Treatment options for patients with castration-resistant prostate cancer (CRPC) are expanding. However, 27,000 men will still die from this disease in 2017. We and others have found that widespread use of novel and more potent androgen receptor (AR)-targeting agents has increased the clinical frequency of virulent and untreatable AR-independent CRPC subsets. These subsets include: AR-indifferent prostate cancer (AIPC) with persistent AR expression but reduced AR function, neuroendocrine prostate cancer (NEPC), and AR-null tumors without neuroendocrine differentiation that we have termed double-negative prostate cancer (DNPC). However, very little is known about what factors promote the transition to and maintenance of specific AR-independent subsets. Furthermore, there are no effective treatments for patients with these tumors. The goal of this proposal is to overcome those deficits. Our studies using human AIPC, NEPC, and DNPC patient tumors and model systems identified specific transcriptional regulators, including BET bromodomain chromatin reader proteins, Master Regulator transcription factors (TFs), and kinases that are activated in AIPC, NEPC, and DNPC. In this proposal, we will test the overarching hypothesis that gene networks regulated by BET bromodomain proteins, aberrantly activated TFs or kinases, and other key signaling pathways promote AR-independent CRPC cell survival. We propose the following Aims:
Aim 1 : Determine the anti-tumor activity of the BET bromodomain inhibitor ZEN-3694 in patients with AR- independent CRPC.
Aim 2 : Identify and target critical Master Regulator transcription factors and kinases that promote AR- independent cell survival.
Aim 3 : Identify molecular markers of transition from AR-active to AR-independent CRPC subsets and identify and target critical pathways that promote survival of specific AR-independent subsets. The completion of the proposed work will lead to the development of rational clinical trials of BETi drug combinations to block critical networks that sustain the survival of AR-independent, lethal prostate cancers.

Public Health Relevance

The goal of this proposal is to clarify transcriptional and cell signaling networks that are critical for survival of lethal metastatic prostate tumors that are no longer reliant on the androgen receptor (AR) ? a tumor subset that is increasing in frequency clinically. A predicted outcome of our efforts is the development of new targeted treatment strategies for men with AR-independent, lethal prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097186-18
Application #
10016185
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2002-09-19
Project End
2023-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
18
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Chalfin, Heather J; Glavaris, Stephanie A; Malihi, Paymaneh D et al. (2018) Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms. J Urol 199:1494-1501
Inoue, Lurdes Y T; Lin, Daniel W; Newcomb, Lisa F et al. (2018) Comparative Analysis of Biopsy Upgrading in Four Prostate Cancer Active Surveillance Cohorts. Ann Intern Med 168:1-9
Cheng, Heather H; Plets, Melissa; Li, Hongli et al. (2018) Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone-sensitive prostate cancer. Prostate 78:121-127
Levesque, Christine; Nelson, Peter S (2018) Cellular Constituents of the Prostate Stroma: Key Contributors to Prostate Cancer Progression and Therapy Resistance. Cold Spring Harb Perspect Med 8:
Barnard, Monique; Quanson, Jonathan L; Mostaghel, Elahe et al. (2018) 11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer. J Steroid Biochem Mol Biol 183:192-201
Ganaie, Arsheed A; Beigh, Firdous H; Astone, Matteo et al. (2018) BMI1 Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models. Clin Cancer Res 24:6421-6432
Schweizer, Michael T; Haugk, Kathleen; McKiernan, Jožefa S et al. (2018) A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer. PLoS One 13:e0198389
Peacock, James W; Takeuchi, Ario; Hayashi, Norihiro et al. (2018) SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1. EMBO Mol Med 10:219-238
Pollan, Sara G; Huang, Fangjin; Sperger, Jamie M et al. (2018) Regulation of inside-out ?1-integrin activation by CDCP1. Oncogene 37:2817-2836
Wu, Yi-Mi; Cie?lik, Marcin; Lonigro, Robert J et al. (2018) Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 173:1770-1782.e14

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