA, Houghton, PJ, and Gururangan, S. "Initial testing of VNP40101M (Cloretazine) by the pediatric preclinical testing program." Pediatr Blood Cancer 51.3 (September 2008): 439-441.
PMID
18493996
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
51
Issue
3
Publish Date
2008
Start Page
439
End Page
441
DOI
10.1002/pbc.21620

Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program.

BACKGROUND: Sunitinib is an orally bioavailable, multi-targeted tyrosine kinase inhibitor with selectivity for PDGF receptors, VEGF receptors, FLT3, and KIT. PROCEDURES: Sunitinib was tested at concentrations ranging from 0.1 nM to 1.0 microM against 23 cell lines from the PPTP in vitro panel. We also compared sunitinib (53.5 mg/kg) or vehicle administered for 28 days by oral gavage in 46 murine xenograft models representing 9 distinct pediatric cancer histologies. RESULTS: The leukemia cell line, Kasumi-1 (gain-of-function KIT(Asn822Lys) mutation) was the only line with an in vitro response to sunitinib (IC(50) 75.7 nM). Sunitinib significantly prolonged EFS in 19 of 35 (54%) of the solid tumor, and in 3 of 8 (38%) of the ALL xenografts analyzed. Using the PPTP time to event measure of efficacy, sunitinib had intermediate (13) and high (1) levels of activity against 14 of 34 evaluable solid tumor xenografts, including 4 of 6 rhabdomyosarcoma, 4 of 5 Ewing tumor, and 2 of 3 rhabdoid tumor xenografts. Following cessation of treatment for the 14 solid tumor xenografts without tumor events by day 28, tumor growth rate increased in most. The only regression noted to sunitinib in the solid tumor panels was a complete response in a rhabdoid tumor xenograft. CONCLUSIONS: Sunitinib demonstrated significant tumor growth inhibition against most of the PPTP's solid tumor panels, but little activity against the neuroblastoma and ALL panel. Antitumor activity was manifested primarily as tumor growth delay, consistent with an anti-angiogenic effect for sunitinib against many of the pediatric preclinical models evaluated. Pediatr Blood Cancer 2008;51:42-48. (c) 2008 Wiley-Liss, Inc.

Authors
Maris, JM; Courtright, J; Houghton, PJ; Morton, CL; Kolb, EA; Lock, R; Tajbakhsh, M; Reynolds, CP; Keir, ST; Wu, J; Smith, MA
MLA Citation
Maris, JM, Courtright, J, Houghton, PJ, Morton, CL, Kolb, EA, Lock, R, Tajbakhsh, M, Reynolds, CP, Keir, ST, Wu, J, and Smith, MA. "Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program." Pediatr Blood Cancer 51.1 (July 2008): 42-48.
PMID
18293383
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
51
Issue
1
Publish Date
2008
Start Page
42
End Page
48
DOI
10.1002/pbc.21535

Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program.

BACKGROUND: Alvespimycin (17-DMAG, KOS-1022), a potent small-molecule inhibitor of the protein chaperone Hsp90, is being developed as an anticancer agent because of the multiple Hsp90 client proteins involved in cancer cell growth and survival. PROCEDURES: Alvespimycin was tested against the in vitro panel of the Pediatric Preclinical Testing Program (PPTP) at concentrations from 1 nM to 10 microM and was tested against the PPTP's in vivo tumor panels by intraperitoneal administration using a 50 mg/kg BID twice weekly x 6 weeks dose and schedule. Hsp70 induction in tumor and liver tissue was used as a pharmacodynamic measure of Hsp90 inhibition and stress response induction. RESULTS: Alvespimycin had a median IC(50) of 68 nM against the PPTP's in vitro panel, with a trend for lower IC(50) values for the rhabdomyosarcoma panel (median IC(50) 32 nM) and for higher IC(50) values for the neuroblastoma panel (median IC(50) 380 nM). Using the time to event activity measure, alvespimycin had intermediate or high activity against 4 of 28 evaluable solid tumor xenografts, including 3 of 4 alveolar rhabdomyosarcoma xenografts (one with a partial response). Hsp70 induction was observed in tumor tissue from both responding and non-responding xenografts. CONCLUSIONS: Alvespimycin demonstrated little in vivo antitumor activity against most of the PPTP's preclinical models. The greatest drug effect was observed for the alveolar rhabdomyosarcoma xenografts in the rhabdomyosarcoma panel. Hsp70 induction was observed in responding and non-responding xenografts, suggesting that tumor-specific events subsequent to HSP90 inhibition are primary determinants of antitumor activity.

Authors
Smith, MA; Morton, CL; Phelps, DA; Kolb, EA; Lock, R; Carol, H; Reynolds, CP; Maris, JM; Keir, ST; Wu, J; Houghton, PJ
MLA Citation
Smith, MA, Morton, CL, Phelps, DA, Kolb, EA, Lock, R, Carol, H, Reynolds, CP, Maris, JM, Keir, ST, Wu, J, and Houghton, PJ. "Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program." Pediatr Blood Cancer 51.1 (July 2008): 34-41.
PMID
18260120
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
51
Issue
1
Publish Date
2008
Start Page
34
End Page
41
DOI
10.1002/pbc.21508

Screening for distress in patients with brain cancer using the NCCN's rapid screening measure.

GOALS OF WORK: Patients with brain cancer are at a risk of experiencing elevated levels of distress due to the severe functional, neurocognitive, and neuropsychological sequelae of the disease. Using the National Comprehensive Cancer Network's Distress Thermometer, we evaluated the extent and sources of distress within a population of patients with brain cancer. PATIENTS AND METHODS: Participants were asked to complete the Distress Thermometer, a single-item rapid screening tool for distress. The Distress Thermometer is a visual analog scale on which participants rate their level of distress from '0' (none) to '10' (extreme). Participants were also asked to designate which items from a 34-item list constitute sources of distress. MAIN RESULTS: Fifty-two percent of participants met the > or =4 cut-off score for distress. The scores were positively correlated with patient-reported emotional sources of distress (r = 0.444, p < 0.001), physical sources of stress (r = 0.231, p < 0.05), and total number of concerns (r = 0.368, p < 0.001). On average, brain tumor patients reported 5.8 cancer-related items of concern. CONCLUSION: Brain cancer patients are likely to experience distress at some point during their disease trajectory. Patient-reported emotional sources of distress should be targeted and interventions should be designed to address sources of distress such as worry, sadness, and depression.

Authors
Keir, ST; Calhoun-Eagan, RD; Swartz, JJ; Saleh, OA; Friedman, HS
MLA Citation
Keir, ST, Calhoun-Eagan, RD, Swartz, JJ, Saleh, OA, and Friedman, HS. "Screening for distress in patients with brain cancer using the NCCN's rapid screening measure." Psychooncology 17.6 (June 2008): 621-625.
PMID
17973236
Source
pubmed
Published In
Psycho-Oncology
Volume
17
Issue
6
Publish Date
2008
Start Page
621
End Page
625
DOI
10.1002/pon.1271

Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program.

BACKGROUND: SCH 717454 (19D12) is a fully human antibody directed against the insulin-like growth factor 1 receptor (IGF-1R), which is implicated in the growth and metastatic phenotype of a broad range of malignancies. The activity of SCH 717454 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: SCH 717454 was tested against the PPTP in vitro panel at concentrations ranging from 0.01 to 100 nM and was tested against the PPTP in vivo panel at a dose of 0.5 mg per mouse administered twice weekly for 4 weeks via intraperitoneal injection. RESULTS: SCH 717454 was ineffective at retarding growth of cell lines in the in vitro panel. In vivo, SCH 717454 significantly increased event-free survival in 20 of 35 (57%) solid tumor xenograft models with tumor regressions in one Ewing sarcoma model (complete response) and 2 osteosarcoma models (maintained complete responses). Using the time to event activity measure, SCH 717454 had intermediate (n = 9) or high (n = 1) activity against 31 evaluable solid tumor xenografts, including xenografts from the rhabdoid tumor, Ewing, rhabdomyosarcoma, glioblastoma, neuroblastoma, and osteosarcoma panels. SCH 717454 showed little activity against the 8 xenografts of the acute lymphoblastic leukemia panel. CONCLUSIONS: SCH 717454 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels. Further characterization of the molecular predictors of response and of the activity of combinations of SCH 717454 with other anticancer agents are anticipated.

Authors
Kolb, EA; Gorlick, R; Houghton, PJ; Morton, CL; Lock, R; Carol, H; Reynolds, CP; Maris, JM; Keir, ST; Billups, CA; Smith, MA
MLA Citation
Kolb, EA, Gorlick, R, Houghton, PJ, Morton, CL, Lock, R, Carol, H, Reynolds, CP, Maris, JM, Keir, ST, Billups, CA, and Smith, MA. "Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program." Pediatr Blood Cancer 50.6 (June 2008): 1190-1197.
PMID
18260118
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
50
Issue
6
Publish Date
2008
Start Page
1190
End Page
1197
DOI
10.1002/pbc.21450

Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program.

BACKGROUND: ABT-263 is a potent (K(i) < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-x(L) and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation. METHODS: ABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 microM using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days. RESULTS: ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC(50) for all of the lines in the panel was 1.91 microM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation. CONCLUSIONS: ABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP's solid tumor panels but showed significant activity against xenografts in the ALL panel.

Authors
Lock, R; Carol, H; Houghton, PJ; Morton, CL; Kolb, EA; Gorlick, R; Reynolds, CP; Maris, JM; Keir, ST; Wu, J; Smith, MA
MLA Citation
Lock, R, Carol, H, Houghton, PJ, Morton, CL, Kolb, EA, Gorlick, R, Reynolds, CP, Maris, JM, Keir, ST, Wu, J, and Smith, MA. "Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program." Pediatr Blood Cancer 50.6 (June 2008): 1181-1189.
PMID
18085673
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
50
Issue
6
Publish Date
2008
Start Page
1181
End Page
1189
DOI
10.1002/pbc.21433

Initial testing of dasatinib by the pediatric preclinical testing program.

BACKGROUND: Dasatinib, a dual inhibitor of the src and abl tyrosine kinases, was recently approved by the Federal Drug Administration for the treatment of imatinib mesylate-resistant chronic myeloid leukemia. PROCEDURES: Dasatinib was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 0.1 nM to 1.0 microM and was tested in vivo at a dose of 50 mg/kg administered orally twice daily 5 days per week for 4 weeks for the solid tumor xenografts and once daily for the acute lymphoblastic leukemia (ALL) xenografts. RESULTS: Dasatinib was selectively active against the cell lines of the PPTP in vitro panel, reaching an IC(50) in 6 of the 22 lines. The most sensitive were the AML line Kasumi-1, which has a gain-of-function c-Kit mutation (Asn822Lys), and the rhabdoid tumor line CHLA-266 (IC(50) approximately 10 nM for each). In the in vivo panel, dasatinib induced significant differences in EFS distribution in 8 of 32 (25%) solid tumor models and 3 of 7 ALL models. Using the time to event activity measure, dasatinib had intermediate activity against 1 of 27 (4%) evaluable solid tumor xenografts and 3 of 7 ALL xenografts. One xenograft in the ALL panel, a Philadelphia chromosome positive (Ph(+)) ALL xenograft, demonstrated a complete response. CONCLUSIONS: Dasatinib was active at low nanomolar concentrations against a small subset of the PPTP's in vitro panel. Dasatinib had limited in vivo activity against the PPTP solid tumor xenografts, but was highly active against a Ph(+) ALL xenograft and also had anti-leukemia activity against two other xenografts.

