Stephen Keir

Overview:

Brain Tumors, Preclinical Testing, Translational Research

Positions:

Professor in Neurosurgery

Neurosurgery, Neuro-Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.P.H. 2001

University of North Carolina - Chapel Hill

DrPH 2004

University of North Carolina - Chapel Hill

M.M.C.i. 2019

Duke University

Grants:

Evaluation of Panobinostat in Patient Derived Adult IDH1 Mutated Brain Tumor Xenografts

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
Midatech Pharma Plc
Role
Principal Investigator
Start Date
End Date

Assessment of ST101 in Glioblastoma

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
Sapience Therapeutics Inc.
Role
Principal Investigator
Start Date
End Date

Truncated GLI1 In Glioblastoma

Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Oncolytic Viral Therapy in Brain Tumor Setting

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
ImmVira Pharma Co., Ltd.
Role
Principal Investigator
Start Date
End Date

Evaluation of Cannabinoid Therapeutics in Brain Tumor Xenografts

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
Diverse Biotech
Role
Principal Investigator
Start Date
End Date

Publications:

Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas.

PURPOSE: To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas. EXPERIMENTAL DESIGN: A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib. RESULTS: Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response. CONCLUSIONS: These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.
Authors
Wei, S; Yin, D; Yu, S; Lin, X; Savani, MR; Du, K; Ku, Y; Wu, D; Li, S; Liu, H; Tian, M; Chen, Y; Bowie, M; Hariharan, S; Waitkus, M; Keir, ST; Sugarman, ET; Deek, RA; Labrie, M; Khasraw, M; Lu, Y; Mills, GB; Herlyn, M; Wu, K; Liu, L; Wei, Z; Flaherty, KT; Abdullah, K; Zhang, G; Ashley, DM
MLA Citation
Wei, Shiyou, et al. “Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas.Clin Cancer Res, vol. 28, no. 10, May 2022, pp. 2180–95. Pubmed, doi:10.1158/1078-0432.CCR-21-0833.
URI
https://scholars.duke.edu/individual/pub1511921
PMID
35247901
Source
pubmed
Published In
Clinical Cancer Research
Volume
28
Published Date
Start Page
2180
End Page
2195
DOI
10.1158/1078-0432.CCR-21-0833

Cold Plasma Discharge Tube Enhances Antitumoral Efficacy of Temozolomide.

Glioblastoma (GBM) is a fatal human brain tumor with a low survival rate. Temozolomide (TMZ) has been widely used in GBM therapy with noticeable side effects. Cold plasma is an ionized gas that is generated near room temperature. Here, we demonstrated the enhancement therapeutic efficacy of TMZ via using a cold plasma source based on nonequilibrium plasma in a sealed glass tube, named a radial cold plasma discharge tube (PDT). The PDT affected glioblastoma cells' function just by its electromagnetic (EM) emission rather than any chemical factors in the plasma. The PDT selectively increased the cytotoxicity of TMZ on two typical glioblastoma cell lines, U87MG and A172, compared with normal astrocyte cell line hTERT/E6/E7 to some extent. Furthermore, on the basis of a patient-derived xenograft model, our preliminary in vivo studies demonstrated the drastically improved mean survival days of the tumor-barrier mice by more than 100% compared to control. The PDT is not only independent of continuous helium supply but is also capable of resisting the interference of environmental changes. Thus, the PDT was a stable and low-cost cold atmospheric plasma source. In short, this study is the first to demonstrate the promising application of PDTs in GBM therapy as a noninvasive and portable modality.
Authors
Yao, X; Yan, D; Lin, L; Sherman, JH; Peters, KB; Keir, ST; Keidar, M
MLA Citation
Yao, Xiaoliang, et al. “Cold Plasma Discharge Tube Enhances Antitumoral Efficacy of Temozolomide.Acs Appl Bio Mater, vol. 5, no. 4, Apr. 2022, pp. 1610–23. Pubmed, doi:10.1021/acsabm.2c00018.
URI
https://scholars.duke.edu/individual/pub1513625
PMID
35324138
Source
pubmed
Published In
Acs Applied Bio Materials
Volume
5
Published Date
Start Page
1610
End Page
1623
DOI
10.1021/acsabm.2c00018

A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.

<h4>Purpose</h4>To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both <i>in vitro</i> and <i>in vivo</i>.<h4>Experimental design</h4>A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO.<h4>Results</h4>THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model.<h4>Conclusions</h4>The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.
Authors
Yu, S; Wei, S; Savani, M; Lin, X; Du, K; Mender, I; Siteni, S; Vasilopoulos, T; Reitman, ZJ; Ku, Y; Wu, D; Liu, H; Tian, M; Chen, Y; Labrie, M; Charbonneau, CM; Sugarman, E; Bowie, M; Hariharan, S; Waitkus, M; Jiang, W; McLendon, RE; Pan, E; Khasraw, M; Walsh, KM; Lu, Y; Herlyn, M; Mills, G; Herbig, U; Wei, Z; Keir, ST; Flaherty, K; Liu, L; Wu, K; Shay, JW; Abdullah, K; Zhang, G; Ashley, DM
MLA Citation
Yu, Shengnan, et al. “A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, vol. 27, no. 24, Dec. 2021, pp. 6800–14. Epmc, doi:10.1158/1078-0432.ccr-21-0374.
URI
https://scholars.duke.edu/individual/pub1497999
PMID
34593527
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
27
Published Date
Start Page
6800
End Page
6814
DOI
10.1158/1078-0432.ccr-21-0374

MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of PROM1/CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of PROM1/CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in MTAP-null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133+ cells in MTAP-null GBM can be effectively depleted by inhibition of de novo purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies.
Authors
Hansen, LJ; Sun, R; Yang, R; Singh, SX; Chen, LH; Pirozzi, CJ; Moure, CJ; Hemphill, C; Carpenter, AB; Healy, P; Ruger, RC; Chen, C-PJ; Greer, PK; Zhao, F; Spasojevic, I; Grenier, C; Huang, Z; Murphy, SK; McLendon, RE; Friedman, HS; Friedman, AH; Herndon, JE; Sampson, JH; Keir, ST; Bigner, DD; Yan, H; He, Y
MLA Citation
Hansen, Landon J., et al. “MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.Cancer Res, vol. 79, no. 13, July 2019, pp. 3383–94. Pubmed, doi:10.1158/0008-5472.CAN-18-1010.
URI
https://scholars.duke.edu/individual/pub1382631
PMID
31040154
Source
pubmed
Published In
Cancer Res
Volume
79
Published Date
Start Page
3383
End Page
3394
DOI
10.1158/0008-5472.CAN-18-1010

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

BACKGROUND: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSIONS: 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, Edward F., et al. “Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 63, no. 2, Feb. 2016, pp. 276–86. Pubmed, doi:10.1002/pbc.25727.
URI
https://scholars.duke.edu/individual/pub1093905
PMID
26398108
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
63
Published Date
Start Page
276
End Page
286
DOI
10.1002/pbc.25727