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Zhang, Tian

Positions:

Assistant Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2009

M.D. — Harvard Medical School

Internal Medicine Residency, Medicine

Duke University School of Medicine

Fellowship In Hematology Oncology, Medicine

Duke University School of Medicine

Grants:

Merrimack MM-310-01-01-01

Administered By
Duke Cancer Institute
AwardedBy
Merrimack Pharmaceuticals
Role
Principal Investigator
Start Date
October 26, 2017
End Date
October 31, 2022

An Open-Label Study of Rovalpituzumab

Administered By
Duke Cancer Institute
AwardedBy
AbbVie Inc.
Role
Principal Investigator
Start Date
October 03, 2017
End Date
September 30, 2022

Pfizer VBIR

Administered By
Duke Cancer Institute
AwardedBy
Pfizer, Inc.
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2021

A Retrospective Study to Evaluate the Clinical Effectiveness of the OmniSeq Immune Advance Test to Predict Response to Checkpoint Inhibitors

Administered By
Medicine, Medical Oncology
AwardedBy
OmniSeq, Inc
Role
Principal Investigator
Start Date
October 27, 2017
End Date
October 26, 2019

A study is to develop a retrospective database to study the PGDx TMB +MSI assay associated with clinical responses to immune checkpoint inhibitors (CPIs)

Administered By
Medicine, Medical Oncology
AwardedBy
Personal Genome Diagnostics, Inc.
Role
Principal Investigator
Start Date
October 03, 2017
End Date
October 02, 2019

A Phase 1b, open label, prospective, non-randomized,single center study of conditional lethalithy to copper as a therapeutic modality in prostate cancer

Administered By
Duke Cancer Institute
AwardedBy
Cantex Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
May 17, 2017
End Date
June 01, 2019

A Phase I/II open label multicenter study of the safety and efficacy of LAG525 single agent in combination with PDR001 adminitered to patients

Administered By
Duke Cancer Institute
AwardedBy
Novartis Pharmaceuticals Corporation
Role
Principal Investigator
Start Date
April 13, 2015
End Date
November 13, 2018

Conditional lethality of copper and disulfiram as a therapeutic modality for prostate cancer

Administered By
Medicine, Medical Oncology
AwardedBy
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
May 15, 2016
End Date
May 15, 2018

Retrospective analysis of docetaxel in castration sensitive setting

Administered By
Medicine, Medical Oncology
AwardedBy
H. Lee Moffitt Cancer Center & Research Institute
Role
Principal Investigator
Start Date
February 27, 2017
End Date
February 26, 2018

CTC-Immune Checkpoints

Administered By
Duke Cancer Institute
AwardedBy
Janssen Research & Development, LLC
Role
Co-Principal Investigator
Start Date
February 01, 2016
End Date
February 01, 2018
Show More

Publications:

Exploiting DNA damage without repair: The activity of platinum chemotherapy in BRCA-mutated prostate cancers.

Authors
Humeniuk, MS; Zhang, T; Armstrong, AJ
MLA Citation
Humeniuk, MS, Zhang, T, and Armstrong, AJ. "Exploiting DNA damage without repair: The activity of platinum chemotherapy in BRCA-mutated prostate cancers." Cancer 123.18 (September 2017): 3441-3444.
PMID
28608923
Source
epmc
Published In
Cancer
Volume
123
Issue
18
Publish Date
2017
Start Page
3441
End Page
3444
DOI
10.1002/cncr.30806

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy.

Immunotherapy holds tremendous promise for improving cancer treatment. To administer radiotherapy with immunotherapy has been shown to improve immune responses and can elicit the 'abscopal effect'. Unfortunately, response rates for this strategy remain low. Herein we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NP formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent on the NP surface properties. We showed that AC-NPs deliver tumour-specific proteins to antigen-presenting cells (APCs) and significantly improve the efficacy of αPD-1 (anti-programmed cell death 1) treatment using the B16F10 melanoma model, generating up to a 20% cure rate compared with 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+T/Treg and CD8+T/Treg ratios (Treg, regulatory T cells). Our work presents a novel strategy to improve cancer immunotherapy with nanotechnology.

Authors
Min, Y; Roche, KC; Tian, S; Eblan, MJ; McKinnon, KP; Caster, JM; Chai, S; Herring, LE; Zhang, L; Zhang, T; DeSimone, JM; Tepper, JE; Vincent, BG; Serody, JS; Wang, AZ
MLA Citation
Min, Y, Roche, KC, Tian, S, Eblan, MJ, McKinnon, KP, Caster, JM, Chai, S, Herring, LE, Zhang, L, Zhang, T, DeSimone, JM, Tepper, JE, Vincent, BG, Serody, JS, and Wang, AZ. "Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy." Nature nanotechnology 12.9 (September 2017): 877-882.
PMID
28650437
Source
epmc
Published In
Nature Nanotechnology
Volume
12
Issue
9
Publish Date
2017
Start Page
877
End Page
882
DOI
10.1038/nnano.2017.113

Acute Myeloid Leukemia After Olaparib Treatment in Metastatic Castration-Resistant Prostate Cancer.

Authors
Zhu, J; Tucker, M; Wang, E; Grossman, JS; Armstrong, AJ; George, DJ; Zhang, T
MLA Citation
Zhu, J, Tucker, M, Wang, E, Grossman, JS, Armstrong, AJ, George, DJ, and Zhang, T. "Acute Myeloid Leukemia After Olaparib Treatment in Metastatic Castration-Resistant Prostate Cancer." Clinical genitourinary cancer (July 14, 2017).
PMID
28780018
Source
epmc
Published In
Clinical genitourinary cancer
Publish Date
2017
DOI
10.1016/j.clgc.2017.07.005

Prostate-specific antigen response in black and white patients treated with abiraterone acetate for metastatic castrate-resistant prostate cancer.

Evidence suggests differences in androgen receptor AR signaling between black (B) and white (W) patients with prostate cancer, but pivotal trials of abiraterone acetate (AA) for patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled few black patients, a population with a higher mortality from prostate cancer. Our primary objective was to determine differences in response to AA between B and W patients.We performed a retrospective case-control study of B vs. W patients treated with AA between May 1, 2008 and June 16, 2015 at Duke University Medical Center. Patients were identified (W control patients were matched 2:1 to B patients stratified based on previous docetaxel exposure) through pharmacy records and were eligible if treated with AA for metastatic castration-resistant prostate cancer. Patients with previous enzalutamide use were excluded. The primary objective was to compare the rate of≥90% prostate-specific antigen (PSA) decline from baseline between B vs. W patients. Secondary outcomes included comparing time on therapy, time to PSA progression, and overall survival among groups.Baseline characteristics among patients (n = 45 B, n = 90 W) were identified; these included Karnofsky performance status, PSA, Gleason score, alkaline phosphatase, albumin, hemoglobin, lactate dehydrogenase, opiate use for pain, and metastatic sites. Baseline characteristics among groups were similar except for median hemoglobin (B = 11.4g/dl, W = 12.3g/dl). The proportion of B patients achieving a≥90% PSA level decline was 37.8% vs. 28.9% for W patients (P = 0.296). Statistically significant differences were found in the proportion of patients achieving a≥50% PSA level decline (B = 68.9%, W = 48.9% [P = 0.028]) and≥30% PSA level decline (B = 77.8%, W = 54.4% [P = 0.008]). Rates of primary abiraterone-refractory disease (PSA increase as best response) trended higher in W (31.1%) than in B (15.6%) patients (P = 0.052). Median treatment duration (B = 9.4 mo, W = 8.3 mo) did not differ (Wilcoxon P = 0.444). Median overall survival (B = 27.3 mo [95% CI: 13.9, not estimable], W = 24.8 mo [95% CI: 19, 31.6] [P = 0.669]) and median time to PSA progression (B = 11.0 mo [95% CI: 4.3, 18.0], W = 9.4 mo [95% CI: 6.2, 13.0] [P = 0.917]) did not differ.Black patients may have a higher PSA response to AA than white patients. An ongoing prospective clinical study (NCT01940276) is evaluating outcomes between black and white patients treated with AA.