Authors
Kolb, EA; Gorlick, R; Houghton, PJ; Morton, CL; Lock, RB; Tajbakhsh, M; Reynolds, CP; Maris, JM; Keir, ST; Billups, CA; Smith, MA
MLA Citation
Kolb, EA, Gorlick, R, Houghton, PJ, Morton, CL, Lock, RB, Tajbakhsh, M, Reynolds, CP, Maris, JM, Keir, ST, Billups, CA, and Smith, MA. "Initial testing of dasatinib by the pediatric preclinical testing program." Pediatr Blood Cancer 50.6 (June 2008): 1198-1206.
PMID
17914733
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
50
Issue
6
Publish Date
2008
Start Page
1198
End Page
1206
DOI
10.1002/pbc.21368

Initial testing of cisplatin by the pediatric preclinical testing program.

BACKGROUND: Cisplatin is one of the most widely used drugs for the treatment of solid tumors in adults and children. Here, we report the activity of cisplatin against the PPTP panels of childhood cancer xenografts. PROCEDURES: Cisplatin was evaluated against 23 cell lines, and 40 xenografts representing brain tumors, neuroblastoma, rhabdoid tumors, sarcoma, Wilms tumor, and acute lymphoblastic leukemia (ALL). The IC(50) concentration in vitro was determined for 96 hr exposure. Solid tumors were grown subcutaneously in immune-deficient mice, and tumor dimensions measured weekly. ALL xenografts were inoculated intravenously and the percent human CD45(+) cells in the peripheral blood determined weekly. The antitumor activity of cisplatin (7 mg/kg administered intraperitoneally on Days 0 and 21) was evaluated using time to event (EFS T/C), tumor growth delay (tumor volume T/C), and objective response measures. RESULTS: The median IC(50) concentration in vitro was 0.87 microM (0.24-4.29 microM), and cisplatin exhibited broad range activity. Cisplatin induced significant differences in EFS distributions compared to controls in 20/28 solid tumors and 4/8 ALL models. Objective responses were observed in 7/28 solid tumor models (25%): partial responses in three rhabdomyosarcomas and one Ewing's sarcoma; complete responses in one rhabdoid tumor and the medulloblastoma; and a maintained complete response in one Wilms tumor. No objective responses were observed in the ALL panel. CONCLUSIONS: Cisplatin exhibits significant antitumor activity against a broad range of solid tumor xenograft models and limited activity against ALL xenografts. This preclinical pattern of activity is generally consistent with cisplatin's clinical activity.

Authors
Tajbakhsh, M; Houghton, PJ; Morton, CL; Kolb, EA; Gorlick, R; Maris, JM; Keir, ST; Wu, J; Reynolds, CP; Smith, MA; Lock, RB
MLA Citation
Tajbakhsh, M, Houghton, PJ, Morton, CL, Kolb, EA, Gorlick, R, Maris, JM, Keir, ST, Wu, J, Reynolds, CP, Smith, MA, and Lock, RB. "Initial testing of cisplatin by the pediatric preclinical testing program." Pediatr Blood Cancer 50.5 (May 2008): 992-1000.
PMID
17554786
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
50
Issue
5
Publish Date
2008
Start Page
992
End Page
1000
DOI
10.1002/pbc.21263

Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program.

BACKGROUND: Rapamycin is a highly specific inhibitor of mTOR, a serine/threonine kinase that controls cap-dependent translation. Here we report the activity of rapamycin against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: Rapamycin was tested against the in vitro panel at concentrations from 0.01 to 100 nM and was tested against the in vivo tumor panels by i.p. administration daily x 5 for 6 consecutive weeks at a dose of 5 mg/kg. RESULTS: Rapamycin variably inhibited growth of the cell lines in the PPTP in vitro panel, with maximal inhibition values ranging from 19% to 85% (median 49%) and a median EC(50) of 0.7 nM. Ten of 23 cell lines achieved at least 50% growth inhibition. Against the in vivo panels, rapamycin induced significant differences in EFS distribution in 27 of 36 solid tumor xenografts and in 5 of 8 ALL xenografts. Using the time to event activity measure, rapamycin had intermediate or high activity against 14 of 31 evaluable solid tumor xenografts and 5 of 8 ALL xenografts. Objective responses were observed in several panels, including: rhabdoid tumor (1PR), rhabdomyosarcoma (2PR), and osteosarcoma (1 maintained CR). Two T-cell ALL xenografts had objective responses (1PR, 1 maintained CR). CONCLUSIONS: Rapamycin demonstrated broad antitumor activity against the PPTP's in vivo tumor panels, with particularly noteworthy activity for selected sarcoma and ALL xenografts. Future work will evaluate the molecular characteristics of responding models and the activity of combinations of rapamycin with other anticancer agents.

Authors
Houghton, PJ; Morton, CL; Kolb, EA; Gorlick, R; Lock, R; Carol, H; Reynolds, CP; Maris, JM; Keir, ST; Billups, CA; Smith, MA
MLA Citation
Houghton, PJ, Morton, CL, Kolb, EA, Gorlick, R, Lock, R, Carol, H, Reynolds, CP, Maris, JM, Keir, ST, Billups, CA, and Smith, MA. "Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program." Pediatr Blood Cancer 50.4 (April 2008): 799-805.
PMID
17635004
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
50
Issue
4
Publish Date
2008
Start Page
799
End Page
805
DOI
10.1002/pbc.21296

Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program.

BACKGROUND: Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: AZD2171 was tested at concentrations from 0.1 nM to 1.0 microM against the in vitro panel and was tested against the in vivo tumor panels using a 6-week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle. RESULTS: One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 microM). Evidence of in vivo antitumor activity (primarily tumor growth delay) was observed in 78% of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6%) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models. CONCLUSIONS: AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti-angiogenesis mechanism of action.

Authors
Maris, JM; Courtright, J; Houghton, PJ; Morton, CL; Gorlick, R; Kolb, EA; Lock, R; Tajbakhsh, M; Reynolds, CP; Keir, ST; Wu, J; Smith, MA
MLA Citation
Maris, JM, Courtright, J, Houghton, PJ, Morton, CL, Gorlick, R, Kolb, EA, Lock, R, Tajbakhsh, M, Reynolds, CP, Keir, ST, Wu, J, and Smith, MA. "Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program." Pediatr Blood Cancer 50.3 (March 2008): 581-587.
PMID
17457854
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
50
Issue
3
Publish Date
2008
Start Page
581
End Page
587
DOI
10.1002/pbc.21232

Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program.

BACKGROUND: Bortezomib is a proteasome inhibitor that has been approved by FDA for the treatment of multiple myeloma and that has completed phase 1 testing in children. The purpose of the current study was to evaluate the antitumor activity of bortezomib against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: Bortezomib was tested against the PPTP in vitro panel at concentrations ranging from 0.1 nM to 1.0 microM and was tested in vivo at a dose of 1 mg/kg for a planned duration of 6 weeks. RESULTS: Bortezomib was uniformly active against the PPTP's in vitro panel, with a median IC(50) of 23 nM and with a steep dose-response curve. The four acute lymphoblastic leukemia (ALL) cell lines had significantly lower IC(50) values compared to the remaining lines of the in vitro panel. Limited in vivo activity was observed for bortezomib against the solid tumor xenografts tested, with one line meeting criteria for intermediate activity for the time to event measure and with the remaining lines showing low activity for this measure. Bortezomib demonstrated in vivo activity against the ALL panel, inducing two complete and two partial responses among seven evaluable lines. CONCLUSIONS: Administered at its MTD in mice, bortezomib demonstrated activity against selected lines of the PPTP's ALL in vivo panel. Further studies are indicated to determine the activity of bortezomib when combined with standard agents to treat childhood ALL.

Authors
Houghton, PJ; Morton, CL; Kolb, EA; Lock, R; Carol, H; Reynolds, CP; Keshelava, N; Maris, JM; Keir, ST; Wu, J; Smith, MA
MLA Citation
Houghton, PJ, Morton, CL, Kolb, EA, Lock, R, Carol, H, Reynolds, CP, Keshelava, N, Maris, JM, Keir, ST, Wu, J, and Smith, MA. "Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program." Pediatr Blood Cancer 50.1 (January 2008): 37-45.
PMID
17420992
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
50
Issue
1
Publish Date
2008
Start Page
37
End Page
45
DOI
10.1002/pbc.21214

Stress and long-term survivors of brain cancer.

INTRODUCTION: Adult brain tumor patients are joining the ranks of cancer survivors in increasing numbers in the United States. As a result, health care providers are faced with new challenges to address the need for psychosocial support in this population. METHODS: Using the Perceived Stress Scale and the National Comprehensive Cancer Network's Distress Thermometer, levels of stress and cancer-related items of concern were assessed in adult long-term survivors of brain cancer. RESULTS: Sixty-one percent of the sample population experienced elevated levels of stress. Scores were not significantly associated with age, gender, treatment status, or tumor grade. Long-term survivors were just as likely to report being stressed (chi(2) = 0.032, NS), while reporting fewer numbers of items of concern (5.02, SD = 3.509), compared to brain tumor patients diagnosed 18 months (M = 6.82, SD = 3.737, t = 2.467, p 0.05). DISCUSSION/CONCLUSION: Despite their long-term survival status, long-term survivors of brain cancer continue to experience elevated levels of stress. Predictors of stress in this population are related to familial, emotional, and practical concerns. While the scientific community continues to examine the specific impact of stress on both the physical and mental outcomes of cancer patients, understanding the sources of stress within cancer populations is key in designing targeted interventions to help patients manage the stress associated with this disease. IMPLICATIONS FOR BRAIN TUMOR SURVIVORS: This study provides a better understanding of the unique needs of long-term survivors of brain cancer. An awareness of the sources and levels of stress experienced by this population could lead to the development of effective supportive care interventions to improve the quality of life of the survivor.

Authors
Keir, ST; Swartz, JJ; Friedman, HS
MLA Citation
Keir, ST, Swartz, JJ, and Friedman, HS. "Stress and long-term survivors of brain cancer." Support Care Cancer 15.12 (December 2007): 1423-1428.
PMID
17609991
Source
pubmed
Published In
Supportive Care in Cancer
Volume
15
Issue
12
Publish Date
2007
Start Page
1423
End Page
1428
DOI
10.1007/s00520-007-0292-1

The pediatric preclinical testing program: description of models and early testing results.

