Since the inception of clinical efforts in prostate cancer (PCa) to suppress androgen receptor (AR) signaling by reducing AR ligands (androgen deprivation therapy, ADT), it was recognized that the administration of testosterone (T) to men who have relapsed after ADT (castration-resistant prostate cancer, CRPC) could result in substantial clinical responses. However, these reports were largely anecdotal and remissions were highly variable. In contrast, abundant data from preclinical models have reproducibly shown biphasic responses of hormone-sensitive cancers, whereby at physiological T concentrations proliferation is induced, but at higher, supraphysiological androgen (SPA) concentrations, proliferation is suppressed and in some instances apoptotic programs are engaged. Though often considered to be an in vitro phenomenon of little clinical importance, recent rigorously controlled clinical trials of SPA produced substantial clinical responses in subsets of men with CRPC. Collectively, these findings support studies designed to determine the molecular mechanism(s) driving these responses. Based on these preclinical and clinical findings to date, we hypothesize that the genomic and epigenomic adaptive processes that contribute to CRPC progression also sensitize tumor cells to the differentiation, quiescence and apoptotic programs regulated by the AR under conditions of SPA. We will test this hypothesis through three linked aims:
AIM 1. Determine the primary mechanism(s) by which SPA represses CRPC.
AIM 2. Define the AR cistrome in prostate cancers reprogrammed by SPA and identify cooperating genes and pathways that are essential or suppressive of SPA effects.
AIM 3. Identify drug combinations that synergize with SPA to repress tumor growth and optimize the effects of AR agonism based on a mechanistic understanding of SPA-mediated growth arrest.
Preclinical studies and recent clinical findings indicate that the genomic and epigenomic adaptive processes that contribute to castration-resistant prostate cancer (CRPC) progression also sensitize tumor cells to the differentiation, quiescence and apoptotic programs regulated by the androgen receptor (AR) under conditions of supraphysiological androgen (SPA) concentrations. Our objectives are to test this hypothesis, to determine mechanisms by which SPA suppresses tumor growth, to identify biomarkers that may predict responses to SPA in patients and to develop treatment strategies that augment SPA anti-tumor effects.
|Beshiri, Michael L; Tice, Caitlin M; Tran, Crystal et al. (2018) A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening. Clin Cancer Res 24:4332-4345|
|Russo, Joshua W; Liu, Xiaming; Ye, Huihui et al. (2018) Phosphorylation of androgen receptor serine 81 is associated with its reactivation in castration-resistant prostate cancer. Cancer Lett 438:97-104|
|Mostaghel, Elahe A (2018) Alternative Acts: Oncogenic Splicing of Steroidogenic Enzymes in Prostate Cancer. Clin Cancer Res :|
|Uo, Takuma; Plymate, Stephen R; Sprenger, Cynthia C (2018) The potential of AR-V7 as a therapeutic target. Expert Opin Ther Targets 22:201-216|
|Arai, Seiji; Jonas, Oliver; Whitman, Matthew A et al. (2018) Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis. Clin Cancer Res 24:5458-5470|
|Viswanathan, Srinivas R; Ha, Gavin; Hoff, Andreas M et al. (2018) Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing. Cell 174:433-447.e19|
|Russo, Joshua W; Gao, Ce; Bhasin, Swati S et al. (2018) Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer. Cancer Res 78:6354-6362|
|Sowalsky, Adam G; Ye, Huihui; Bhasin, Manoj et al. (2018) Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations. Cancer Res 78:4716-4730|
|Zhu, Yezi; Sharp, Adam; Anderson, Courtney M et al. (2018) Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Eur Urol 73:727-735|
|Penning, Trevor M (2018) Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer. Vitam Horm 108:309-331|
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