Our understanding of prostate cancer has grown enormously over the past several years. From a treatment perspective, it has become clear that castration-resistant prostate cancer (CRPC) mainly owes this property to reactivation of androgen receptor (AR) signaling pathways. This has led to new targeted therapies, which have just received or are nearing FDA approval, but these have substantial shortcomings. One of these is the novel antiandrogen MDV3100 discovered and developed by our lab (Tran et al Science 2009). Roughly half of CRPC patients present with therapy-resistant disease and most of those who initially respond acquire resistance over time. We have conducted in vitro and in vivo screens of acquired resistance to MDV3100 in two human prostate cancer model systems. Transcriptome analysis of dozens of drug-sensitive and drug-resistant pairs revealed a novel, common resistance mechanism. Unlike the primary mechanism of resistance to first generation antiandrogen therapy which occurs due to upregulation of AR (Chen et al Nat Med 2004), resistance to MDV3100 is consistently associated with upregulation of the glucocorticoid receptor (GR). Furthermore, many AR target genes remain inhibited in drug-resistant tumors, indicating that the classical AR signaling pathway remains """"""""inhibited"""""""" by MDV3100. However, expression of some AR target genes is restored but in a manner that is now dependent on GR. We propose a model whereby resistance to MDV3100 (and perhaps other next generation antiandrogens) occurs through nuclear receptor bypass (GR replaces AR). Here we will explore the molecular basis by which GR selectively activates certain AR target genes (Aim 1), the functional role of GR, AR and the GR/AR target gene SGK1 in maintaining drug resistance (Aim 2), and the clinical relevance of these findings in circulating tumor cells obtained from patients t treatment start and at relapse (Aim 3).

Public Health Relevance

There is much excitement in the prostate cancer community today based on the clinical success of new drugs that target androgen receptor signaling. These drugs represent terrific progress but they are not cures. This work explores why men with prostate cancer develop resistance to these drugs and provide a strategy to overcome this resistance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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Sloan-Kettering Institute for Cancer Research
New York
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Karthaus, Wouter R; Sawyers, Charles L (2018) Strategies to Identify and Target Cells of Origin in Prostate Cancer. J Natl Cancer Inst :
Luo, Jun; Attard, Gerhardt; Balk, Steven P et al. (2018) Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting. Eur Urol 73:715-723
Hieronymus, Haley; Murali, Rajmohan; Tin, Amy et al. (2018) Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. Elife 7:
Puca, Loredana; Bareja, Rohan; Prandi, Davide et al. (2018) Patient derived organoids to model rare prostate cancer phenotypes. Nat Commun 9:2404
Armenia, Joshua; Wankowicz, Stephanie A M; Liu, David et al. (2018) The long tail of oncogenic drivers in prostate cancer. Nat Genet 50:645-651
Nava Rodrigues, Daniel; Rescigno, Pasquale; Liu, David et al. (2018) Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest 128:4441-4453
Shah, Neel; Wang, Ping; Wongvipat, John et al. (2017) Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife 6:
Bose, Rohit; Karthaus, Wouter R; Armenia, Joshua et al. (2017) ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis. Nature 546:671-675
Ku, Sheng Yu; Rosario, Spencer; Wang, Yanqing et al. (2017) Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355:78-83
Mu, Ping; Zhang, Zeda; Benelli, Matteo et al. (2017) SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355:84-88

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