BACKGROUND: The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide. PROCEDURES: Solid tumors were grown subcutaneously in immune-deficient mice and tumor dimensions were measured weekly. ALL xenografts were inoculated intravenously and human CD45-positive cells were enumerated weekly. RESULTS: Vincristine-induced objective responses in 6 of 24 (25%) and cyclophosphamide-induced objective responses in 18 of 28 (64%) solid tumor models. Comparable assessments of high levels of activity for these two agents were obtained using a tumor growth delay (TGD) measure. Both agents induced regressions in each of the ALL models evaluated. CONCLUSIONS: We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity.

Authors
Houghton, PJ; Morton, CL; Tucker, C; Payne, D; Favours, E; Cole, C; Gorlick, R; Kolb, EA; Zhang, W; Lock, R; Carol, H; Tajbakhsh, M; Reynolds, CP; Maris, JM; Courtright, J; Keir, ST; Friedman, HS; Stopford, C; Zeidner, J; Wu, J; Liu, T; Billups, CA; Khan, J; Ansher, S; Zhang, J; Smith, MA
MLA Citation
Houghton, PJ, Morton, CL, Tucker, C, Payne, D, Favours, E, Cole, C, Gorlick, R, Kolb, EA, Zhang, W, Lock, R, Carol, H, Tajbakhsh, M, Reynolds, CP, Maris, JM, Courtright, J, Keir, ST, Friedman, HS, Stopford, C, Zeidner, J, Wu, J, Liu, T, Billups, CA, Khan, J, Ansher, S, Zhang, J, and Smith, MA. "The pediatric preclinical testing program: description of models and early testing results." Pediatr Blood Cancer 49.7 (December 2007): 928-940.
PMID
17066459
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
49
Issue
7
Publish Date
2007
Start Page
928
End Page
940
DOI
10.1002/pbc.21078

Levels of stress and intervention preferences of caregivers of brain tumor patients.

The purpose of this pilot study was to assess the level of stress experienced by caregivers of brain tumor patients and to examine both their interest in and preferences for stress reduction programs. Using a convenience sample of 60 adult caregivers, we distributed a study questionnaire that examined the caregivers' level of stress, beliefs, past experiences, and preferences in regard to stress reduction programs. A majority of respondents reported elevated stress levels (72%), believed that stress reduction techniques can help reduce stress (87%), and were interested in learning about programs to reduce stress (81%). Overall, most participants wanted to receive information about stress reduction programs (65%) and were interested in programs such as exercise (73%) and massage (66%) as methods to reduce stress. Concerning mode and format preferences, 46% indicated that they could participate in a program at least twice a week, and 70% could participate in a program for an interval of 30 minutes or more. Ninety percent of the caregivers preferred programs that could be undertaken in their own homes either alone (37%), with a spouse (35%), or with the brain tumor patient for whom they were providing care (28%). Overall, 44% of caregivers sampled were interested in participating in the various stress reduction programs presented to them in this study. These data provide further evidence that caregivers experience elevated levels of stress and are willing to learn more about and participate in programs to reduce stress.

Authors
Keir, ST
MLA Citation
Keir, ST. "Levels of stress and intervention preferences of caregivers of brain tumor patients." Cancer Nurs 30.6 (November 2007): E33-E39.
PMID
18025910
Source
pubmed
Published In
Cancer Nursing
Volume
30
Issue
6
Publish Date
2007
Start Page
E33
End Page
E39
DOI
10.1097/01.NCC.0000300174.18584.f9

Program preferences to reduce stress in caregivers of patients with brain tumors.

Providing care for patients with cancer places caregivers at risk for experiencing elevated levels of stress. Caregivers of patients with brain tumors may be at increased risk because of the multifaceted needs of this patient population. As such, the authors sought to determine caregiver preferences toward various types of stress-reduction programs for a population of stressed caregivers. This information provides valuable insight for researchers designing studies to address the experiences of stressed caregivers.

Authors
Swartz, JJ; Keir, ST
MLA Citation
Swartz, JJ, and Keir, ST. "Program preferences to reduce stress in caregivers of patients with brain tumors." Clin J Oncol Nurs 11.5 (October 2007): 723-727.
PMID
17962180
Source
pubmed
Published In
Clinical Journal of Oncology Nursing
Volume
11
Issue
5
Publish Date
2007
Start Page
723
End Page
727
DOI
10.1188/07.CJON.723-727

The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion.

Monotherapies have proven largely ineffective for the treatment of glioblastomas, suggesting that increased patient benefit may be achieved by combining therapies. Two protumorigenic pathways known to be active in glioblastoma include RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/target of rapamycin (TOR). We investigated the efficacy of a combination of novel low molecular weight inhibitors LBT613 and RAD001 (everolimus), which were designed to target RAF and TOR, respectively. LBT613 decreased phosphorylation of extracellular signal-regulated kinase 1 and 2, downstream effectors of RAF, in a human glioma cell line. RAD001 resulted in decreased phosphorylation of the TOR effector S6. To determine if targeting RAF and TOR activities could result in decreased protumorigenic glioma cellular behaviors, we evaluated the abilities of LBT613 and RAD001 to affect the proliferation, migration, and invasion of human glioma cells. Treatment with either LBT613 or RAD001 alone significantly decreased the proliferation of multiple human glioma cell lines. Furthermore, LBT613 and RAD001 in combination synergized to decrease glioma cell proliferation in association with G(1) cell cycle arrest. Glioma invasion is a critical contributor to tumor malignancy. The combination of LBT613 and RAD001 inhibited the invasion of human glioma cells through Matrigel to a greater degree than treatment with either drug alone. These data suggest that the combination of LBT613 and RAD001 reduces glioma cell proliferation and invasion and support examination of the combination of RAF and TOR inhibitors for the treatment of human glioblastoma patients.

Authors
Hjelmeland, AB; Lattimore, KP; Fee, BE; Shi, Q; Wickman, S; Keir, ST; Hjelmeland, MD; Batt, D; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Hjelmeland, AB, Lattimore, KP, Fee, BE, Shi, Q, Wickman, S, Keir, ST, Hjelmeland, MD, Batt, D, Bigner, DD, Friedman, HS, and Rich, JN. "The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion." Mol Cancer Ther 6.9 (September 2007): 2449-2457.
PMID
17766837
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
6
Issue
9
Publish Date
2007
Start Page
2449
End Page
2457
DOI
10.1158/1535-7163.MCT-07-0155

Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice.

VNP40101M, or 1,2-bis(methylsulfonyl)-1-(2-choloroethyl)-2-(methylamino)carbonylhydrazine (Cloretazine), is a bifunctional prodrug that belongs to a class of DNA-modifying agents-the sulfonylhydrazines-that has been synthesized and been shown to have activity against a wide spectrum of xenografts. The current study was designed to assess the activity of VNP40101M administered at a dose of 18 mg/kg daily for five days against a panel of human adult and pediatric CNS tumors growing subcutaneously or intracranially in athymic nude mice. The results demonstrated statistically significant (p < 0.05) growth delays of 15.0, 8.3, 51.0, 60+, 60+, and 60+ days in subcutaneous xenografts derived from childhood glioblastoma multiforme (D-456 MG), childhood ependymoma (D-528 EP and D-612 EP), childhood medulloblastoma (D-425 MED), and adult malignant glioma (D-245 MG and D-54 MG), respectively, with corresponding tumor regressions in 10 of 10, 4 of 10, 8 of 10, 9 of 10, 9 of 10, and 10 of 10 treated mice, respectively. Delayed toxicity was seen more than 60 days after treatment, with 23 deaths in 100 treated animals, despite a median weight loss of only 0.06%. In mice bearing intracranial D-245 MG xenografts, treatment with VNP40101M at a dose of 18 mg/kg daily for five days produced a 50% increase in median survival compared with controls. Additional experiments conducted against subcutaneous D-245 MG xenografts by using reduced doses of 13.5 or 9.0 mg/kg daily for five days demonstrated tumor growth delays of 82.2 and 53.5 days, with corresponding tumor regressions in 8 of 9 and 9 of 10 treated mice, respectively (all values, p < 0.001), with one toxic death. These findings suggest that VNP40101M is active in the treatment of a wide range of human central nervous system tumors and warrants translation to the clinic.

Authors
Badruddoja, MA; Keir, ST; King, I; Zeidner, J; Vredenburgh, JJ; Muhlbaier, LH; Bigner, DD; Friedman, HS
MLA Citation
Badruddoja, MA, Keir, ST, King, I, Zeidner, J, Vredenburgh, JJ, Muhlbaier, LH, Bigner, DD, and Friedman, HS. "Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice." Neuro Oncol 9.3 (July 2007): 240-244.
PMID
17522334
Source
pubmed
Published In
Neuro-Oncology
Volume
9
Issue
3
Publish Date
2007
Start Page
240
End Page
244
DOI
10.1215/15228517-2007-011

A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth.

Glioblastomas are highly lethal cancers that resist current therapies. Novel therapies under development target molecular mechanisms that promote glioblastoma growth. In glioblastoma patient specimens, the non-receptor tyrosine kinase focal adhesion kinase (FAK) is overexpressed. Upon growth factor receptor stimulation or integrin engagement, FAK is activated by phosphorylation on critical tyrosine residues. Activated FAK initiates a signal transduction cascade which promotes glioma growth and invasion by increasing cellular adhesion, migration, invasion, and proliferation. We find that human glioma cell lines express different levels of total FAK protein and activating phosphorylation of tyrosine residues Tyr397, Tyr861, and Tyr925. As all glioma cell lines examined expressed phosphorylated FAK, we examined the efficacy of a novel low-molecular weight inhibitor of FAK, TAE226, against human glioma cell lines. TAE226 inhibited the phosphorylation of FAK as well as the downstream effectors AKT, extracellular signal-related kinase, and S6 ribosomal protein in multiple glioma cell lines. TAE226 induced a concentration-dependent decrease in cellular proliferation with an associated G(2) cell cycle arrest in every cell line and an increase in apoptosis in a cell-line-specific manner. TAE226 also decreased glioma cell adhesion, migration, and invasion through an artificial extracellular matrix. Together, these data demonstrate the potential benefit of TAE226 for glioma therapy.

Authors
Shi, Q; Hjelmeland, AB; Keir, ST; Song, L; Wickman, S; Jackson, D; Ohmori, O; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Shi, Q, Hjelmeland, AB, Keir, ST, Song, L, Wickman, S, Jackson, D, Ohmori, O, Bigner, DD, Friedman, HS, and Rich, JN. "A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth." Mol Carcinog 46.6 (June 2007): 488-496.
PMID
17219439
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
46
Issue
6
Publish Date
2007
Start Page
488
End Page
496
DOI
10.1002/mc.20297

Using the theory of planned behavior to understand the determinants of exercise intention in patients diagnosed with primary brain cancer.