Authors
Ramalingam, S; Humeniuk, MS; Hu, R; Rasmussen, J; Healy, P; Wu, Y; Harrison, MR; Armstrong, AJ; George, DJ; Zhang, T
MLA Citation
Ramalingam, S, Humeniuk, MS, Hu, R, Rasmussen, J, Healy, P, Wu, Y, Harrison, MR, Armstrong, AJ, George, DJ, and Zhang, T. "Prostate-specific antigen response in black and white patients treated with abiraterone acetate for metastatic castrate-resistant prostate cancer." Urologic oncology 35.6 (June 2017): 418-424.
PMID
28126272
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
35
Issue
6
Publish Date
2017
Start Page
418
End Page
424
DOI
10.1016/j.urolonc.2016.12.016

Cabozantinib in genitourinary malignancies.

Cabozantinib inhibits a variety of cellular receptors including VEGFR1-3, MET, AXL, RET, FLT3 and KIT. These signaling pathways have been shown to be important in genitourinary malignancies. Along its clinical development, it has shown most activity in advanced renal cell carcinoma; the METEOR study compared cabozantinib to everolimus and showed clinically and statistically significant improvements in both progression-free survival and overall survival. Herein, we review the development of cabozantinib in the genitourinary malignancies of renal cell carcinoma, prostate adenocarcinoma and urothelial carcinoma.

Authors
Zhang, T; Park, SE; Hong, C; George, DJ
MLA Citation
Zhang, T, Park, SE, Hong, C, and George, DJ. "Cabozantinib in genitourinary malignancies." Future oncology (London, England) 13.8 (April 2017): 755-765. (Review)
PMID
27842445
Source
epmc
Published In
Future oncology (London, England)
Volume
13
Issue
8
Publish Date
2017
Start Page
755
End Page
765
DOI
10.2217/fon-2016-0358

Nanoparticle delivery of chemotherapy combination regimen improves the therapeutic efficacy in mouse models of lung cancer.

The combination chemotherapy regimen of cisplatin (CP) and docetaxel (DTX) is effective against a variety of cancers. However, combination therapies present unique challenges that can complicate clinical application, such as increases in toxicity and imprecise exposure of tumors to specific drug ratios that can produce treatment resistance. Drug co-encapsulation within a single nanoparticle (NP) formulation can overcome these challenges and further improve combinations' therapeutic index. In this report, we employ a CP prodrug (CPP) strategy to formulate poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs carrying both CPP and DTX. The dually loaded NPs display differences in drug release kinetics and in vitro cytotoxicity based on the structure of the chosen CPP. Furthermore, NPs containing both drugs showed a significant improvement in treatment efficacy versus the free drug combination in vivo.

Authors
Tian, J; Min, Y; Rodgers, Z; Wan, X; Qiu, H; Mi, Y; Tian, X; Wagner, KT; Caster, JM; Qi, Y; Roche, K; Zhang, T; Cheng, J; Wang, AZ
MLA Citation
Tian, J, Min, Y, Rodgers, Z, Wan, X, Qiu, H, Mi, Y, Tian, X, Wagner, KT, Caster, JM, Qi, Y, Roche, K, Zhang, T, Cheng, J, and Wang, AZ. "Nanoparticle delivery of chemotherapy combination regimen improves the therapeutic efficacy in mouse models of lung cancer." Nanomedicine : nanotechnology, biology, and medicine 13.3 (April 2017): 1301-1307.
PMID
27884641
Source
epmc
Published In
Nanomedicine: Nanotechnology, Biology and Medicine
Volume
13
Issue
3
Publish Date
2017
Start Page
1301
End Page
1307
DOI
10.1016/j.nano.2016.11.007

Investigational nanomedicines in 2016: a review of nanotherapeutics currently undergoing clinical trials.

Nanomedicine is a relatively new field that is rapidly evolving. Formulation of drugs on the nanoscale imparts many physical and biological advantages. Such advantages can in turn translate into improved therapeutic efficacy and reduced toxicity. While approximately 50 nanotherapeutics have already entered clinical practice, a greater number of drugs are undergoing clinical investigation for a variety of indications. This review aims to examine all the nanoformulations that are currently undergoing clinical investigation and their outlook for ultimate clinical translation. WIREs Nanomed Nanobiotechnol 2017, 9:e1416. doi: 10.1002/wnan.1416 For further resources related to this article, please visit the WIREs website.

Authors
Caster, JM; Patel, AN; Zhang, T; Wang, A
MLA Citation
Caster, JM, Patel, AN, Zhang, T, and Wang, A. "Investigational nanomedicines in 2016: a review of nanotherapeutics currently undergoing clinical trials." Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology 9.1 (January 2017). (Review)
PMID
27312983
Source
epmc
Published In
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology
Volume
9
Issue
1
Publish Date
2017
DOI
10.1002/wnan.1416

Systemic Therapy for Non-Clear Cell Renal Cell Carcinoma.

Treatment options for metastatic clear cell renal cell carcinoma (ccRCC) have evolved markedly over the past decade, with multiple targeted therapies approved for the disease. In contrast, little improvement has been made in the management of metastatic non-clear cell RCC (nccRCC). Non-clear cell disease is an umbrella term that encompasses multiple biologically distinct entities, including but not limited to papillary, chromophobe, and sarcomatoid RCC. To date, prospective studies have largely explored treatments for ccRCC (e.g., VEGF- and mTOR-directed therapies) in trials that aggregate non-clear cell histologies. However, the studies do not acknowledge the varying biology of each non-clear cell subtype. Emerging studies in nccRCC should examine individual histologies and apply biologically relevant therapies. An example of this is SWOG 1500, a randomized phase II study that will compare a VEGF-inhibitor to one of three MET-directed therapies in patients with metastatic papillary RCC. Until the biologic diversity of nccRCC is appreciated, outcomes are likely to remain dismal.

Authors
Zhang, T; Gong, J; Maia, MC; Pal, SK
MLA Citation
Zhang, T, Gong, J, Maia, MC, and Pal, SK. "Systemic Therapy for Non-Clear Cell Renal Cell Carcinoma." American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting 37 (January 2017): 337-342.
PMID
28561708
Source
epmc
Published In
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting
Volume
37
Publish Date
2017
Start Page
337
End Page
342
DOI
10.14694/edbk_175572

Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies.

The therapeutic armamentarium for metastatic renal cell carcinoma has rapidly expanded over the past decade to include a number of anti-angiogenic therapies and more recently, an immunotherapy. Biomarkers in the peripheral circulation are easily accessible, can provide important prognostic value, and have the potential to give important information about disease progression and treatment sensitivity or response.Herein, we review a variety of circulating markers including circulating protein markers (VEGF-A, inflammatory cytokines, and LDH), circulating nucleic acids (cell free DNA and micro RNAs), and circulating cellular factors (circulating tumor cells, circulating endothelial cells, and immune cell subsets). We discuss these biomarkers in the context of their ability to provide prognostic and predictive information to anti-angiogenic and immunotherapeutic agents.While promising, there is still much work to be done, and prospective evaluation of any potential predictive biomarker for these therapies is greatly needed.

Authors
Zhang, T; Zhu, J; George, DJ; Nixon, AB
MLA Citation
Zhang, T, Zhu, J, George, DJ, and Nixon, AB. "Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies." Urologic oncology 34.11 (November 2016): 510-518. (Review)
PMID
27498927
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
34
Issue
11
Publish Date
2016
Start Page
510
End Page
518
DOI
10.1016/j.urolonc.2016.06.020

Preclinical Evaluation of Promitil, a Radiation-Responsive Liposomal Formulation of Mitomycin C Prodrug, in Chemoradiotherapy.

