Men with advanced prostate cancer are treated with hormonal therapy, which leads to an initial response that inevitably recurs in the lethal form of the disease termed castration-resistant prostate cancer (CRPC). While the androgen-signaling axis is the predominant target for therapy in the field, pathways promoting survival and proliferation that are independent of the AR axis need to be identified for potent combinatorial therapeutic strategies. Importantly, therapies aimed at depleting stem/progenitor cell mechanisms, such as self-renewal, have not been adequately explored. We have recently discovered that the stem cell marker Trop2 is a new regulator of self-renewal and proliferation in the prostate and is strongly associated with a castration-resistant state. We have defined a mechanism of action for Trop2 through regulated proteolysis, leading to release of an intracellular domain, similar to activation of Notch. As Trop2 marks and regulates stem cells and is associated with castration-resistance, we propose that blocking Trop2 proteolysis/ activation will inhibit stem-like capacities including self-renewal and proliferation and prevent disease-recurrence. In this proposal, we will utilize clinical specimens, primary regenerated tumors and established cancer xenografts to evaluate Trop2 proteolytic processing as a therapeutic target for future clinical trials in prostate cancer. The goal of AIM 1 is to validate Trop2 as a target in clinical prostate cancer specimens by measuring Trop2, its proteolytic products and downstream effectors in prostate cancer subjects. The goal of AIM 2 is to determine the role of Trop2 in human prostate self-renewal and tumorigenesis, using a dissociated cell tissue recombination strategy to evaluate Trop2+ cells and Trop2 itself in genetically defined primary tumors in vivo. The goal of AIM 3 is to investigate mechanisms to target Trop2 in pre-clinical studies. These experiments will utilize genetic and chemical approaches to establish the role of Trop2 regulated proteolysis, and assess monoclonal antibodies for their ability to interfere with Trop2 processing and tumor growth.

Public Health Relevance

This proposal will evaluate a new target, Trop2, in advanced prostate cancer and establish the feasibility of inhibiting Trop2 in future clinical trials. Blocking Trop2 and its associated growth-promoting effects may be an effective strategy to treat patients with advanced disease and prevent recurrence in the form of the lethal castration-resistant prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of California Los Angeles
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Chen, Changhao; Cai, Qingqing; He, Wang et al. (2016) An NKX3.1 binding site polymorphism in the l-plastin promoter leads to differential gene expression in human prostate cancer. Int J Cancer 138:74-86
Yan, Yunwen; Li, Zhen; Xu, Xiang et al. (2016) All-trans retinoic acids induce differentiation and sensitize a radioresistant breast cancer cells to chemotherapy. BMC Complement Altern Med 16:113
Hurley, Paula J; Sundi, Debasish; Shinder, Brian et al. (2016) Germline Variants in Asporin Vary by Race, Modulate the Tumor Microenvironment, and Are Differentially Associated with Metastatic Prostate Cancer. Clin Cancer Res 22:448-58
Faltermeier, Claire M; Drake, Justin M; Clark, Peter M et al. (2016) Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A 113:E172-81
Liang, Pei; Henning, Susanne M; Schokrpur, Shiruyeh et al. (2016) Effect of Dietary Omega-3 Fatty Acids on Tumor-Associated Macrophages and Prostate Cancer Progression. Prostate 76:1293-302
Lee, John K; Phillips, John W; Smith, Bryan A et al. (2016) N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells. Cancer Cell 29:536-47
Wang, Piwen; Henning, Susanne M; Magyar, Clara E et al. (2016) Green tea and quercetin sensitize PC-3 xenograft prostate tumors to docetaxel chemotherapy. J Exp Clin Cancer Res 35:73
Hu, Yangyang; Dong, Xuecheng; Wang, Guangchun et al. (2016) Five-Year Follow-Up Study of Transurethral Plasmakinetic Resection of the Prostate for Benign Prostatic Hyperplasia. J Endourol 30:97-101
Park, Jung Wook; Lee, John K; Phillips, John W et al. (2016) Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay. Proc Natl Acad Sci U S A 113:4482-7
Stoyanova, Tanya; Riedinger, Mireille; Lin, Shu et al. (2016) Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. Proc Natl Acad Sci U S A 113:E6457-E6466

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