Tian Zhang

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

Harvard Medical School

M.H.S. 2019

Duke University School of Medicine

Internal Medicine Residency, Medicine

Duke University School of Medicine

Fellowship in Hematology-Oncology, Medicine

Duke University School of Medicine

Grants:

Duke-UNC-Wash U Partnership for Early Phase Clinical Trials in Cancer

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Significant Contributor
Start Date
End Date

Defining the Relevant Immune Checkpoints Expressed on Metastatic Prostate Cancer Circulating Tumor Cells

Administered By
Duke Cancer Institute
Awarded By
Janssen Research & Development, LLC
Role
Co-Principal Investigator
Start Date
End Date

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

Administered By
Medicine, Medical Oncology
Awarded By
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
End Date

A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)

Administered By
Duke Cancer Institute
Awarded By
Merck
Role
Principal Investigator
Start Date
End Date

A Salvage Trial of AR Inhibition with ADT and Apalutamide with Docetaxel followed by Radiation Therapy in Men with PSA Recurrent Prostate Cancer after Radical Prostatectomy (¿STARTAR¿)

Administered By
Duke Cancer Institute
Awarded By
Janssen Pharmaceutica, Inc.
Role
Principal Investigator
Start Date
End Date

Publications:

Dual-targeted hybrid nanoparticles of synergistic drugs for treating lung metastases of triple negative breast cancer in mice.

Lung metastasis is the major cause of death in patients with triple negative breast cancer (TNBC), an aggressive subtype of breast cancer with no effective therapy at present. It has been proposed that dual-targeted therapy, ie, targeting chemotherapeutic agents to both tumor vasculature and cancer cells, may offer some advantages. The present work was aimed to develop a dual-targeted synergistic drug combination nanomedicine for the treatment of lung metastases of TNBC. Thus, Arg-Gly-Asp peptide (RGD)-conjugated, doxorubicin (DOX) and mitomycin C (MMC) co-loaded polymer-lipid hybrid nanoparticles (RGD-DMPLN) were prepared and characterized. The synergism between DOX and MMC and the effect of RGD-DMPLN on cell morphology and cell viability were evaluated in human MDA-MB-231 cells in vitro. The optimal RGD density on nanoparticles (NPs) was identified based on the biodistribution and tumor accumulation of the NPs in a murine lung metastatic model of MDA-MB-231 cells. The microscopic distribution of RGD-conjugated NPs in lung metastases was examined using confocal microscopy. The anticancer efficacy of RGD-DMPLN was investigated in the lung metastatic model. A synergistic ratio of DOX and MMC was found in the MDA-MB-231 human TNBC cells. RGD-DMPLN induced morphological changes and enhanced cytotoxicity in vitro. NPs with a median RGD density showed the highest accumulation in lung metastases by targeting both tumor vasculature and cancer cells. Compared to free drugs, RGD-DMPLN exhibited significantly low toxicity to the host, liver and heart. Compared to non-targeted DMPLN or free drugs, administration of RGD-DMPLN (10 mg/kg, iv) resulted in a 4.7-fold and 31-fold reduction in the burden of lung metastases measured by bioluminescence imaging, a 2.4-fold and 4.0-fold reduction in the lung metastasis area index, and a 35% and 57% longer median survival time, respectively. Dual-targeted RGD-DMPLN, with optimal RGD density, significantly inhibited the progression of lung metastasis and extended host survival.
Authors
Zhang, T; Prasad, P; Cai, P; He, C; Shan, D; Rauth, AM; Wu, XY
MLA Citation
Zhang, Tian, et al. “Dual-targeted hybrid nanoparticles of synergistic drugs for treating lung metastases of triple negative breast cancer in mice.Acta Pharmacol Sin, vol. 38, no. 6, June 2017, pp. 835–47. Pubmed, doi:10.1038/aps.2016.166.
URI
https://scholars.duke.edu/individual/pub1452395
PMID
28216624
Source
pubmed
Published In
Acta Pharmacol Sin
Volume
38
Published Date
Start Page
835
End Page
847
DOI
10.1038/aps.2016.166

A randomized phase 2 trial of pembrolizumab versus pembrolizumab and acalabrutinib in patients with platinum-resistant metastatic urothelial cancer.