The purpose of the present study was to examine the demographic, medical, and social cognitive determinants of exercise intentions in a institution-based cohort of primary brain tumor patients. Using a cross-sectional survey, 100 primary brain tumor patients completed a mailed survey that assessed medical and demographic characteristics, past exercise behavior using the Godin Leisure Time Exercise Questionnaire (GLTEQ), and social cognitive beliefs towards exercise using Aizen's theory of planned behavior (TPB; i.e. intention, perceived behavioral control, subjective norm, affective and instrumental attitude). Descriptive statistics indicated that participants had positive social cognitive beliefs towards exercise. In support of the tenets of the TPB, we found moderate to large (>0.40) positive correlations between the majority of TPB constructs. Moreover, the TPB constructs combined to explain 32% of the variance in exercise intentions with affective attitude (beta = 0.24; p = 0.020) and perceived behavioral control (beta = 0.36; p<0.001) being the most important determinants. Except past exercise behavior, medical and demographic variables were not consistently correlated with any TPB constructs. Finally, participant's gender and body mass index influenced the association between instrumental attitude and exercise intention with male and overweight/obese patients (> or =25 kg/m(2)) considering the health benefits of exercise to be more important than their female and normal weight (<25 kg/m(2)) counterparts. Information gained from this study suggests that the TPB is a useful framework to design and implement theoretically based interventions to promote exercise in primary brain cancer patients.

Authors
Jones, LW; Guill, B; Keir, ST; Carter, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, LW, Guill, B, Keir, ST, Carter, K, Friedman, HS, Bigner, DD, and Reardon, DA. "Using the theory of planned behavior to understand the determinants of exercise intention in patients diagnosed with primary brain cancer." Psychooncology 16.3 (March 2007): 232-240.
PMID
16929468
Source
pubmed
Published In
Psycho-Oncology
Volume
16
Issue
3
Publish Date
2007
Start Page
232
End Page
240
DOI
10.1002/pon.1077

Exercise interest and preferences among patients diagnosed with primary brain cancer.

GOALS OF THE WORK: The purpose of the present investigation was to examine the interest and exercise preferences of an institution-based sample of brain tumor patients. Secondary aims were to examine potential differences in participant's interest and preferences by exercise behavior and select demographic/medical variables. MATERIALS AND METHODS: Using a cross-sectional design, 106 brain tumor patients (age range, 32 to 83 years) who received treatment at the Preston Robert Tisch Brain Tumor Center (BTC) at Duke completed a questionnaire that assessed self-reported exercise behavior, exercise interest and preferences during active and off-treatment periods. MAIN RESULTS: For exercise program preferences, participants were significantly more interested and felt more capable of participating in an exercise program following compared to during adjuvant therapy. Approximately equal proportions of brain tumor patients preferred to exercise at home with their spouse or other family members. These preferences were consistent across both cancer treatment-related time periods. For exercise information preferences, a higher proportion of respondents preferred receiving information via technologically based approaches (i.e., Internet, CD-ROM, and mailed correspondence) compared with more traditional methods (i.e., mail or face-to-face counseling). Chi-square analyses revealed that a small number of exercise program and information preferences were modified by exercise, medical, and demographic variables. CONCLUSIONS: Brain tumor patients may have unique and varied preferences compared with other cancer populations. Incorporating patient's preferences into rehabilitation programs and clinical exercise investigations may optimize the potential benefits of this modality for patients with neurologic malignancies.

Authors
Jones, LW; Guill, B; Keir, ST; Carter, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, LW, Guill, B, Keir, ST, Carter, K, Friedman, HS, Bigner, DD, and Reardon, DA. "Exercise interest and preferences among patients diagnosed with primary brain cancer." Support Care Cancer 15.1 (January 2007): 47-55.
PMID
16819629
Source
pubmed
Published In
Supportive Care in Cancer
Volume
15
Issue
1
Publish Date
2007
Start Page
47
End Page
55
DOI
10.1007/s00520-006-0096-8

Stress and intervention preferences of patients with brain tumors.

BACKGROUND: Despite advances in diagnosis, treatment, and management of brain tumors, a brain tumor (BT) can significantly disrupt a person's life and create stress. To design effective stress reduction interventions, it is essential to have an understanding of the beliefs, past experiences, and preferences concerning stress reduction techniques and programs among patients with BTs. MATERIALS AND METHODS: Using a convenience sample, 60 adult patients with primary BTs completed the study questionnaire. Demographic information and patient preferences were collected using self-reported measures, medical information was collected via medical chart review, and stress was assessed using Perceived Stress Scale. RESULTS: Sixty-three percent of the population sampled experienced elevated levels of stress. Eighty-six percent wanted to learn about techniques to reduce stress and 78% believed stress reduction techniques can help reduce stress. However, only 56% indicated they would be able to participate in a stress reduction program twice a week and only 40% of the sample wanted to participate in the various stress reduction programs presented to them in this study. Furthermore, only 26% of the sample actually wanted to receive information about stress reduction programs and only 25% would participate in programs using the various modes presented. CONCLUSION: The results of this study clearly indicate that patients with BTs experience stress. Furthermore, the data is encouraging in regard to the patients' desire to learn about stress reduction techniques. However, the lack of interest in actually receiving information and the inability to envision themselves participating in programs present a major challenge.

Authors
Keir, ST; Guill, AB; Carter, KE; Friedman, HS
MLA Citation
Keir, ST, Guill, AB, Carter, KE, and Friedman, HS. "Stress and intervention preferences of patients with brain tumors." Support Care Cancer 14.12 (December 2006): 1213-1219.
PMID
16733656
Source
pubmed
Published In
Supportive Care in Cancer
Volume
14
Issue
12
Publish Date
2006
Start Page
1213
End Page
1219
DOI
10.1007/s00520-006-0087-9

Differential levels of stress in caregivers of brain tumor patients--observations from a pilot study.

OBJECTIVE: Caregivers of patients with brain tumors (BT) experience elevated levels of stress. Using pilot data, we sought to determine which caregivers are at risk for experiencing elevated levels of stress based on caregiver-demographic and patient-medical information. METHODS: Using a convenience sample of 60 caregivers, participants were asked to complete the Perceived Stress Scale and to provide demographic information. The Perceived Stress Scale is a 10-item scale designed to measure the degree to which situations in life are perceived as stressful. Demographic information was collected using self-reported measures. Medical data concerning tumor grade of patient were obtained from most recent medical note. Data for study were standardized using z-scores and analyzed using SPSS software. RESULTS: Seventy-two percent (n=43) of caregivers reported experiencing elevated levels of stress within the last 30 days. Thirty-five percent (n=21) of the sample scored at least one standard deviation above the mean. A statistical trend [F(1, 57)=3.12, p=0.08] exists between caregiver stress and tumor grade of patients for which they are providing care. CONCLUSIONS: Caregivers of patients with BT experience significant stress. Furthermore, this data provide an indication of the profound levels of stress these caregivers experience. Caregivers of patients with grade I/II tumors are at increased risk for experiencing stress. Younger caregiver age and higher levels of education were also found to correlate to higher levels of stress.

Authors
Keir, ST; Guill, AB; Carter, KE; Boole, LC; Gonzales, L; Friedman, HS
MLA Citation
Keir, ST, Guill, AB, Carter, KE, Boole, LC, Gonzales, L, and Friedman, HS. "Differential levels of stress in caregivers of brain tumor patients--observations from a pilot study." Support Care Cancer 14.12 (December 2006): 1258-1261.
PMID
16775683
Source
pubmed
Published In
Supportive Care in Cancer
Volume
14
Issue
12
Publish Date
2006
Start Page
1258
End Page
1261
DOI
10.1007/s00520-006-0090-1

AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma.

Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.

Authors
Sathornsumetee, S; Hjelmeland, AB; Keir, ST; McLendon, RE; Batt, D; Ramsey, T; Yusuff, N; Rasheed, BKA; Kieran, MW; Laforme, A; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Sathornsumetee, S, Hjelmeland, AB, Keir, ST, McLendon, RE, Batt, D, Ramsey, T, Yusuff, N, Rasheed, BKA, Kieran, MW, Laforme, A, Bigner, DD, Friedman, HS, and Rich, JN. "AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma." Cancer Res 66.17 (September 1, 2006): 8722-8730.
PMID
16951188
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
17
Publish Date
2006
Start Page
8722
End Page
8730
DOI
10.1158/0008-5472.CAN-06-0284

Patterns of exercise across the cancer trajectory in brain tumor patients.

BACKGROUND: Exercise may represent a supportive intervention that may complement existing neurooncologic therapies and address a multitude of therapy-induced debilitating side effects in patients with brain tumors. Given the limited evidence, the authors conducted a survey to examine the exercise patterns of brain tumor patients across the cancer trajectory. METHODS: Using a cross-sectional design, 386 brain tumor patients who received treatment at the Brain Tumor Center at Duke University were sent a questionnaire that assessed self-reported exercise behavior prior to diagnosis, during adjuvant therapy, and after the completion of therapy. RESULTS: The response rate was 28% (106 of 383 patients). Descriptive analyses indicated that 42%, 38%, and 41% of participants, respectively, met national exercise prescription guidelines prior to diagnosis, during treatment, and after the completion of adjuvant therapy. Repeated measures analyses indicated no significant changes in the majority of exercise behavior outcomes over the cancer trajectory. However, exploratory analyses indicated that males and younger participants may be at the greatest risk of reducing exercise levels after a brain tumor diagnosis. These analyses remained unchanged after controlling for relevant demographic and medical covariates. CONCLUSIONS: A relatively high percentage of brain tumor patients are exercising at recommended levels across the cancer trajectory. Moreover, these patients have unique exercise patterns that may be modified by select demographic variables. This preliminary study provides important informative data for future studies examining the potential role of exercise in patients diagnosed with neurologic malignancies.

Authors
Jones, LW; Guill, B; Keir, ST; Carter B S, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, LW, Guill, B, Keir, ST, Carter B S, K, Friedman, HS, Bigner, DD, and Reardon, DA. "Patterns of exercise across the cancer trajectory in brain tumor patients." Cancer 106.10 (May 15, 2006): 2224-2232.
PMID
16586497
Source
pubmed
Published In
Cancer
Volume
106
Issue
10
Publish Date
2006
Start Page
2224
End Page
2232
DOI
10.1002/cncr.21858

ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.

PURPOSE: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. EXPERIMENTAL DESIGN: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. RESULTS: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. CONCLUSIONS: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

Authors
Rich, JN; Sathornsumetee, S; Keir, ST; Kieran, MW; Laforme, A; Kaipainen, A; McLendon, RE; Graner, MW; Rasheed, BKA; Wang, L; Reardon, DA; Ryan, AJ; Wheeler, C; Dimery, I; Bigner, DD; Friedman, HS
MLA Citation
Rich, JN, Sathornsumetee, S, Keir, ST, Kieran, MW, Laforme, A, Kaipainen, A, McLendon, RE, Graner, MW, Rasheed, BKA, Wang, L, Reardon, DA, Ryan, AJ, Wheeler, C, Dimery, I, Bigner, DD, and Friedman, HS. "ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors." Clin Cancer Res 11.22 (November 15, 2005): 8145-8157.
PMID
16299247
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
22
Publish Date
2005
Start Page
8145
End Page
8157
DOI
10.1158/1078-0432.CCR-05-0319

Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft.