To examine the effect of radiation on in vitro drug activation and release of Promitil, a pegylated liposomal formulation of a mitomycin C (MMC) lipid-based prodrug; and examine the efficacy and toxicity of Promitil with concurrent radiation in colorectal cancer models.Promitil was obtained from Lipomedix Pharmaceuticals (Jerusalem, Israel). We tested the effects of radiation on release of active MMC from Promitil in vitro. We next examined the radiosensitization effect of Promitil in vitro. We further evaluated the toxicity of a single injection of free MMC or Promitil when combined with radiation by assessing the effects on blood counts and in-field skin and hair toxicity. Finally, we compared the efficacy of MMC and Promitil in chemoradiotherapy using mouse xenograft models.Mitomycin C was activated and released from Promitil in a controlled-release profile, and the rate of release was significantly increased in medium from previously irradiated cells. Both Promitil and MMC potently radiosensitized HT-29 cells in vitro. Toxicity of MMC (8.4 mg/kg) was substantially greater than with equivalent doses of Promitil (30 mg/kg). Mice treated with human-equivalent doses of MMC (3.3 mg/kg) experienced comparable levels of toxicity as Promitil-treated mice at 30 mg/kg. Promitil improved the antitumor efficacy of 5-fluorouracil-based chemoradiotherapy in mouse xenograft models of colorectal cancer, while equitoxic doses of MMC did not.We demonstrated that Promitil is an attractive agent for chemoradiotherapy because it demonstrates a radiation-triggered release of active drug. We further demonstrated that Promitil is a well-tolerated and potent radiosensitizer at doses not achievable with free MMC. These results support clinical investigations using Promitil in chemoradiotherapy.

Authors
Tian, X; Warner, SB; Wagner, KT; Caster, JM; Zhang, T; Ohana, P; Gabizon, AA; Wang, AZ
MLA Citation
Tian, X, Warner, SB, Wagner, KT, Caster, JM, Zhang, T, Ohana, P, Gabizon, AA, and Wang, AZ. "Preclinical Evaluation of Promitil, a Radiation-Responsive Liposomal Formulation of Mitomycin C Prodrug, in Chemoradiotherapy." International journal of radiation oncology, biology, physics 96.3 (November 2016): 547-555.
PMID
27681751
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
3
Publish Date
2016
Start Page
547
End Page
555
DOI
10.1016/j.ijrobp.2016.06.2457

Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.

Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.

Authors
Ware, KE; Somarelli, JA; Schaeffer, D; Li, J; Zhang, T; Park, S; Patierno, SR; Freedman, J; Foo, W-C; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Ware, KE, Somarelli, JA, Schaeffer, D, Li, J, Zhang, T, Park, S, Patierno, SR, Freedman, J, Foo, W-C, Garcia-Blanco, MA, and Armstrong, AJ. "Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer." Oncotarget 7.31 (August 2016): 50507-50521.
Website
http://hdl.handle.net/10161/15123
PMID
27409172
Source
epmc
Published In
Oncotarget
Volume
7
Issue
31
Publish Date
2016
Start Page
50507
End Page
50521
DOI
10.18632/oncotarget.10476

Is Advanced Imaging in Early-Stage Breast Cancer Ever Warranted? Reconciling Clinical Judgment With Common Quality Measures.

The American Board of Internal Medicine Foundation's Choosing Wisely initiative aims to reduce unnecessary advanced imaging for early-stage breast cancer (ESBC). Additionally, NCCN Clinical Practice Guidelines in Oncology for Breast Cancer permit such images when oncologists perceive clinical clues of advanced disease. The utility of advanced imaging in ESBC is not known.We analyzed all patients with ESBC from January 2010 to June 2012 at a large tertiary cancer center. Early-stage was defined as stage IIb or less. We included advanced imaging within 60 days after diagnosis. Three independent reviewers manually abstracted a sample of charts to determine reason for ordering.A total of 1,143 ESBC cases were identified; 21.8% of which had at least one advanced imaging procedure performed. Imaging modalities varied widely (38% CT, 21% PET, 34% bone scans, and 6% MRI). Patients who underwent advanced imaging were more likely to have triple-negative disease, be younger (age <50 years), and have higher stage disease (stage IIb vs ≤ stage IIa; all P<.001). A total of 100 cases (40%) were abstracted; 5 were excluded due to bilateral disease. Of the 95 cases remaining, 62% of the imaging studies were performed for staging, 17% for significant concurrent disease, and 22% for findings atypical of ESBC. Of the studies performed for staging, 15% produced clinically meaningful findings. Overall, 45% of studies were ordered for suspicious findings, complex history, or produced a meaningful result.Of patients with ESBC, 21.8% had at least one advanced imaging procedure within 60 days of diagnosis; almost half were clinically useful. Chart abstraction helped clarify intent. Conversations between clinicians and patients are needed to balance patient preferences and clinician judgment.

Authors
Kamal, A; Zhang, T; Power, S; Marcom, PK
MLA Citation
Kamal, A, Zhang, T, Power, S, and Marcom, PK. "Is Advanced Imaging in Early-Stage Breast Cancer Ever Warranted? Reconciling Clinical Judgment With Common Quality Measures." Journal of the National Comprehensive Cancer Network : JNCCN 14.8 (August 2016): 993-998.
PMID
27496115
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
14
Issue
8
Publish Date
2016
Start Page
993
End Page
998
DOI
10.6004/jnccn.2016.0106

What is the role of sipuleucel-T in the treatment of patients with advanced prostate cancer? An update on the evidence.

Prostate cancer is the most common cancer in men and the second most deadly. About one-third of patients with prostate cancer will develop metastatic disease. We discuss the six United States Food and Drug Administration (FDA) approved treatments for metastatic castrate-resistant prostate cancer (mCRPC) with a strong focus on sipuleucel-T. Sipuleucel-T is the first immunotherapy shown to improve survival in asymptomatic or minimally-symptomatic mCRPC. Herein, we discuss the proposed mechanism of sipuleucel-T and its synthesis. We describe in detail the three randomized controlled trials (RTCs) that led to its approval. We also compiled the newest research regarding use of sipuleucel-T with other agents and in different patient populations. Finally, we discuss the current ongoing trials.

Authors
Hu, R; George, DJ; Zhang, T
MLA Citation
Hu, R, George, DJ, and Zhang, T. "What is the role of sipuleucel-T in the treatment of patients with advanced prostate cancer? An update on the evidence." Therapeutic advances in urology 8.4 (August 2016): 272-278. (Review)
PMID
27928429
Source
epmc
Published In
Therapeutic Advances in Urology
Volume
8
Issue
4
Publish Date
2016
Start Page
272
End Page
278

Development of a Novel c-MET-Based CTC Detection Platform.

Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers.This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. ©2016 AACR.

Authors
Zhang, T; Boominathan, R; Foulk, B; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; Hsu, DS; Healy, P; Li, J; Pi, C; Prendergast, KM; Hobbs, C; Gemberling, S; George, DJ; Hurwitz, HI; Connelly, M; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Zhang, T, Boominathan, R, Foulk, B, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, Hsu, DS, Healy, P, Li, J, Pi, C, Prendergast, KM, Hobbs, C, Gemberling, S, George, DJ, Hurwitz, HI, Connelly, M, Garcia-Blanco, MA, and Armstrong, AJ. "Development of a Novel c-MET-Based CTC Detection Platform." Molecular cancer research : MCR 14.6 (June 2016): 539-547.
Website
http://hdl.handle.net/10161/11944
PMID
26951228
Source
epmc
Published In
Molecular cancer research : MCR
Volume
14
Issue
6
Publish Date
2016
Start Page
539
End Page
547
DOI
10.1158/1541-7786.mcr-16-0011

Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic.

Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of this novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80-85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis.

Authors
Au, KM; Satterlee, A; Min, Y; Tian, X; Kim, YS; Caster, JM; Zhang, L; Zhang, T; Huang, L; Wang, AZ
MLA Citation
Au, KM, Satterlee, A, Min, Y, Tian, X, Kim, YS, Caster, JM, Zhang, L, Zhang, T, Huang, L, and Wang, AZ. "Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic." Biomaterials 82 (March 2016): 178-193.
PMID
26763733
Source
epmc
Published In
Biomaterials
Volume
82
Publish Date
2016
Start Page
178
End Page
193
DOI
10.1016/j.biomaterials.2015.12.018

A role for the androgen receptor in the treatment of male breast cancer.