BACKGROUND: Inhibition of the programmed cell death protein 1 (PD-1) pathway has demonstrated clinical benefit in metastatic urothelial cancer (mUC); however, response rates of 15% to 26% highlight the need for more effective therapies. Bruton tyrosine kinase (BTK) inhibition may suppress myeloid-derived suppressor cells (MDSCs) and improve T-cell activation. METHODS: The Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum-Resistant Metastatic Urothelial Carcinoma (RAPID CHECK; also known as ACE-ST-005) was a randomized phase 2 trial evaluating the PD-1 inhibitor pembrolizumab with or without the BTK inhibitor acalabrutinib for patients with platinum-refractory mUC. The primary objectives were safety and objective response rates (ORRs) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Immune profiling was performed to analyze circulating monocytic MDSCs and T cells. RESULTS: Seventy-five patients were treated with pembrolizumab (n = 35) or pembrolizumab plus acalabrutinib (n = 40). The ORR was 26% with pembrolizumab (9% with a complete response [CR]) and 20% with pembrolizumab plus acalabrutinib (10% with a CR). The grade 3/4 adverse events (AEs) that occurred in ≥15% of the patients were anemia (20%) with pembrolizumab and fatigue (23%), increased alanine aminotransferase (23%), urinary tract infections (18%), and anemia (18%) with pembrolizumab plus acalabrutinib. One patient treated with pembrolizumab plus acalabrutinib had high MDSCs at the baseline, which significantly decreased at week 7. Overall, MDSCs were not correlated with a clinical response, but some subsets of CD8+ T cells did increase during the combination treatment. CONCLUSIONS: Both treatments were generally well tolerated, although serious AE rates were higher with the combination. Acalabrutinib plus pembrolizumab did not improve the ORR, PFS, or OS in comparison with pembrolizumab alone in mUC. Baseline and on-treatment peripheral monocytic MDSCs were not different in the treatment cohorts. Proliferating CD8+ T-cell subsets increased during treatment, particularly in the combination cohort. Ongoing studies are correlating these peripheral immunome findings with tissue-based immune cell infiltration.
Authors
Zhang, T; Harrison, MR; O'Donnell, PH; Alva, AS; Hahn, NM; Appleman, LJ; Cetnar, J; Burke, JM; Fleming, MT; Milowsky, MI; Mortazavi, A; Shore, N; Sonpavde, GP; Schmidt, EV; Bitman, B; Munugalavadla, V; Izumi, R; Patel, P; Staats, J; Chan, C; Weinhold, KJ; George, DJ
URI
https://scholars.duke.edu/individual/pub1453944
PMID
32757302
Source
pubmed
Published In
Cancer
Published Date
DOI
10.1002/cncr.33067

The landscape of contemporary clinical trials for untreated metastatic clear cell renal cell carcinoma.

Since the approval of immunotherapy checkpoint inhibitors for first-line treatment of metastatic renal cell carcinoma, new and clinically relevant questions have emerged that ongoing clinical trials and trials in development will address. These questions include how to integrate combination immunotherapy approaches like ipilimumab/nivolumab with targeted therapies against vascular endothelial growth factor (VEGF) receptors, which patients can discontinue treatment, and who needs ipilimumab to maximize clinical responses. Furthermore, with new approvals of treatment regimens combining checkpoint inhibitors with targeted therapies, new questions arise in the clinic regarding optimal treatment selection for first-line clear cell renal cell carcinoma. This review will highlight the contemporary clinical trials in metastatic clear cell renal cell carcinoma that try to address some of these knowledge gaps.
Authors
MLA Citation
Zhang, Tian, et al. “The landscape of contemporary clinical trials for untreated metastatic clear cell renal cell carcinoma.Cancer Treat Res Commun, vol. 24, June 2020, p. 100183. Pubmed, doi:10.1016/j.ctarc.2020.100183.
URI
https://scholars.duke.edu/individual/pub1448033
PMID
32563923
Source
pubmed
Published In
Cancer Treatment and Research Communications
Volume
24
Published Date
Start Page
100183
DOI
10.1016/j.ctarc.2020.100183

Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients

© 2020, © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. Background: Biomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice. Methods: Tumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome. Results: For 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant (p = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved (p = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%). Conclusions: Cell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progression-free survival (PFS) along with sufficiently powered subgroups are required to further support these findings.
Authors
Zhang, T; Pabla, S; Lenzo, FL; Conroy, JM; Nesline, MK; Glenn, ST; Papanicolau-Sengos, A; Burgher, B; Giamo, V; Andreas, J; Wang, Y; Bshara, W; Madden, KG; Shirai, K; Dragnev, K; Tafe, LJ; Gupta, R; Zhu, J; Labriola, M; McCall, S; George, DJ; Ghatalia, P; Dayyani, F; Edwards, R; Park, MS; Singh, R; Jacob, R; George, S; Xu, B; Zibelman, M; Kurzrock, R; Morrison, C
MLA Citation
Zhang, T., et al. “Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients.” Oncoimmunology, vol. 9, no. 1, Jan. 2020. Scopus, doi:10.1080/2162402X.2020.1773200.
URI
https://scholars.duke.edu/individual/pub1449567
Source
scopus
Published In
Oncoimmunology
Volume
9
Published Date
DOI
10.1080/2162402X.2020.1773200

Blood-brain barrier-penetrating amphiphilic polymer nanoparticles deliver docetaxel for the treatment of brain metastases of triple negative breast cancer.

Brain metastasis is a fatal disease with limited treatment options and very short survival. Although systemic chemotherapy has some effect on peripheral metastases of breast cancer, it is ineffective in treating brain metastasis due largely to the blood-brain barrier (BBB). Here we developed a BBB-penetrating amphiphilic polymer-lipid nanoparticle (NP) system that efficiently delivered anti-mitotic drug docetaxel (DTX) for the treatment of brain metastasis of triple negative breast cancer (TNBC). We evaluated the biodistribution, brain accumulation, pharmacokinetics and efficacy of DTX-NP in a mouse model of brain metastasis of TNBC. Confocal fluorescence microscopy revealed extravasation of dye-loaded NPs from intact brain microvessels in healthy mice. DTX-NP also extravasated from brain microvessels and accumulated in micrometastasis lesions in the brain. Intravenously injected DTX-NPs increased the blood circulation time of DTX by 5.5-fold and the AUC0-24h in tumor-bearing brain by 5-fold compared to the clinically used DTX formulation Taxotere®. The kinetics of NPs in the brain, determined by ex vivo fluorescence imaging, showed synchronization with DTX kinetics in the brain measured by LC-MS/MS. This result confirmed successful delivery of DTX by the NPs into the brain and suggested that ex vivo fluorescence imaging of NP could be an effective and quick means for probing drug disposition in the brain. Treatment with the DTX-NP formulation delayed tumor growth by 11-fold and prolonged median survival of tumor-bearing mice by 94% compared to an equivalent dose of Taxotere®, without inducing histological changes in the major organs.
Authors
He, C; Cai, P; Li, J; Zhang, T; Lin, L; Abbasi, AZ; Henderson, JT; Rauth, AM; Wu, XY
MLA Citation
He, Chunsheng, et al. “Blood-brain barrier-penetrating amphiphilic polymer nanoparticles deliver docetaxel for the treatment of brain metastases of triple negative breast cancer.J Control Release, vol. 246, Jan. 2017, pp. 98–109. Pubmed, doi:10.1016/j.jconrel.2016.12.019.
URI
https://scholars.duke.edu/individual/pub1452396
PMID
28017889
Source
pubmed
Published In
J Control Release
Volume
246
Published Date
Start Page
98
End Page
109
DOI
10.1016/j.jconrel.2016.12.019