Temozolomide is a DNA-methylating agent used in the treatment of malignant gliomas. In this study, we have examined if inhibition of poly(ADP-ribose) polymerase (PARP) could increase the cytotoxicity of temozolomide, particularly in cells deficient in DNA mismatch repair. Athymic mice, transplanted with mismatch repair-proficient [D-245 MG] or deficient [D-245 MG (PR)] xenografts, were treated with a combination of temozolomide and the PARP inhibitor, INO-1001. For the tumors deficient in mismatch repair, the most effective dose of INO-1001 was found to be 150 mg/kg, given i.p. thrice at 4-hour intervals with the first injection in combination with 262.5 mg/kg temozolomide (0.75 LD(10)). This dose of temozolomide by itself induced no partial regressions and a 4-day growth delay. In two separate experiments, the combination therapy increased the growth delay by 21.6 and 9.7 days with partial regressions observed in four of eight and three of nine mice, respectively. The addition of INO-1001 had a more modest, yet statistically significant, increase in tumor growth delay in the mismatch repair-proficient xenografts. In these experiments, mice were treated with a lower amount of temozolomide (88 mg/kg), which resulted in growth delays of 43.1 and 39.2 days. When the temozolomide treatment was in combination with 200 mg/kg INO-1001, there was an increase in growth delay to 48.9 and 45.7 days, respectively. These results suggest that inhibition of PARP may increase the efficacy of temozolomide in the treatment of malignant gliomas, particularly in tumors deficient in DNA mismatch repair.

Authors
Cheng, CL; Johnson, SP; Keir, ST; Quinn, JA; Ali-Osman, F; Szabo, C; Li, H; Salzman, AL; Dolan, ME; Modrich, P; Bigner, DD; Friedman, HS
MLA Citation
Cheng, CL, Johnson, SP, Keir, ST, Quinn, JA, Ali-Osman, F, Szabo, C, Li, H, Salzman, AL, Dolan, ME, Modrich, P, Bigner, DD, and Friedman, HS. "Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft." Mol Cancer Ther 4.9 (September 2005): 1364-1368.
PMID
16170028
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
4
Issue
9
Publish Date
2005
Start Page
1364
End Page
1368
DOI
10.1158/1535-7163.MCT-05-0128

Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition.

Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.

Authors
Goudar, RK; Shi, Q; Hjelmeland, MD; Keir, ST; McLendon, RE; Wikstrand, CJ; Reese, ED; Conrad, CA; Traxler, P; Lane, HA; Reardon, DA; Cavenee, WK; Wang, X-F; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Goudar, RK, Shi, Q, Hjelmeland, MD, Keir, ST, McLendon, RE, Wikstrand, CJ, Reese, ED, Conrad, CA, Traxler, P, Lane, HA, Reardon, DA, Cavenee, WK, Wang, X-F, Bigner, DD, Friedman, HS, and Rich, JN. "Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition." Mol Cancer Ther 4.1 (January 2005): 101-112.
PMID
15657358
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
4
Issue
1
Publish Date
2005
Start Page
101
End Page
112

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors

Irinotecan is a water-soluble derivative of camptothecin, an alkylator originally extracted from the Chinese tree Camptotheca acuminata. Laboratory studies have demonstrated the activity of irinotecan in a broad panel of pediatric and adult central nervous system tumor xenografts in athymic nude mice. These studies led to a Phase II trial that confirmed the activity of this agent in the treatment of recurrent malignant glioma. Subsequent laboratory studies have demonstrated that a combination of irinotecan (CPT-11) and alkylating agents, particularly 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), increases antitumor effects to a level well above the additive effects of the individual agents. These laboratory studies generated a recently completed Phase I trial of CPT-11 + BCNU, which now is being evaluated in a formal Phase II trial for adults with newly diagnosed or recurrent malignant glioma. More recent studies have demonstrated similar interaction between CPT-11 and temozolomide and have led to a Phase I trial of these agents in the treatment of adults with malignant glioma. Studies currently are addressing the role of O6-alkylguanine-DNA alkyltransferase (AGT) in reducing the benefits of combining CPT-11 with temozolomide and the potential therapeutic gain from utilizing an inhibitor of AGT. © 2003 American Cancer Society.

Authors
Friedman, HS; Keir, ST; Houghton, PJ
MLA Citation
Friedman, HS, Keir, ST, and Houghton, PJ. "The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors." Cancer 97.9 SUPPL. (2003): 2359-2362.
Source
scival
Published In
Cancer
Volume
97
Issue
9 SUPPL.
Publish Date
2003
Start Page
2359
End Page
2362

O6-benzylguanine-mediated enhancement of chemotherapy.

We have previously demonstrated (A. E. Pegg, Cancer Res., 50: 6119-6129, 1990) that O6-benzylguanine (O6-BG) enhances nitrosourea, temozolomide, and cyclophosphamide activity in malignant glioma xenografts growing in athymic nude mice. More recently, we have demonstrated (V. J. Patel et al., Clin. Cancer Res., 6: 4154-4157, 2000; P. Pourquier et al., Cancer Res., 61: 53-58, 2001) that the combination of temozolomide plus irinotecan (CPT-11) displays a schedule-dependent enhancement of antitumor activity secondary to trapping of topoisomerase I by O6-methylguanine residues in DNA. These studies suggested that there might be favorable therapeutic interactions between O6-BG and combinations of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus cyclophosphamide or temozolomide plus CPT-11, respectively. Our present results indicate that the combination of cyclophosphamide plus BCNU plus O6-BG produces growth delays modestly-to-markedly-superior to combinations of cyclophosphamide with BCNU. Although the combination of temozolomide and CPT-11 reveals a marked increase in activity compared with either agent used alone, the addition of O6-BG to this combination dramatically increased the growth delay of the O6-alkylguanine-DNA alkyltransferase (AGT)-positive malignant glioma D-456 MG. These results suggest that a Phase I trial of CPT-11 plus temozolomide plus O6-BG in AGT-positive tumors may be an important intervention to maximize the therapeutic benefits of the combination of CPT-11 and temozolomide.

Authors
Friedman, HS; Keir, S; Pegg, AE; Houghton, PJ; Colvin, OM; Moschel, RC; Bigner, DD; Dolan, ME
MLA Citation
Friedman, HS, Keir, S, Pegg, AE, Houghton, PJ, Colvin, OM, Moschel, RC, Bigner, DD, and Dolan, ME. "O6-benzylguanine-mediated enhancement of chemotherapy." Mol Cancer Ther 1.11 (September 2002): 943-948.
PMID
12481416
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
1
Issue
11
Publish Date
2002
Start Page
943
End Page
948

Activity of irofulven (6-hydroxymethylacylfulvene) in the treatment of glioblastoma multiforme-derived xenografts in athymic mice.

PURPOSE: This study was conducted to define the activity of irofulven in the treatment of a series of xenografts derived from human glioblastoma multiforme growing subcutaneously and intracranially in athymic nude mice. METHODS: Athymic mice bearing subcutaneous or intracranial tumors were treated with irofulven at a 10% lethal dose with responses compared to tumor-bearing mice treated with drug vehicle. RESULTS: Irofulven was active against all tumor lines tested with growth delays ranging from 5.6 to 81.6 days (all values statistically significant, P < or = 0.001). Irofulven also produced a statistically significant (P < or = 0.001) increase in the median survival of mice bearing D-456 intracranial xenografts with a 162% increase in median survival. CONCLUSIONS: Irofulven is active in a spectrum of human glioblastoma multiforme-derived xenografts and evaluation in patients with this neoplasm is warranted.

Authors
Friedman, HS; Keir, ST; Houghton, PJ; Lawless, AA; Bigner, DD; Waters, SJ
MLA Citation
Friedman, HS, Keir, ST, Houghton, PJ, Lawless, AA, Bigner, DD, and Waters, SJ. "Activity of irofulven (6-hydroxymethylacylfulvene) in the treatment of glioblastoma multiforme-derived xenografts in athymic mice." Cancer Chemother Pharmacol 48.5 (November 2001): 413-416.
PMID
11761460
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
48
Issue
5
Publish Date
2001
Start Page
413
End Page
416
DOI
10.1007/s002800100358

Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyla-2-hydroxyl) ethylamino-12,13-dihydro-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]-pyrrolo[3,4-c]-carbazole-5,7(6H)-dione]] against pediatric and adult central nervous system tumor xenografts.

PURPOSE: The in vivo antitumor activity of a novel topoisomerase I inhibitor, J-107088, was tested in athymic nude mice bearing subcutaneous or intracranial pediatric and adult malignant CNS tumor-derived xenografts. METHODS: J-107088 was administered to animals on days 1-5 and 8-12 via intraperitoneal injection at a dose of 54 mg/kg (162 mg/m2) per day in 10% dimethyl sulfoxide in 0.9% saline. The xenografts evaluated were derived from a childhood glioblastoma multiforme (D-456 MG), a childhood medulloblastoma (D-341 MED), an adult anaplastic astrocytoma (D-54 MG), an adult glioblastoma multiforme (D-245 MG), and a procarbazine-resistant subline of D-245 MG [D-245 MG (PR)]. RESULTS: J-107088 produced regressions and significant growth inhibition in all five of the xenograft lines growing subcutaneously. Growth delays ranged from 7.6 days with D-245 MG to 62.1 days with D-456 MG (P < 0.001). J-107088 also produced an 83% increase in survival in mice bearing intracranial D-456 MG (P < 0.001). CONCLUSION: These results indicate that J-107088 may be active in the treatment of childhood and adult malignant brain tumors and provide the rationale for initiation of clinical trials with this agent.

Authors
Cavazos, CM; Keir, ST; Yoshinari, T; Bigner, DD; Friedman, HS
MLA Citation
Cavazos, CM, Keir, ST, Yoshinari, T, Bigner, DD, and Friedman, HS. "Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyla-2-hydroxyl) ethylamino-12,13-dihydro-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]-pyrrolo[3,4-c]-carbazole-5,7(6H)-dione]] against pediatric and adult central nervous system tumor xenografts." Cancer Chemother Pharmacol 48.3 (September 2001): 250-254.
PMID
11592348
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
48
Issue
3
Publish Date
2001
Start Page
250
End Page
254

Acyl derivatives of demethylpenclomedine, an antitumor-active, non-neurotoxic metabolites of penclomedine.

PURPOSE: The purpose of this investigation was to compare the antitumor activities of a series of acyl derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma metabolite of penclomedine (PEN) observed to be an active antitumor agent in vivo and non-neurotoxic in a rat model with that of DM-PEN. METHODS: Acyl derivatives were prepared from DM-PEN and evaluated in vivo against human MX-1 breast tumor xenografts implanted subcutaneously (s.c.) or intracerebrally (i.c.). Several derivatives were also evaluated against other human tumor xenografts and murine P388 leukemia cell lines. RESULTS: Several of the acyl derivatives were found to be superior to DM-PEN against MX-1, human ZR-75-1 breast tumor, human U251 CNS tumor and the P388 leukemia parent cell line and lines resistant to cyclophosphamide and carmustine. 4-Demethyl-4-methoxyacetylpenclomedine showed inferior activity to current clinical brain tumor drugs against a glioma cell line, superior activity to temozolomide and procarbazine against the derived mismatch repair-deficient cell line, and superior activity to cyclophosphamide and carmustine but inferior activity to temozolomide against two ependymoma cell lines, all of which were implanted s.c. CONCLUSION: Proposed mechanisms of activation and action of DM-PEN and the acyl derivatives support the potential clinical superiority of the acyl derivatives.