Male breast cancer (BC) is relatively rare, making up less than 1% of all breast cancer cases in the United States. Treatment guidelines for male BC are derived from studies on the treatment of female BC, and are based molecular and clinical characteristics, such as hormone receptor positivity. For female estrogen receptor positive (ER+) breast cancers, the standard of care includes three classes of endocrine therapies: selective estrogen receptor modulators, aromatase inhibitors, and pure anti-estrogens. In contrast to female ER+ breast cancers, there is less known about the optimal treatment for male ER+ BC. Furthermore, in contrast to ER, less is known about the role of the androgen receptor (AR) in male and female BC. We report here the treatment of a 28-year-old man with metastatic AR+, ER+ breast cancer otherwise refractory to chemotherapy, who has had a durable clinical response to hormonal suppression with the combination of aromatase inhibition (Letrozole) in conjunction with a GnRH agonist (Leuprolide).

Authors
Zhu, J; Davis, CT; Silberman, S; Spector, N; Zhang, T
MLA Citation
Zhu, J, Davis, CT, Silberman, S, Spector, N, and Zhang, T. "A role for the androgen receptor in the treatment of male breast cancer." Critical reviews in oncology/hematology 98 (February 2016): 358-363. (Review)
PMID
26669267
Source
epmc
Published In
Critical Reviews in Oncology/Hematology
Volume
98
Publish Date
2016
Start Page
358
End Page
363
DOI
10.1016/j.critrevonc.2015.11.013

Clinical Utility of Circulating Tumor Cells in Advanced Prostate Cancer.

Men with metastatic castration-resistant prostate cancer (mCRPC) frequently have circulating tumor cells (CTCs) that are detectable in their peripheral blood. The CellSearch® method of enumerating CTCs is presently the only FDA-cleared CTC test available clinically for men with mCRPC and has been shown to have prognostic significance in this setting, both before and during systemic therapy. Clinical utility, reflecting the ability of this test to favorably change outcomes, is a more controversial and higher bar. The CellSearch® CTC assay can provide updated prognostic and potentially surrogate information in specific clinical scenarios and in clinical trials, but formal randomized trials of clinical utility remain an unmet clinical need. Recent data suggest that CTCs may harbor genetic information (such as the androgen receptor splice variant 7, AR-V7) relevant to changing clinical management and predicting treatment sensitivity or resistance to cancer therapies such as enzalutamide, abiraterone, and taxane chemotherapies. Further molecular characterization of CTCs, cell-free DNA, or RNA can also provide additional information that may have clinical utility. Thus, CTC research is moving toward predictive medicine, based on the biologic characterization and improvements in clinical outcomes associated with heterogeneous cell types both within and between patients.

Authors
Zhang, T; Armstrong, AJ
MLA Citation
Zhang, T, and Armstrong, AJ. "Clinical Utility of Circulating Tumor Cells in Advanced Prostate Cancer." Current oncology reports 18.1 (January 2016): 3-. (Review)
PMID
26700506
Source
epmc
Published In
Current Oncology Reports
Volume
18
Issue
1
Publish Date
2016
Start Page
3
DOI
10.1007/s11912-015-0490-9

Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians.

Quality improvement measures are uniformly applied to all oncology providers, regardless of their roles. Little is known about differences in adherence to these measures between oncology fellows, advance practice providers (APP), and attending physicians. We investigated conformance across Quality Oncology Practice Initiative (QOPI) measures for oncology fellows, advance practice providers, and attending physicians at the Durham Veterans Affairs Medical Center (DVAMC). Using data collected from the Spring 2012 and 2013 QOPI cycles, we abstracted charts of patients and separated them based on their primary provider. Descriptive statistics and the chi-square test were calculated for each QOPI measure between fellows, advanced practice providers (APPs), and attending physicians. A total of 169 patients were reviewed. Of these, 31 patients had a fellow, 39 had an APP, and 99 had an attending as their primary oncology provider. Fellows and attending physicians performed similarly on 90 of 94 QOPI metrics. High-performing metrics included several core QOPI measures including documenting consent for chemotherapy, recommending adjuvant chemotherapy when appropriate, and prescribing serotonin antagonists when prescribing emetogenic chemotherapies. Low-performing metrics included documentation of treatment summary and taking action to address problems with emotional well-being by the second office visit. Attendings documented the plan for oral chemotherapy more often (92 vs. 63%, P=0.049). However, after the chart audit, we found that fellows actually documented the plan for oral chemotherapy 88% of the time (p=0.73). APPs and attendings performed similarly on 88 of 90 QOPI measures. The quality of oncology care tends to be similar between attendings and fellows overall; some of the significant differences do not remain significant after a second manual chart review, highlighting that the use of manual data collection for QOPI analysis is an imperfect system, and there may be significant inter-observer variability.

Authors
Zhu, J; Zhang, T; Shah, R; Kamal, AH; Kelley, MJ
MLA Citation
Zhu, J, Zhang, T, Shah, R, Kamal, AH, and Kelley, MJ. "Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians." Journal of cancer education : the official journal of the American Association for Cancer Education 30.4 (December 2015): 774-778.
PMID
25686787
Source
epmc
Published In
Journal of Cancer Education
Volume
30
Issue
4
Publish Date
2015
Start Page
774
End Page
778
DOI
10.1007/s13187-015-0798-z

Docetaxel Resistance in Prostate Cancer: Taking It Up a Notch.

Notch signaling is implicated in prostate cancer progression and docetaxel resistance. Cui and colleagues describe the additive efficacy and mechanisms of a γ-secretase inhibitor, PF-03084014, and docetaxel in preclinical models of prostate cancer, suggesting the need for further clinical development of Notch pathway modulators in men with metastatic prostate cancer.

Authors
Zhang, T; Armstrong, AJ
MLA Citation
Zhang, T, and Armstrong, AJ. "Docetaxel Resistance in Prostate Cancer: Taking It Up a Notch." Clinical cancer research : an official journal of the American Association for Cancer Research 21.20 (October 2015): 4505-4507.
Website
http://hdl.handle.net/10161/10916
PMID
26307134
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
20
Publish Date
2015
Start Page
4505
End Page
4507
DOI
10.1158/1078-0432.ccr-15-1613

Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer.

Abiraterone acetate (AA) has demonstrated improved outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). However, data are lacking on the effect of AA on subsequent efficacy of enzalutamide or docetaxel.We included men with mCRPC who received AA and subsequent enzalutamide or docetaxel by August 12, 2013. Patients were separated into 3 groups: group A, treated with AA then enzalutamide before chemotherapy; group B, treated with AA then docetaxel; and group C, treated with AA and enzalutamide after chemotherapy. The primary objective was to describe the response and overall survival with subsequent therapy.There were 28 evaluable patients who received enzalutamide after AA (9 in group A and 19 in group C) and 13 patients who received docetaxel after AA (group B). Group A patients had more visceral disease and higher baseline prostate-specific antigen (PSA) levels, and group C men had a higher level of pain and multiple poor prognostic features. Median progression-free survival was 3.6, 5.1, and 2.8 months, respectively, and median overall survival was 8.5, not reached, and 9.6 months, respectively. A ≥ 50% PSA decline was achieved in 11%, 63%, and 5% of group A, B, and C patients, respectively. Radiographic or clinical progression as best response was noted in 55.5%, 30.8%, and 68.4% in each respective group.In this chart review of consecutive men with progressive mCRPC after AA, we found modest activity for enzalutamide and docetaxel, with clear cross-resistance for AA and enzalutamide. These data might inform the complex treatment decisions after AA treatment.

Authors
Zhang, T; Dhawan, MS; Healy, P; George, DJ; Harrison, MR; Oldan, J; Chin, B; Armstrong, AJ
MLA Citation
Zhang, T, Dhawan, MS, Healy, P, George, DJ, Harrison, MR, Oldan, J, Chin, B, and Armstrong, AJ. "Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer." Clinical genitourinary cancer 13.4 (August 2015): 392-399.
PMID
25708161
Source
epmc
Published In
Clinical genitourinary cancer
Volume
13
Issue
4
Publish Date
2015
Start Page
392
End Page
399
DOI
10.1016/j.clgc.2015.01.004

Mismatch repair gone awry: Management of Lynch syndrome.

