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).
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.
|Doran, Michael G; Carnazza, Kathryn E; Steckler, Jeffrey M et al. (2016) Applying â¸â¹Zr-Transferrin To Study the Pharmacology of Inhibitors to BET Bromodomain Containing Proteins. Mol Pharm 13:683-8|
|Drost, Jarno; Karthaus, Wouter R; Gao, Dong et al. (2016) Organoid culture systems for prostate epithelial and cancer tissue. Nat Protoc 11:347-58|
|Wheeler, Douglas B; Zoncu, Roberto; Root, David E et al. (2015) Identification of an oncogenic RAB protein. Science 350:211-7|
|Watson, Philip A; Arora, Vivek K; Sawyers, Charles L (2015) Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer 15:701-11|
|Wanjala, Jackie; Taylor, Barry S; Chapinski, Caren et al. (2015) Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling. Mol Cancer Ther 14:278-88|
|Spratt, Daniel E; Evans, Michael J; Davis, Brian J et al. (2015) Androgen Receptor Upregulation Mediates Radioresistance after Ionizing Radiation. Cancer Res 75:4688-96|
|Schwartz, Sarit; Wongvipat, John; Trigwell, Cath B et al. (2015) Feedback suppression of PI3KÎ± signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3KÎ². Cancer Cell 27:109-22|
|Robinson, Dan; Van Allen, Eliezer M; Wu, Yi-Mi et al. (2015) Integrative clinical genomics of advanced prostate cancer. Cell 161:1215-28|
|Agarwal, Supreet; Hynes, Paul G; Tillman, Heather S et al. (2015) Identification of Different Classes of Luminal Progenitor Cells within Prostate Tumors. Cell Rep 13:2147-58|
|Karthaus, Wouter R; Iaquinta, Phillip J; Drost, Jarno et al. (2014) Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 159:163-75|
Showing the most recent 10 out of 17 publications