Authors
Struck, RF; Tiwari, A; Friedman, HS; Keir, S; Morgan, LR; Waud, WR
MLA Citation
Struck, RF, Tiwari, A, Friedman, HS, Keir, S, Morgan, LR, and Waud, WR. "Acyl derivatives of demethylpenclomedine, an antitumor-active, non-neurotoxic metabolites of penclomedine." Cancer Chemother Pharmacol 48.1 (July 2001): 47-52.
PMID
11488524
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
48
Issue
1
Publish Date
2001
Start Page
47
End Page
52

Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice.

PURPOSE: Camptothecins have emerged as an important new class of antitumor drugs. Camptothecin derivatives such as CPT-11 and topotecan are commercially available and approved for the treatment of colorectal (CPT-11) and ovarian and small-cell lung cancer (topotecan). This study was designed to test the efficacy of karenitecin, a novel highly lipophilic camptothecin derivative, against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies growing in athymic nude mice. METHODS: Xenografts evaluated were derived from childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D-341 MED, D-487 MED), and ependymomas (D-528 EP, D-612 EP), as well as sublines with demonstrated resistance to procarbazine (D-245 MG (PR)) and busulfan (D-456 (BR)). In replicate experiments, karenitecin was given at 1.0 mg/kg per dose via intraperitoneal injection for a period of 10 consecutive days, which is the dosage lethal to 10% of treated animals. RESULTS: Karenitecin produced statistically significant (P < or = 0.001) growth delays in all subcutaneous xenografts tested, including the sublines resistant to procarbazine and busulfan. Growth delays ranged from 12.1 days in D-456 MG (BR) to 90+ days in D-212 MG and D-341 MED. Karenitecin also produced statistically significant (P < or = 0.001) increases in survival of animals bearing D-341 MED intracranial xenografts (69% increase) and those bearing D-456 MG xenografts (62% increase). CONCLUSION: These preclinical studies confirm that karenitecin is active against human central nervous system xenografts and should undergo clinical evaluation in patients with malignant central nervous system tumors.

Authors
Keir, ST; Hausheer, F; Lawless, AA; Bigner, DD; Friedman, HS
MLA Citation
Keir, ST, Hausheer, F, Lawless, AA, Bigner, DD, and Friedman, HS. "Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice." Cancer Chemother Pharmacol 48.1 (July 2001): 83-87.
PMID
11488529
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
48
Issue
1
Publish Date
2001
Start Page
83
End Page
87

Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft.

Temozolomide, an imidazole tetrazinone, and CPT-11, a camptothecin derivative, have previously been shown to have anti-central nervous system tumor activity in laboratory and clinical studies. The current experiments were designed to evaluate the activity of temozolomide plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c. in athymic nude mice. The initial schedule of i.p. drug administration was temozolomide at 0.1 LD10 on day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14. The combination of these two agents produced greater than additive activity against D-54 MG. This enhanced activity was maintained when the initial administration of CPT-11 was delayed to day 3 or day 5. However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the single dose schedule) followed by temozolomide (0.1 LD10) 5 h, 3 days, or 5 days later, the enhancement of activity was substantially reduced. These results demonstrate that the combination of temozolomide plus CPT-11 displays a schedule-dependent enhancement of antitumor activity, suggest a mechanistic explanation for the enhanced activity, and provide the rationale for a Phase I trial of this regimen.

Authors
Patel, VJ; Elion, GB; Houghton, PJ; Keir, S; Pegg, AE; Johnson, SP; Dolan, ME; Bigner, DD; Friedman, HS
MLA Citation
Patel, VJ, Elion, GB, Houghton, PJ, Keir, S, Pegg, AE, Johnson, SP, Dolan, ME, Bigner, DD, and Friedman, HS. "Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft." Clin Cancer Res 6.10 (October 2000): 4154-4157.
PMID
11051270
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
6
Issue
10
Publish Date
2000
Start Page
4154
End Page
4157

O6-benzylguanine-mediated enhancement of nitrosourea activity in Mer- central nervous system tumor xenografts--implications for clinical trials.

PURPOSE: To evaluate the role of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus O6-benzylguanine (O6-BG) in the treatment of both Mer+ and Mer- tumors. METHODS: The effect of pretreatment with O6-BG on the activity of BCNU against Mer- human central nervous tumor xenografts D-54 MG and D-245 MG was evaluated in athymic nude mice. RESULTS: BCNU (1.0 LD10; dose lethal to 10% of treated animals) produced growth delays of 8.9 days and 7.5 days and tumor regressions in six of ten and one of nine animals against D-54 MG, which was derived from a human malignant glioma xenograft. Dose reduction of BCNU to 0.38 LD10 eliminated antitumor activity. The combination of BCNU (0.38 LD10) plus O6-BG produced growth delays of 8.8 days and 7.9 days, with tumor regressions in four of ten and two of nine animals, respectively. BCNU (1.0 LD10) produced a growth delay of 49.8 days and ten of ten tumor regressions against D-245 MG, which was derived from a glioblastoma multiforme. BCNU (0.38 LD10) produced a growth delay of 19.4 days, with nine of ten tumor regressions. The combination of BCNU (0.38 LD10) plus O6-BG produced a growth delay of 65.7 days and seven of eight tumor regressions. CONCLUSION: These results suggest that the combination of BCNU plus O6-BG may be a rational intervention for both Mer+ as well as Mer- tumors.

Authors
Keir, ST; Dolan, ME; Pegg, AE; Lawless, A; Moschel, RC; Bigner, DD; Friedman, HS
MLA Citation
Keir, ST, Dolan, ME, Pegg, AE, Lawless, A, Moschel, RC, Bigner, DD, and Friedman, HS. "O6-benzylguanine-mediated enhancement of nitrosourea activity in Mer- central nervous system tumor xenografts--implications for clinical trials." Cancer Chemother Pharmacol 45.6 (2000): 437-440.
PMID
10854129
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
45
Issue
6
Publish Date
2000
Start Page
437
End Page
440

Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts.

PURPOSE: To further evaluate the activity of irinotecan (CPT-11) plus 1,3-bis-(chloroethyl)-1-nitrosourea (BCNU) in the treatment of central nervous system tumor-derived xenografts in athymic nude mice. METHODS: We report studies evaluating the schedule-dependence of this regimen in the treatment of the malignant glioma xenograft D-54 MG. RESULTS: The combination of BCNU and CPT-11 showed the highest enhancement index (2.0-3.3) when BCNU was given on day 1 and CPT-11 was given on days 1-5 and 8-12. Delay of CPT-11 administration to day 3 or day 5 substantially decreased activity with enhancement indices of 1.6-1.8 and 0.6-1.0, respectively. Delay of BCNU administration to day 8 also reduced the CPT-11 activity with enhancement indices of 1.2-1.4. CONCLUSIONS: These results suggest that the presence of a BCNU-induced adduct or possibly crosslink prior to administration of CPT-11 is critical for enhanced activity. Although the mechanism of this enhancement is not currently known, a phase I trial of CPT-11 plus BCNU for adults with recurrent malignant glioma based on these results is in progress.

Authors
Castellino, RC; Elion, GB; Keir, ST; Houghton, PJ; Johnson, SP; Bigner, DD; Friedman, HS
MLA Citation
Castellino, RC, Elion, GB, Keir, ST, Houghton, PJ, Johnson, SP, Bigner, DD, and Friedman, HS. "Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts." Cancer Chemother Pharmacol 45.4 (2000): 345-349.
PMID
10755324
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
45
Issue
4
Publish Date
2000
Start Page
345
End Page
349
DOI
10.1007/s002800050050

Erratum: Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts (Cancer Chemotherapy and Pharmacology 45 (345- 349))

Authors
Friedman, HS; Castellino, RC; Elion, GB; Keir, ST; Houghton, PJ; Johnson, SP; Bigner, DD
MLA Citation
Friedman, HS, Castellino, RC, Elion, GB, Keir, ST, Houghton, PJ, Johnson, SP, and Bigner, DD. "Erratum: Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts (Cancer Chemotherapy and Pharmacology 45 (345- 349))." Cancer Chemotherapy and Pharmacology 46.1 (2000): 84--.
Source
scival
Published In
Cancer Chemotherapy and Pharmacology
Volume
46
Issue
1
Publish Date
2000
Start Page
84-

O6-benzylguanine-mediated enhancement of nitrosourea activity in Mer- central nervous system tumor xenografts - Implications for clinical trials

Purpose: To evaluate the role of 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) plus O6-benzylguanine (O6-BG) in the treatment of both Mer+ and Mer- tumors. Methods: The effect of pretreatment with O6-BG on the activity of BCNU against Mer- human central nervous tumor xenografts D-54 MG and D- 245 MG was evaluated in athymic nude mice. Results: BCNU (1.0 LD10; dose lethal to 10% of treated animals) produced growth delays of 8.9 days and 7.5 days and tumor regressions in six of ten and one of nine animals against D-54 MG, which was derived from a human malignant glioma xenograft. Dose reduction of BCNU to 0.38 LD10 eliminated antitumor activity. The combination of BCNU (0.38 LD10) plus O6-BG produced growth delays of 8.8 days and 7.9 days, with tumor regressions in four of ten and two of nine animals, respectively. BCNU (1.0 LD10) produced a growth delay of 49.8 days and ten of ten tumor regressions against D-245 MG, which was derived from a glioblastoma multiforme. BCNU (0.38 LD10) produced a growth delay of 19.4 days, with nine of ten tumor regressions. The combination of BCNU (0.38 LD10) plus O6-BG produced a growth delay of 65.7 days and seven of eight tumor regressions. Conclusion: These results suggest that the combination of BCNU plus O6-BG may be a rational intervention for both Mer+ as well as Mer- tumors.

Authors
Keir, ST; Dolan, ME; Pegg, AE; Lawless, A; Moschel, RC; Bigner, DD; Friedman, HS
MLA Citation
Keir, ST, Dolan, ME, Pegg, AE, Lawless, A, Moschel, RC, Bigner, DD, and Friedman, HS. "O6-benzylguanine-mediated enhancement of nitrosourea activity in Mer- central nervous system tumor xenografts - Implications for clinical trials." Cancer Chemotherapy and Pharmacology 45.6 (2000): 437-440.
Source
scival
Published In
Cancer Chemotherapy and Pharmacology
Volume
45
Issue
6
Publish Date
2000
Start Page
437
End Page
440

Modulation of cyclophosphamide activity by O6-alkylguanine-DNA alkyltransferase.