The hallmark of Lynch syndrome involves germline mutations of genes important in DNA mismatch repair. Affected family kindreds will have multiple associated malignancies, the most common of which is colorectal adenocarcinoma. Recently, evidence has shown that clinical diagnostic criteria provided by the Amsterdam Criteria and the Bethesda Guidelines must be linked with microsatellite instability testing to correctly diagnose Lynch syndrome. We present a case of metachronous colorectal adenocarcinomas in a patient less than 50 years of age, followed by a discussion of Lynch syndrome, with an emphasis on surveillance and prevention of malignancies.

Authors
Zhang, T; Boswell, EL; McCall, SJ; Hsu, DS
MLA Citation
Zhang, T, Boswell, EL, McCall, SJ, and Hsu, DS. "Mismatch repair gone awry: Management of Lynch syndrome." Critical reviews in oncology/hematology 93.3 (March 2015): 170-179. (Review)
PMID
25459670
Source
epmc
Published In
Critical Reviews in Oncology/Hematology
Volume
93
Issue
3
Publish Date
2015
Start Page
170
End Page
179
DOI
10.1016/j.critrevonc.2014.10.005

Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer.

Over the past decade, treatment options for men with metastatic castration-resistant prostate cancer (CRPC) have expanded with the addition of abiraterone acetate (AA), enzalutamide, sipuleucel-T, radium-223, docetaxel and cabazitaxel. The optimal sequencing of therapies in the context of efficacy and known cross-resistance remains uncertain.We review the development of enzalutamide (MDV3100, Xtandi), a novel second-generation androgen receptor (AR), and AA (Zytiga), a selective, irreversible inhibitor of cytochrome P17. In addition to discussing the clinical evidence, we also address evolving evidence of mechanisms of resistance and clinical cross-resistance during sequential therapy with these agents.AA and enzalutamide have both demonstrated tolerability and clinical benefit for multiple outcomes in patients with CRPC, in both post-chemotherapy and pre-chemotherapy settings. Both agents target the androgen-signaling pathway and have similar efficacy; however, they differ in prednisone use and their toxicity profiles, impacting the decision of upfront therapy. Mechanisms of resistance emerging after treatment include both alterations in AR signaling as well as mechanisms that bypass the AR. Retrospective analyses have demonstrated evidence that sequential treatment with these agents results in limited clinical benefit, supporting mechanisms of cross-resistance. Trials are ongoing to determine optimal timing, sequence and combination of these agents.

Authors
Zhang, T; Zhu, J; George, DJ; Armstrong, AJ
MLA Citation
Zhang, T, Zhu, J, George, DJ, and Armstrong, AJ. "Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer." Expert opinion on pharmacotherapy 16.4 (March 2015): 473-485. (Review)
PMID
25534660
Source
epmc
Published In
Expert Opinion on Pharmacotherapy
Volume
16
Issue
4
Publish Date
2015
Start Page
473
End Page
485
DOI
10.1517/14656566.2015.995090

Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians

© 2015, Springer Science+Business Media New York.Quality improvement measures are uniformly applied to all oncology providers, regardless of their roles. Little is known about differences in adherence to these measures between oncology fellows, advance practice providers (APP), and attending physicians. We investigated conformance across Quality Oncology Practice Initiative (QOPI) measures for oncology fellows, advance practice providers, and attending physicians at the Durham Veterans Affairs Medical Center (DVAMC). Using data collected from the Spring 2012 and 2013 QOPI cycles, we abstracted charts of patients and separated them based on their primary provider. Descriptive statistics and the chi-square test were calculated for each QOPI measure between fellows, advanced practice providers (APPs), and attending physicians. A total of 169 patients were reviewed. Of these, 31 patients had a fellow, 39 had an APP, and 99 had an attending as their primary oncology provider. Fellows and attending physicians performed similarly on 90 of 94 QOPI metrics. High-performing metrics included several core QOPI measures including documenting consent for chemotherapy, recommending adjuvant chemotherapy when appropriate, and prescribing serotonin antagonists when prescribing emetogenic chemotherapies. Low-performing metrics included documentation of treatment summary and taking action to address problems with emotional well-being by the second office visit. Attendings documented the plan for oral chemotherapy more often (92 vs. 63 %, P = 0.049). However, after the chart audit, we found that fellows actually documented the plan for oral chemotherapy 88 % of the time (p = 0.73). APPs and attendings performed similarly on 88 of 90 QOPI measures. The quality of oncology care tends to be similar between attendings and fellows overall; some of the significant differences do not remain significant after a second manual chart review, highlighting that the use of manual data collection for QOPI analysis is an imperfect system, and there may be significant inter-observer variability.

Authors
Zhu, J; Zhang, T; Shah, R; Kamal, AH; Kelley, MJ
MLA Citation
Zhu, J, Zhang, T, Shah, R, Kamal, AH, and Kelley, MJ. "Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians." Journal of Cancer Education 30.4 (2015): 774-778.
Source
scival
Published In
Journal of Cancer Education
Volume
30
Issue
4
Publish Date
2015
Start Page
774
End Page
778
DOI
10.1007/s13187-015-0798-z

Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes.

Neuroendocrine prostate cancer (NEPC) encompasses various clinical contexts, ranging from the de novo presentation of small cell prostatic carcinoma to a treatment-emergent transformed phenotype that arises from typical adenocarcinoma of the prostate. The development of resistance to potent androgen receptor signaling inhibition may be associated with the emergence of aggressive phenotype, advanced castration-resistant NEPC. Clinically, small cell prostate cancer and NEPC are often manifested by the presence of visceral or large soft tissue metastatic disease, a disproportionately low serum prostate-specific antigen level relative to the overall burden of disease, and a limited response to targeting of the androgen signaling axis. These tumors are often characterized by loss of androgen receptor expression, loss of retinoblastoma tumor suppressor copy number or expression, amplification of Aurora kinase A and N-Myc, and activation of the PI3K pathway. However, a consensus phenotype-genotype definition of NEPC has yet to emerge, and molecularly based biomarkers are needed to expand on traditional morphologic and immunohistochemical markers of NEPC to fully define the spectrum of this aggressive, androgen receptor-independent disease. Emerging studies implicate a shared clonal origin with prostatic adenocarcinoma in many cases, with the adaptive emergence of unique cellular programming and gene expression profiles. Ongoing clinical studies are focused on developing novel targeted therapeutic approaches for this high-risk, lethal subset of disease, to improve on the limited durations of response often observed with traditional platinum-based chemotherapy.

Authors
Aggarwal, R; Zhang, T; Small, EJ; Armstrong, AJ
MLA Citation
Aggarwal, R, Zhang, T, Small, EJ, and Armstrong, AJ. "Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes." Journal of the National Comprehensive Cancer Network : JNCCN 12.5 (May 2014): 719-726. (Review)
PMID
24812138
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12
Issue
5
Publish Date
2014
Start Page
719
End Page
726
DOI
10.6004/jnccn.2014.0073

Standardizing and Evaluating Transitions of Care in the Era of Duty Hour Reform: One Institution's Resident-Led Effort.

BACKGROUND: Compliance with the Accreditation Council for Graduate Medical Education duty hour standards may necessitate more frequent transitions of patient responsibility. INTERVENTION: We created a multidisciplinary Patient Safety and Quality Council with a Task Force on Handoffs (TFH), engaging residents at a large, university-based institution. METHODS: The TFH identified core content of effective handoffs and patterned institutional content on the SIGNOUTT mnemonic. A web-based module highlighting core content was developed for institutional orientation of all trainees beginning summer 2011 to standardize handoff education. The TFH distributed handoff material and catalogued additional program initiatives in teaching and evaluating handoffs. A standard handoff evaluation tool, assessing content, culture, and communication, was developed and "preloaded" into the institution-wide electronic evaluation system to standardize evaluation. The TFH developed questions pertaining to handoffs for an annual institutional survey in 2011 and 2012. Acceptability of efforts was measured by program participation, and feasibility was measured by estimating time and financial costs. RESULTS: Programs found the TFH's efforts to improve handoffs acceptable; to date, 13 program-specific teaching initiatives have been implemented, and the evaluation tool is being used by 5 programs. Time requirements for TFH participants average 2 to 3 h/mo, and financial costs are minimal. More residents reported having education on handoffs (58% [388 of 668] versus 42% [263 of 625], P < .001) and receiving adequate signouts (69% [469 of 680] versus 61% [384 of 625], P  =  .004) in the 2012 survey, compared with 2011. CONCLUSIONS: Use of a multispecialty resident leadership group to address content, education, and evaluation of handoffs was feasible and acceptable to most programs at a large, university-based institution.