PURPOSE: The human medulloblastoma cell line D283 Med (4-HCR), a line resistant to 4-hydroperoxycyclophosphamide (4-HC), displays enhanced repair of DNA interstrand crosslinks induced by phosphoramide mustard. D283 Med (4-HCR) cells are cross-resistant to 1,3-bis(2-chloroethyl)- -nitrosourea, but partial sensitivity is restored after elevated levels of O6-alkylguanine-DNA alkyltransferase (AGT) are depleted by O6-benzylguanine (O6-BG). Studies were conducted to define the activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide against D283 Med (4-HCR) after AGT is depleted by O6-BG. METHODS: Limiting dilution and xenograft studies were conducted to define the activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide with or without O6-BG. RESULTS: The activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide against D283 Med (4-HCR) was increased after AGT depletion by O6-BG preincubation. Similar studies with Chinese hamster ovary cells, with or without stable transfection with a plasmid expressing the human AGT protein, revealed that the AGT-expressing cells were significantly less sensitive to 4-HC and 4-hydroperoxydidechlorocyclophosphamide. Reaction of DNA with 4-HC, phosphoramide mustard, or acrolein revealed that only 4-HC and acrolein caused a decrease in AGT levels. CONCLUSIONS: We propose that a small but potentially significant part of the cellular toxicity of cyclophosphamide in these cells is due to acrolein, and that this toxicity is abrogated by removal of the acrolein adduct from DNA by AGT.

Authors
Friedman, HS; Pegg, AE; Johnson, SP; Loktionova, NA; Dolan, ME; Modrich, P; Moschel, RC; Struck, R; Brent, TP; Ludeman, S; Bullock, N; Kilborn, C; Keir, S; Dong, Q; Bigner, DD; Colvin, OM
MLA Citation
Friedman, HS, Pegg, AE, Johnson, SP, Loktionova, NA, Dolan, ME, Modrich, P, Moschel, RC, Struck, R, Brent, TP, Ludeman, S, Bullock, N, Kilborn, C, Keir, S, Dong, Q, Bigner, DD, and Colvin, OM. "Modulation of cyclophosphamide activity by O6-alkylguanine-DNA alkyltransferase." Cancer Chemother Pharmacol 43.1 (1999): 80-85.
PMID
9923545
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
43
Issue
1
Publish Date
1999
Start Page
80
End Page
85
DOI
10.1007/s002800050866

Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors.

PURPOSE: The activity of vinorellbine, a new semisynthetic vinca alkaloid, was evaluated against a battery of human tumor xenografts derived from adult and pediatric CNS malignancies. METHODS: Tumors included adult high-grade gliomas (D-54 MG, D-245 MG), childhood high-grade gliomas (D-212 MG, D-456 MG), medulloblastomas (D-341 MED, D-487 MED), ependymomas (D-612 EP, D-528 EP), and a mismatch repair-deficient procarbazine-resistant glioma [D-245 MG (PR)]. Tumors were grown subcutaneously in athymic nude mice and vinorelbine was administered at a dose of 11 mg/kg on days 1, 5, and 9. Additionally, vinorelbine was also administered in combination with BCNU against D-54 MG. RESULTS: Vinorelbine produced statistically significant growth delays in D-456 MG, D-245 MG, and D-245 MG (PR). No statistically significant growth delays were observed in D-54 MG, D-487 MED, D-212 MG, D-528 EP, D-341 MED or D-612 EP. The antitumor effects of the vinorelbine/BCNU combination were additive. Growth delays observed in the procarbazine-resistant line [D-245 MG (PR)] were greater than twofold the delays seen in the parent line (D-245 MG). Vincristine was equally potent against D-245 MG and D-245 MG (PR). Taxol demonstrated little activity against D-245 MG but produced 32- and 18-day growth delays in D245 MG (PR). CONCLUSIONS: These studies indicate that vinorelbine possesses antitumor activity against several glioma tumor xenografts with marked activity in a mismatch repair deficient-tumor.

Authors
Hanley, ML; Elion, GB; Colvin, OM; Modrich, PL; Keir, S; Adams, DJ; Bigner, DD; Friedman, HS
MLA Citation
Hanley, ML, Elion, GB, Colvin, OM, Modrich, PL, Keir, S, Adams, DJ, Bigner, DD, and Friedman, HS. "Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors." Cancer Chemother Pharmacol 42.6 (1998): 479-482.
PMID
9788574
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
42
Issue
6
Publish Date
1998
Start Page
479
End Page
482

Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents.

Two major obstacles in the treatment of patients with central nervous system malignancies are drug resistance and host toxicity. The goal of combination chemotherapy is to achieve therapeutic effects that are more favorable than using a single drug alone, but without an increase in normal organ toxicity. The study reported here examined the combination of a topoisomerase I inhibitor, irinotecan (CPT-11), with three different alkylating agents: 1,3-bis(2-chloroethyl)-1-nitrosourea, busulfan, and cyclophosphamide. We evaluated the antitumor effects of these three combinations against a panel of human tumor xenografts derived from central nervous system malignancies, including adult high-grade gliomas (D-54 MG, D-245 MG) and a childhood ependymoma (D-612 EP). In replicate experiments, the alkylating agents were given on day 1 in doses varying from 10% to 75% of the dose lethal to 10% of the animals, and CPT-11 was given on days 1-5 and 8-12 in doses varying from 10% to 100% of the dose lethal to 10% of the animals. The antitumor effects of the various combinations ranged from less than additive (7.61 days below additive with 0.5 CPT-11 + 0.75 cyclophosphamide in D-54 MG) to statistically significant (P < 0.001) supraadditive effects (18.80 days above additive with 0.5 CPT-11 + 0.5 1,3-bis(2-chloroethyl)-1-nitrosourea in D-54 MG). These studies show that the combination of the topoisomerase inhibitor CPT-11 and alkylating agents may increase the antitumor effect in some cases well above additive with no increase in host toxicity (0/10 deaths in both experiments cited above) and should be considered for combination chemotherapy of central nervous system malignancies.

Authors
Coggins, CA; Elion, GB; Houghton, PJ; Hare, CB; Keir, S; Colvin, OM; Bigner, DD; Friedman, HS
MLA Citation
Coggins, CA, Elion, GB, Houghton, PJ, Hare, CB, Keir, S, Colvin, OM, Bigner, DD, and Friedman, HS. "Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents." Cancer Chemother Pharmacol 41.6 (1998): 485-490.
PMID
9554593
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
41
Issue
6
Publish Date
1998
Start Page
485
End Page
490

Methylator resistance mediated by mismatch repair deficiency in a glioblastoma multiforme xenograft.

A methylator-resistant human glioblastoma multiforme xenograft, D-245 MG (PR), in athymic nude mice was established by serially treating the parent xenograft D-245 MG with procarbazine. D-245 MG xenografts were sensitive to procarbazine, temozolomide, N-methyl-N-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, 9-aminocamptothecin, topotecan, CPT-11, cyclophosphamide, and busulfan. D-245 MG (PR) xenografts were resistant to procarbazine, temozolomide, N-methyl-N-nitrosourea, and busulfan, but they were sensitive to the other agents. Both D-245 MG and D-245 MG (PR) xenografts displayed no O6-alkylguanine-DNA alkyltransferase activity, and their levels of glutathione and glutathione-S-transferase were similar. D-245 MG xenografts expressed the human mismatch repair proteins hMSH2 and hMLH1, whereas D-245 MG (PR) expressed hMLH1 but not hMSH2.

Authors
Friedman, HS; Johnson, SP; Dong, Q; Schold, SC; Rasheed, BK; Bigner, SH; Ali-Osman, F; Dolan, E; Colvin, OM; Houghton, P; Germain, G; Drummond, JT; Keir, S; Marcelli, S; Bigner, DD; Modrich, P
MLA Citation
Friedman, HS, Johnson, SP, Dong, Q, Schold, SC, Rasheed, BK, Bigner, SH, Ali-Osman, F, Dolan, E, Colvin, OM, Houghton, P, Germain, G, Drummond, JT, Keir, S, Marcelli, S, Bigner, DD, and Modrich, P. "Methylator resistance mediated by mismatch repair deficiency in a glioblastoma multiforme xenograft." Cancer Res 57.14 (July 15, 1997): 2933-2936.
PMID
9230204
Source
pubmed
Published In
Cancer Research
Volume
57
Issue
14
Publish Date
1997
Start Page
2933
End Page
2936

Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts.

Therapy of patients with malignant central nervous system tumors is frequently unsuccessful, reflecting limitations of current surgical, radiotherapeutic, and pharmacotherapeutic treatments. The camptothecin derivative irinotecan (CPT-11) has been shown to possess antitumor activity in phase II trials for patients with carcinoma of the lung, cervix, ovary, colon, or rectum and for patients with non-Hodgkin's lymphoma. The current study was designed to test the efficacy of the drug against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies. Tumors included childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D341 Med, D487 Med), ependymomas (D528 EP, D612 EP), and a rhabdomyosarcoma (TE-671), as well as sublines with demonstrated resistance to busulfan (D-456 MG (BR)), cyclophosphamide (TE-671 CR), procarbazine (D-245 MG (PR)) or melphalan (TE-671 MR), growing subcutaneously and intracranially in athymic nude mice. In replicate experiments, CPT-11 was given at a dosage of 40 mg/kg per dose via intraperitoneal injection in 10% dimethylsulfoxide on days 1-5 and 8-12, which is the dosage lethal to 10% of treated animals. CPT-11 produced statistically significant (P < 0.001) growth delays in all subcutaneous xenografts tested, including those resistant to busulfan, cyclophosphamide, procarbazine, and melphalan, with growth delays ranging from 21.3 days in D487 Med to 90+ days in several tumor lines. Further, tumor regression was evident in every treated animal bearing a subcutaneous tumor, with some xenografts yielding complete tumor regression. Statistically significant (P < 0.001) increases in survival were demonstrated in the two intracranial xenografts-D341 EP (73.0% increase) and D-456 MG (114.2% increase)-treated with CPT-11. These studies demonstrate that, of over 40 drugs evaluated in this laboratory, CPT-11 is the most active against central nervous system xenografts and should be advanced to clinical trial as soon as possible.

Authors
Hare, CB; Elion, GB; Houghton, PJ; Houghton, JA; Keir, S; Marcelli, SL; Bigner, DD; Friedman, HS
MLA Citation
Hare, CB, Elion, GB, Houghton, PJ, Houghton, JA, Keir, S, Marcelli, SL, Bigner, DD, and Friedman, HS. "Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts." Cancer Chemother Pharmacol 39.3 (1997): 187-191.
PMID
8996518
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
39
Issue
3
Publish Date
1997
Start Page
187
End Page
191

Characterization of the mechanisms of busulfan resistance in a human glioblastoma multiforme xenograft.