Authors
Boggan, JC; Zhang, T; Derienzo, C; Frush, K; Andolsek, K
MLA Citation
Boggan, JC, Zhang, T, Derienzo, C, Frush, K, and Andolsek, K. "Standardizing and Evaluating Transitions of Care in the Era of Duty Hour Reform: One Institution's Resident-Led Effort." Journal of graduate medical education 5.4 (December 2013): 652-657.
PMID
24455017
Source
epmc
Published In
Journal of graduate medical education
Volume
5
Issue
4
Publish Date
2013
Start Page
652
End Page
657
DOI
10.4300/jgme-d-12-00287

Clinical phenotypes of castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is defined as prostate cancer that no longer responds to androgen deprivation therapy. At the genome level, CRPC is a heterogeneous disease that is marked by a range of genetic and epigenetic lesions. These lesions differ from patient to patient, but have common pathway-based themes. Clinically, a range of phenotypic presentations or subtypes of CRPC are observed that mirror this underlying heterogeneity as the disease progresses; each phenotype carries a different prognosis and different implications for treatment. In this review, we discuss the clinical subtypes of CRPC based on histology; the presence of metastatic disease and pattern of spread; patient-reported symptoms; and levels of biomarkers, such as serum bone turn- over biomarkers, prostate-specific antigen, circulating tumor cell enumeration, and neuroendocrine biomarkers. We then address the potential relationship between these clinical phenotypes (with their underlying molecular subtypes) and therapeutic decision- making and prognosis, as well as ongoing research strategies.

Authors
Zhang, T; Armstrong, AJ
MLA Citation
Zhang, T, and Armstrong, AJ. "Clinical phenotypes of castration-resistant prostate cancer." Clinical advances in hematology & oncology : H&O 11.11 (November 2013): 707-718. (Review)
PMID
24896544
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
11
Issue
11
Publish Date
2013
Start Page
707
End Page
718

PET with 62Cu-ATSM and 62Cu-PTSM is a useful imaging tool for hypoxia and perfusion in pulmonary lesions.

Hypoxia is a characteristic of many tumors and portends a worse prognosis in lung, cervical, prostate, and rectal cancers. Unlike the others, lung cancers present a unique challenge in measuring hypoxia, with invasive biopsies and higher rates of complications. Noninvasive imaging studies detecting hypoxia using isotopes of copper-diacetyl-bis(N4-methylthiosemicarbazone) ((62)Cu-ATSM) have predicted prognosis and treatment outcomes in some small feasibility trials. These images, however, may not identify all areas of hypoxia. Hence, we hypothesize that the addition of another PET imaging agent, copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) ((62)Cu-PTSM), which can detect areas of perfusion, can augment the information obtained in (62)Cu-ATSM PET scans.To characterize tumors on the basis of both perfusion and hypoxia, 10 patients were studied using both (62)Cu-ATSM and (62)Cu-PTSM PET scans. In addition, proteomic arrays looking at specific proangiogenic, survival, and proinflammatory targets were assessed.Six of 10 patients had evaluable PET scans. Our initial experience of characterizing lung tumor hypoxia using (62)Cu-ATSM and (62)Cu-PTSM PET scans showed that visualization of areas with hypoxia normalized for perfusion is feasible. All studied tumors exhibited some hypoxia. Despite the small sample size, a positive relationship was noted between epidermal growth factor levels and (62)Cu-ATSM-detected hypoxia.This initial series of (62)Cu-ATSM and (62)Cu-PTSM PET scans shows that evaluating lung masses by visualizing hypoxia and perfusion is a feasible and novel technique to provide more information. Further investigation is warranted to assess the potential role of (62)Cu-ATSM and (62)Cu-PTSM PET techniques combined with proteomics as alternatives to invasive biopsy techniques in clinical care.

Authors
Zhang, T; Das, SK; Fels, DR; Hansen, KS; Wong, TZ; Dewhirst, MW; Vlahovic, G
MLA Citation
Zhang, T, Das, SK, Fels, DR, Hansen, KS, Wong, TZ, Dewhirst, MW, and Vlahovic, G. "PET with 62Cu-ATSM and 62Cu-PTSM is a useful imaging tool for hypoxia and perfusion in pulmonary lesions." AJR. American journal of roentgenology 201.5 (November 2013): W698-W706.
PMID
24147499
Source
epmc
Published In
AJR. American journal of roentgenology
Volume
201
Issue
5
Publish Date
2013
Start Page
W698
End Page
W706
DOI
10.2214/ajr.12.9698

Biochemical failure in prostate cancer

© 2013 Springer-Verlag London. All rights are reserved. Prostate cancer treatment failure after local therapy can be detected through changes in PSA prior to any clinical evidence of disease. Therefore, posttreatment elevation, also called biochemical failure, has been utilized as a surrogate for disease recurrence. The ability to consistently define biochemical failure is important both for the prognostic risk stratification of patients for clinical recurrence and survival and for the standardization of research when comparing multiple series of patients who undergo the same treatment. Due to the difference in PSA posttreatment, the definition of biochemical failure varies between treatments. In this chapter, we will explore the definitions of biochemical failure for each type of prostate cancer treatment, the clinical workup at time of biochemical failure, and the management decisions that clinicians encounter after patients develop biochemical failure.

Authors
Zhang, T; Wang, AZ
MLA Citation
Zhang, T, and Wang, AZ. "Biochemical failure in prostate cancer." Prostate Cancer: A Comprehensive Perspective. July 1, 2013. 807-811.
Source
scopus
Publish Date
2013
Start Page
807
End Page
811
DOI
10.1007/978-1-4471-2864-9_67

Prevalence and impact of correlative science in breast cancer phase II trials.

Correlative science (CS) can potentially augment clinical trial results by identifying biomarkers of response and resistance to a novel intervention. We evaluated recently published breast cancer phase II trials (BP2T) to determine prevalence, characteristics, and outcomes of CS. Through Pubmed, we identified BP2T of systemic therapy published between June 2005 and June 2010. A study-specific abstraction tool recorded trial characteristics, CS endpoints, source of tissue, adequacy of samples, biopsy safety, and CS outcomes. BP2T authors were contacted to verify abstraction results. Results were abstracted from 298 eligible trials enrolling 18,782 patients, of which 81 (27.2 %) involved CS. Of these, 57 (70.4 %) included tissue with 16 (28 %) using optional research biopsies and 17 (30 %) requiring mandatory research biopsies. No trial addressed biopsy safety issues. Trials were more likely to include CS if they were: industry versus non-industry sponsored (33.7 % vs. 17.1 %, p = 0.0017), neoadjuvant versus metastatic setting (47 % vs. 21.2 %, p = 0.0001), or U.S. versus non-U.S. trials (37 % vs. 21 %, p = 0.005). A minority of phase II breast cancer trials include CS representing a missed opportunity to learn more from clinical research. When CS is included, consistent reporting of endpoints, feasibility, outcomes, and safety is needed.

Authors
Zhang, T; Schneider, A; Hamilton, EP; Patel, K; Kamal, AH; Lyman, GH; Peppercorn, JM
MLA Citation
Zhang, T, Schneider, A, Hamilton, EP, Patel, K, Kamal, AH, Lyman, GH, and Peppercorn, JM. "Prevalence and impact of correlative science in breast cancer phase II trials." Breast Cancer Res Treat 139.3 (June 2013): 845-850.
PMID
23771715
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
139
Issue
3
Publish Date
2013
Start Page
845
End Page
850
DOI
10.1007/s10549-013-2590-2

Prevalence and impact of correlative science in breast cancer phase II trials

Correlative science (CS) can potentially augment clinical trial results by identifying biomarkers of response and resistance to a novel intervention. We evaluated recently published breast cancer phase II trials (BP2T) to determine prevalence, characteristics, and outcomes of CS. Through Pubmed, we identified BP2T of systemic therapy published between June 2005 and June 2010. A study-specific abstraction tool recorded trial characteristics, CS endpoints, source of tissue, adequacy of samples, biopsy safety, and CS outcomes. BP2T authors were contacted to verify abstraction results. Results were abstracted from 298 eligible trials enrolling 18,782 patients, of which 81 (27.2 %) involved CS. Of these, 57 (70.4 %) included tissue with 16 (28 %) using optional research biopsies and 17 (30 %) requiring mandatory research biopsies. No trial addressed biopsy safety issues. Trials were more likely to include CS if they were: industry versus non-industry sponsored (33.7 % vs. 17.1 %, p = 0.0017), neoadjuvant versus metastatic setting (47 % vs. 21.2 %, p = 0.0001), or U.S. versus non-U.S. trials (37 % vs. 21 %, p = 0.005). A minority of phase II breast cancer trials include CS representing a missed opportunity to learn more from clinical research. When CS is included, consistent reporting of endpoints, feasibility, outcomes, and safety is needed. © 2013 Springer Science+Business Media New York.

Authors
Zhang, T; Schneider, A; Hamilton, EP; Patel, K; Kamal, AH; Lyman, GH; Peppercorn, JM
MLA Citation
Zhang, T, Schneider, A, Hamilton, EP, Patel, K, Kamal, AH, Lyman, GH, and Peppercorn, JM. "Prevalence and impact of correlative science in breast cancer phase II trials." Breast Cancer Research and Treatment 139.3 (2013): 845-850.
Source
scival
Published In
Breast Cancer Research and Treatment
Volume
139
Issue
3
Publish Date
2013
Start Page
845
End Page
850
DOI
10.1007/s10549-013-2590-2

Handoffs in the era of duty hours reform: a focused review and strategy to address changes in the Accreditation Council for Graduate Medical Education Common Program Requirements.

With changes in the Accreditation Council for Graduate Medical Education (ACGME) Common Program Requirements related to transitions in care effective July 1, 2011, sponsoring institutions and training programs must develop a common structure for transitions in care as well as comprehensive curricula to teach and evaluate patient handoffs. In response to these changes, within the Duke University Health System, the resident-led Graduate Medical Education Patient Safety and Quality Council performed a focused review of the handoffs literature and developed a plan for comprehensive handoff education and evaluation for residents and fellows at Duke. The authors present the results of their focused review, concentrating on the three areas of new ACGME expectations--structure, education, and evaluation--and describe how their findings informed the broader initiative to comprehensively address transitions in care managed by residents and fellows. The process of developing both institution-level and program-level initiatives is reviewed, including the development of an interdisciplinary minimal data set for handoff core content, training and education programs, and an evaluation strategy. The authors believe the final plan fully addresses both Duke's internal goals and the revised ACGME Common Program Requirements and may serve as a model for other institutions to comprehensively address transitions in care and to incorporate resident and fellow leadership into a broad, health-system-level quality improvement initiative.

Authors
DeRienzo, CM; Frush, K; Barfield, ME; Gopwani, PR; Griffith, BC; Jiang, X; Mehta, AI; Papavassiliou, P; Rialon, KL; Stephany, AM; Zhang, T; Andolsek, KM; Duke University Health System Graduate Medical Education Patient Safety and Quality Council,
MLA Citation
DeRienzo, CM, Frush, K, Barfield, ME, Gopwani, PR, Griffith, BC, Jiang, X, Mehta, AI, Papavassiliou, P, Rialon, KL, Stephany, AM, Zhang, T, Andolsek, KM, and Duke University Health System Graduate Medical Education Patient Safety and Quality Council, . "Handoffs in the era of duty hours reform: a focused review and strategy to address changes in the Accreditation Council for Graduate Medical Education Common Program Requirements." Acad Med 87.4 (April 2012): 403-410. (Review)
PMID
22361790
Source
pubmed
Published In
Academic Medicine
Volume
87
Issue
4
Publish Date
2012
Start Page
403
End Page
410
DOI
10.1097/ACM.0b013e318248e5c2

Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis.

Peritoneal metastasis is a major cause of morbidity and mortality in ovarian cancer. While intraperitoneal chemotherapy and radiotherapy have shown favorable clinical results, both are limited by their non-targeted nature. We aimed to develop a biologically targeted nanoparticle therapeutic for the treatment of ovarian cancer peritoneal metastasis. Folate-targeted nanoparticles encapsulating chemotherapy and/or radiotherapy were engineered. Paclitaxel (Ptxl) was used as the chemotherapeutic and yittrium-90 ((90)Y) was employed as the therapeutic radioisotope. Folate was utilized as the targeting ligand as most ovarian cancers overexpress the folate receptor. Nanoparticle characterization studies showed monodispersed particles with controlled Ptxl release. Folate targeting ligand mediated the uptake of NPs into tumor cells. In vitro efficacy studies demonstrated folate-targeted NPs containing chemoradiotherapy was the most effective therapeutic compared to folate-targeted NPs containing a single therapeutic or any non-targeted NP therapeutics. In vivo efficacy studies using an ovarian peritoneal metastasis model showed that folate-targeted NP therapeutics were significantly more effective than non-targeted NP therapeutics. Among the folate-targeted therapeutics, the NP containing chemoradiotherapy appeared to be the most effective. Our results suggest that folate-targeted nanoparticles containing chemoradiotherapy have the potential as a treatment for ovarian peritoneal metastasis.

Authors
Werner, ME; Karve, S; Sukumar, R; Cummings, ND; Copp, JA; Chen, RC; Zhang, T; Wang, AZ
MLA Citation
Werner, ME, Karve, S, Sukumar, R, Cummings, ND, Copp, JA, Chen, RC, Zhang, T, and Wang, AZ. "Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis." Biomaterials 32.33 (November 2011): 8548-8554.
PMID
21843904
Source
epmc
Published In
Biomaterials
Volume
32
Issue
33
Publish Date
2011
Start Page
8548
End Page
8554
DOI
10.1016/j.biomaterials.2011.07.067

Outcomes in phase II trials of metastatic breast cancer: Where is the bar?

2590 Background: Phase II trials serve to provide safety and efficacy data for evaluating novel interventions that may be selected for large Phase III trials. To help define benchmarks for efficacy, we evaluated outcomes of all recently published metastatic breast cancer Phase II trials (MBP2).All English language MBP2 published from June 2005 through June 2010 were identified by Pubmed search. Trial characteristics (type, line, regimen), tumor type, and outcomes were analyzed. Line of therapy was categorized as first-line (first line only), early-line (2nd and 1-2 line), and any/late-line (2+ lines or not specified). Descriptive statistics, Wilcoxon signed rank, and univariate linear regression were performed.226 Phase II trials were abstracted. 31% were first-line, 30% early-line, and 39% any/late-line. 83% (187) were single-arm design; 12% (27) and 5% (11) were randomized and cohort studies, respectively. Overall response rate (ORR) was reported in 204 (90%) MBP2, stable disease (SD) in 127 (56%), time to progression (TTP) in 185 (82%), progression free survival in 20 (9%), and overall survival (OS) in 143 (63%). SD was defined as 6 months in 29%, but definitions varied, and SD was not defined in 43%. Overall, median ORR was 36% (IQR: 16-52, range 0-98%); TTP was 27 weeks (IQR: 15-36, range 4-122), and OS was 65 weeks (IQR: 52-95). For first-line, median ORR, TTP, and OS were 53%, 35 weeks, and 97 weeks, respectively. In first-line, ORR ranged from 5%-98%, TTP from 9-72 weeks, and OS from 13-884 weeks. For early-line vs. any/late line, median ORR was 30% vs. 22%, median TTP was 24 vs. 19 weeks, and median OS was 60 vs. 56 weeks. ORR, TTP, and OS differed significantly by line of therapy (all p<0.0001). Univariate linear regression demonstrated a significant association between ORR, TTP, and OS (p<0.005).Appraisal of recent trials can provide benchmarks for evaluation of novel therapy. As with standard interventions, outcomes in MBP2 vary by line of therapy. Standardization in reporting outcomes, particularly definition of SD, would improve assessment and support rational decision making for which interventions should move forward to Phase III trials.