Busulfan is an alkylating agent commonly used in the treatment of chronic myelogenous leukemia and in combination with cyclophosphamide in preparation for allogeneic bone marrow transplantation. Serial treatment of a childhood high-grade glioma xenograft (D-456 MG) with busulfan resulted in a busulfan-resistant xenograft, D-456 MG(BR). Cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea was seen but not resistance to cyclophosphamide or CPT-11. Cytoplasmic levels of glutathione in D-456 MG(BR) were approximately one-half those found in D-456 MG. This depletion could not be explained by levels of glutathione-S-transferase, or by amplification, rearrangement, or increased levels of transcript of gamma-glutamylcysteine synthetase. Furthermore, depletion of glutathione in D-456 MG did not alter busulfan activity. Quantitation of busulfan levels in D-456 MG and D-456 MG(BR) xenografts following treatment of mice at the dose lethal to 10% of the animals demonstrated that significantly lower levels of drug were achieved in D-456 MG(BR). These studies suggest that alterations in drug transport or metabolism of busulfan may play a role in the resistance of D-456 MG(BR) to this alkylator.

Authors
Hare, CB; Elion, GB; Colvin, OM; Ali-Osman, F; Griffith, OW; Petros, WP; Keir, S; Marcelli, SL; Bigner, DD; Friedman, HS
MLA Citation
Hare, CB, Elion, GB, Colvin, OM, Ali-Osman, F, Griffith, OW, Petros, WP, Keir, S, Marcelli, SL, Bigner, DD, and Friedman, HS. "Characterization of the mechanisms of busulfan resistance in a human glioblastoma multiforme xenograft." Cancer Chemother Pharmacol 40.5 (1997): 409-414.
PMID
9272117
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
40
Issue
5
Publish Date
1997
Start Page
409
End Page
414
DOI
10.1007/s002800050678

Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model.

A paired-label biodistribution was performed in athymic mice bearing SK-N-SH human neuroblastoma xenografts to compare the tissue uptake of meta-[211At]astatobenzylguanidine ([211At]MABG) and [131I]MIBG. Significantly higher (p < 0.05) uptake of [211At]MABG was seen in tumor (3.8 +/- 0.8% ID/g vs. 3.1 +/- 0.7% ID/g at 8 h) compared to [131I]MIBG. Desipramine reduced tumor uptake of [211At] MABG by 43%, suggesting that its accumulation was related to the specific uptake-1 mechanism. Higher uptake of [211At]MABG was also seen in normal tissue targets such as heart (6.0 +/- 0.9% ID/g vs. 4.5 +/- 0.8% ID/g at 8 h; p < 0.05). Pretreatment of mice with unlabeled MIBG increased tumor uptake of [211At]MABG by 1.5-fold while reducing uptake in heart and several other normal tissues. The vesicular uptake inhibitor tetrabenazine reduced heart uptake by 30% without reducing the tumor uptake. These results suggest such strategies might be useful for improving [211At]MABG tumor-to-normal tissue ratios.

Authors
Vaidyanathan, G; Friedman, HS; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Keir, ST, and Zalutsky, MR. "Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model." Nucl Med Biol 23.6 (August 1996): 851-856.
PMID
8940730
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
23
Issue
6
Publish Date
1996
Start Page
851
End Page
856

Localisation of [131I]MIBG in nude mice bearing SK-N-SH human neuroblastoma xenografts: effect of specific activity.

The biodistribution of no-carrier-added (n.c.a.) meta-[131I]iodobenzylguanidine ([131I]MIBG) and that prepared by the standard isotopic exchange method were compared in athymic mice bearing SK-N-SH human neuroblastoma xenografts. No advantage in tumour uptake was observed for the n.c.a. preparation. BALB/c nu/nu mice exhibited lower uptake in highly innervated normal tissues (heart and adrenals) than normal BALB/c mice. In another experiment, the distribution of n.c.a. [131I]MIBG in the absence or presence (3-9 micrograms) of MIBG carrier was determined. At both 4 h and 24 h, the heart uptake was reduced by a factor of 1.5 even at a dose of 3 micrograms MIBG. Tumour uptake was not significantly altered by various amounts of unlabelled MIBG at either time point.

Authors
Vaidyanathan, G; Friedman, HS; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Keir, ST, and Zalutsky, MR. "Localisation of [131I]MIBG in nude mice bearing SK-N-SH human neuroblastoma xenografts: effect of specific activity." Br J Cancer 73.10 (May 1996): 1171-1177.
Website
http://hdl.handle.net/10161/11050
PMID
8630274
Source
pubmed
Published In
British Journal of Cancer
Volume
73
Issue
10
Publish Date
1996
Start Page
1171
End Page
1177

Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta.

Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-alpha and DNA polymerase-beta. The present study evaluated the alteration of melphalan activity in TE-671 (melphalan-sensitive) and TE-671 MR (melphalan-resistant) subcutaneous xenografts in nude mice after DNA polymerase-alpha was inhibited using aphidicolin glycinate (AG) and DNA polymerase-beta was inhibited using dideoxycytidine (DDC). Administration of AG or DDC did not produce toxicity or demonstrate antineoplastic activity when given alone. AG (90 mg/m2) enhanced the activity of melphalan against TE-671, with growth delays increasing by 8.4, 15.8, and 21.2 days over the regimen with melphalan only. AG (180 mg/m2) only modestly increased melphalan activity against TE-671 MR, with the growth delays increasing from 9.6 and 12.1 days using melphalan alone to 12.1 and 14.5 days using melphalan plus AG. AG (180 mg/m2) plus melphalan (the dose lethal to 10% of animals) produced greater weight loss compared with melphalan alone, whereas DDC plus melphalan produced no additional toxicity. DDC modestly enhanced the activity of melphalan plus AG against TE-671 MR. AG plus O6-benzylguanine did not increase the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea against TE-671 or TE-671 MR. AG (90 mg/m2 and 180 mg/m2) inhibited DNA polymerase-alpha to 80% and 72% of control in TE-671 and 64% and 37% in TE-671 MR, and DDC inhibited DNA polymerase-beta to 59% in TE-671 and 48% in TE-671 MR. These results suggest a role for AG-mediated enhancement of melphalan activity, particularly in the treatment of newly diagnosed, melphalan-sensitive tumors.

Authors
Moynihan, K; Elion, GB; Ali-Osman, F; Marcelli, S; Keir, S; Bigner, DD; Friedman, HS
MLA Citation
Moynihan, K, Elion, GB, Ali-Osman, F, Marcelli, S, Keir, S, Bigner, DD, and Friedman, HS. "Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta." Cancer Chemother Pharmacol 38.4 (1996): 349-354.
PMID
8674158
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
38
Issue
4
Publish Date
1996
Start Page
349
End Page
354

Activity of temozolomide in the treatment of central nervous system tumor xenografts.

The activity of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin- 4(3H)-one (temozolomide) in the treatment of a panel of xenografts derived from ependymoma, medulloblastoma, and childhood and adult high-grade glioma was evaluated in athymic nude mice bearing s.c. and intracranial tumors. Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 1,3-bis(2-chloroethyl)-1-nitrosourea. The growth delays produced by temozolomide in these xenografts were 1.8-7.5-fold greater than those produced by procarbazine. Although temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285% (adult glioma D-54 MG), 323% (childhood glioma D-456 MG), and 68% (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of temozolomide, in duplicate experiments, from -3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that temozolomide may be active in the treatment of a broad spectrum of central nervous system cancers, including Mer+ tumors resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea.

Authors
Friedman, HS; Dolan, ME; Pegg, AE; Marcelli, S; Keir, S; Catino, JJ; Bigner, DD; Schold, SC
MLA Citation
Friedman, HS, Dolan, ME, Pegg, AE, Marcelli, S, Keir, S, Catino, JJ, Bigner, DD, and Schold, SC. "Activity of temozolomide in the treatment of central nervous system tumor xenografts." Cancer Res 55.13 (July 1, 1995): 2853-2857.
PMID
7796412
Source
pubmed
Published In
Cancer Research
Volume
55
Issue
13
Publish Date
1995
Start Page
2853
End Page
2857

Busulfan therapy of central nervous system xenografts in athymic mice.

We evaluated the antitumor activity of busulfan against a panel of tumor cell lines and xenografts in athymic nude mice derived from childhood high-grade glioma, adult high-grade glioma, ependymoma, and medulloblastoma. Busulfan displayed similar activity against a panel of four medulloblastoma cell lines (D283 Med, Daoy, D341 Med, and D425 Med) and four corresponding sublines with laboratory-generated or clinically acquired resistance to 4-hydroperoxycyclophosphamide [D283 Med (4-HCR), Daoy (4-HCR), D341 Med (4-HCR), and D458 Med] and cross-resistance to melphalan. This is consistent with a nearly total lack of cross-resistance of busulfan to 4-hydroperoxycyclophosphamide. Busulfan was active in the therapy of all but one of the subcutaneous xenografts tested, with growth delays ranging from 14.3 days in D612 EP to 58.4 days in D528 EP. Busulfan produced statistically significant increases in the median survival of mice bearing intracranial D456 MG (66%-90%), D612 EP (18%-33%), and D528 EP (89%) xenografts. These studies suggest that busulfan may be active against medulloblastomas, high-grade gliomas, and ependymomas as well as against cyclophosphamide-resistant neoplasms.

Authors
Aaron, RH; Elion, GB; Colvin, OM; Graham, M; Keir, S; Bigner, DD; Friedman, HS
MLA Citation
Aaron, RH, Elion, GB, Colvin, OM, Graham, M, Keir, S, Bigner, DD, and Friedman, HS. "Busulfan therapy of central nervous system xenografts in athymic mice." Cancer Chemother Pharmacol 35.2 (1994): 127-131.
PMID
7987988
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
35
Issue
2
Publish Date
1994
Start Page
127
End Page
131
DOI
10.1007/BF00686634

Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts.

The activity of dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts derived from ependymomas (D528 EP, D612 EP), childhood high-grade gliomas (D-456 MG, D-212 MG), adult high-grade gliomas (D-245 MG, D-54 MG), and medulloblastomas (D425 Med) growing s.c. and i.c. (intracranially) in athymic nude mice. Topotecan was given at a dose of 1.9 mg/kg by i.p. injection in 0.9% saline using a volume of 90 ml/m2 on days 1-5 and 8-12, which represents the dose lethal to 10% of treated animals. Topotecan was active in the therapy of all s.c. xenografts tested, with growth delays ranging from 6.3 days in D-54 MG to 55.7 days in D528 EP. Topotecan produced statistically significant tumor regressions in D425 Med, D-456 MG, D-245 MG, D528 EP, and D612 EP. No tumor regression was seen in any control animal. Statistically significant increases in median survival were seen in the two i.c. xenografts--D-456 MG (28.6% increase) and D-54 MG (39% increase)--treated with topotecan. These studies suggest that topotecan may be an important new addition to the therapy of central nervous system tumors.

Authors
Friedman, HS; Houghton, PJ; Schold, SC; Keir, S; Bigner, DD
MLA Citation
Friedman, HS, Houghton, PJ, Schold, SC, Keir, S, and Bigner, DD. "Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts." Cancer Chemother Pharmacol 34.2 (1994): 171-174.
PMID
8194169
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
34
Issue
2
Publish Date
1994
Start Page
171
End Page
174
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