Authors
Kamal, A; Zhang, T; Schneider, A; Patel, K; Hamilton, EP; Marcom, PK; Peppercorn, JM
MLA Citation
Kamal, A, Zhang, T, Schneider, A, Patel, K, Hamilton, EP, Marcom, PK, and Peppercorn, JM. "Outcomes in phase II trials of metastatic breast cancer: Where is the bar?." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 2590-.
PMID
28022234
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2590

Pharmaceutical involvement in phase II breast cancer clinical trials.

6104 Background: Pharmaceutical industry (PHI) involvement in breast cancer clinical trials is increasing and may correlate with positive outcomes. We sought to further investigate the prevalence and potential impact of PHI involvement in breast cancer research through evaluation of recently published breast cancer phase II trials (BP2T).Phase II clinical trials from June 2005 - June 2010 were identified in MEDLINE by search terms "breast cancer" and "phase II" and limits of English language, human subjects, and "clinical trials". Trials were abstracted by 2 independent reviewers for industry involvement, report of possible conflicts of interest (COI), trial design, setting, interventions, accrual, and outcomes. PHI trials were defined by any report of industry involvement. "Positive" outcomes was defined by assessment of authors conclusions. Descriptive statistics and Fisher's exact test are reported.298 eligible trials were abstracted. 181 (61%) reported PHI including 44 (15%) with industry authorship. For 114 (38%) trials a COI was identified. COI was reported more frequently among PHI trials vs. non-PHI trials (58% vs. 7%, p < 0.001 ). Among PHI trials, 132 (73%) involved metastatic disease, 44 (24%) neoadjuvant, and 9 (5%) other settings. 125 (69%) PHI trials were single arm, 29 (16%) randomized, 15 (9%) Phase I/II, 13 (7%) nonrandomized with multiple cohorts. PHI trials were more likely to have US sites (78% vs. 52%, p < 0.001), to include > 50 patients (54% vs. 38%, p = 0.006), to evaluate biologic therapy (38% vs. 25%, p = 0.04) and to include correlative science (34% vs. 17%, p = 0.002) compared to non-PHI trials. Average time to accrual was 27 months for PHI vs. 30 months for non-PHI trials. 140 (77%) PHI trials and 93 (79%) non-PHI trials were positive (p = 0.8).The majority of BP2T involve pharmaceutical industry support, and many include an author with COI. The prevalence of PHI support and frequency of COI highlights the importance of managing COI while supporting academia/industry collaboration. PHI support correlates with some aspects of study design and study characteristics, but correlation with positive outcomes as noted in some prior studies is not seen among this more homogenous dataset.

Authors
Schneider, A; Zhang, T; Kamal, A; Patel, K; Hamilton, EP; Peppercorn, JM
MLA Citation
Schneider, A, Zhang, T, Kamal, A, Patel, K, Hamilton, EP, and Peppercorn, JM. "Pharmaceutical involvement in phase II breast cancer clinical trials." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 6104-.
PMID
28022553
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
6104

Prevalence and impact of correlative science in breast cancer phase II trials.

1046 Background: Correlative science (CS) can augment clinical trial results by identifying biomarkers of response and resistance to a novel intervention. There is little data on how frequently CS is included in breast cancer phase II trials (BP2T). We evaluated recently published BP2T to identify prevalence, characteristics, and outcomes of CS.Using search terms "breast cancer" and "phase II trials" in Pubmed, we identified BP2T of systemic therapy published between June 2005 and June 2010. Reports were abstracted by 2 independent reviewers for trial characteristics, report of CS, CS features including endpoints, material, nature of sample (clinical, optional or mandatory biopsy), adequacy of samples, biopsy safety, and CS outcomes. Descriptive statistics, Fisher's exact test, and Chi-square analysis were performed.298 eligible trials enrolling a total of 18,782 patients were abstracted. 81 trials (27.2%) enrolling 5807 patients (30.9%) involved CS. Of these, 57 (70.4%) included tissue, 16 (28%) used optional research biopsy and 17 (30%) required mandatory biopsy. No trial reported biopsy safety. 55 (68%) of trials with CS specified the CS endpoint. For 44 trials (54%) the authors reported that CS was successful, while for 17 trials (21%) they specifically reported insufficient material. CS predicted response, toxicity or further characterized the tumor in 50 trials (62%). BP2T sponsored by pharmaceutical industry were more likely to involve CS (33.7% vs. 17.1%, p=0.0017). Neoadjuvant trials vs. metastatic trials and U.S.-based vs. non-U.S. trials were more likely to include CS (47% vs. 21.2%, p=0.0001; 37% vs. 21%, p=0.005). Single arm BP2T were less likely to include CS vs. randomized BP2T and phase I/II trials (22.5% vs. 42.3%, p=0.0011). There was no statistical difference between likelihood of reporting success or insufficient material for mandatory vs. optional research biopsy trials.A minority of recently published BP2T trials included CS. When CS is included, results frequently add to trial information. Reporting of CS endpoints, adequacy of samples, and biopsy safety is inconsistent or absent, and should be considered in all trials to inform policy debates over optimal and ethical CS design.

Authors
Zhang, T; Hamilton, EP; Schneider, A; Patel, K; Kamal, A; Peppercorn, JM
MLA Citation
Zhang, T, Hamilton, EP, Schneider, A, Patel, K, Kamal, A, and Peppercorn, JM. "Prevalence and impact of correlative science in breast cancer phase II trials." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 1046-.
PMID
28020693
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
1046

The role of biologic therapy in phase II breast cancer clinical trials.

e13048 Background: Molecularly-targeted biologics (BioRx) hold the promise of improving outcomes and reducing toxicity of breast cancer therapy. We evaluated outcomes and trial characteristics of recently published breast cancer phase II trials (BCT) compared to other systemic therapy interventions.We reviewed all English language phase II BCT published between June 2005 and June 2010 identified in Pubmed. Eligible trials reporting disease specific outcomes were each abstracted by two investigators. We recorded intervention, treatment setting, correlative science, and disease outcomes. Results were analyzed by descriptive statistics, chi-square analysis, student's t-test, and Wilcoxon ranked sums test.297 trials enrolling 18,319 patients were abstracted. 98 (32.7%) trials incorporated 31 unique BioRx interventions. Among these trials, 37 (37.8%) used BioRx as single agent therapy and 61 (62.2%) used BioRx combined with chemotherapy or hormone therapy. Neoadjuvant BCT were less likely to include BioRx than metastatic trials (17.4% vs. 37.2%, p = 0.006). 1st or 2nd line metastatic BCT were also less likely to include BioRx vs. late/any line trials (46.4% vs 70.4%; p<0.0003). In the metastatic setting, the median ORR for BioRx vs non-BioRx was 26.0% vs 44.2% (p<0.001). However, neither mean of medians for TTP (6.9 mo vs 7.5 mo; p=0.48) nor OS (19.6 mo vs 19.9 mo; p=0.51) were different for BioRx vs non-BioRx. Among metastatic BCT with single agent BioRx, median ORR = 6.0%, (interquartile range 1.4%-18.0%), TTP = 2.4 mo (interquartile range 1.8-5.5 mo), OS = 13.0 mo (interquartile range 6.9 -16.8 mo). Among all BioRx trials, 35.9% report no hematologic grade III/IV toxicity and 6.4% report no grade III/IV non-hematologic toxicity. Absence of grade III/IV hematologic toxicity was more common among single agent BioRx vs. combination BioRx (61.1% vs. 19%, p < 0.001).BioRx were used in 1/3 of recently published phase II BCTs. As single agents, BioRx often have reduced toxicity, but efficacy is highly variable. While median reported ORR for all BioRx trials is lower than that for other interventions, TTP and OS appear similar, supporting the belief that ORR may not be the optimal measure of BioRx efficacy.

Authors
Patel, K; Kamal, A; Zhang, T; Schneider, A; Hamilton, EP; Peppercorn, JM
MLA Citation
Patel, K, Kamal, A, Zhang, T, Schneider, A, Hamilton, EP, and Peppercorn, JM. "The role of biologic therapy in phase II breast cancer clinical trials." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): e13048-.
PMID
28019865
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
e13048
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