The observation that androgen-regulated genes are almost universally expressed in CRPC has prompted a search for processes that contribute to androgen receptor (AR) activation in the castrate environment. While pathways leading to prostate cancer growth and AR signaling may be entirely ligand-independent, many of the processes identified to date either still require or are enhanced by the presence of ligand. We hypothesize that castration-resistant prostate cancers arise through a process of metabolic adaptation involving the biosynthesis of AR ligands, rather than the selective propagation of rare tumor cells harboring advantageous genomic mutations/chromosomal alterations. Determining the key adaptive components has important implications for developing effective treatment strategies focused on modulating steroidogenic mechanisms. Thus, we also hypothesize that targeting components of androgen metabolism will inhibit the development or progression of CRPC. This proposal will i) evaluate the phenotype(s) of prostate tumor cells arising during metabolic adaptation to castration;and ii) define the AR ligand-generating pathways that emerge, providing novel data on critical nodes amenable to exploitation as therapeutic targets and for stratification of patients for appropriate interventions. We propose the following Specific Aims:
AIM 1. Determine the contribution of steroid biosynthetic enzymes to the generation of intratumoral androgens and consequent tumor cell survival in CRPC. These studies will determine the frequency and mechanism(s) by which prostate tumors synthesize androgens de novo, determine the rate-limiting reactions, and determine if enhanced androgen metabolism contributes to tumor progression.
AIM 2. Determine the mechanism(s) underlying the coordinate regulation of androgen biosynthetic enzymes and activation of the AR gene expression program in prostate cancers following the systemic reduction of androgens.
AIM 3. Determine the therapeutic effectiveness of progressive inhibition of androgen metabolism and identify resistance mechanisms to metabolism-directed therapy in CRPC. These studies will determine the efficacy of progressively severe AR-pathway blockade on inhibiting intratumoral androgen production, evaluate the attendant effects on CRPC, and identify mechanisms leading to further tumor progression/resistance
This persistent, or indeed insistent AR signaling in CRPC, coupled with the expression of genes that contribute to invasive cancer behavior (e.g. ERG), indicates that the AR program continues to represent an important treatment target. As androgens represent a driver of AR activity, identifying and subsequently inhibiting key ligand-generating mechanisms would reduce AR signaling, and could substantially improve responses, reduce morbidity, and prolong survival.
|Damodarasamy, Mamatha; Vernon, Robert B; Chan, Christina K et al. (2015) Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation. In Vitro Cell Dev Biol Anim 51:50-8|
|Chen, Eddy J; Sowalsky, Adam G; Gao, Shuai et al. (2015) Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res 21:1273-80|
|Sowalsky, Adam G; Xia, Zheng; Wang, Liguo et al. (2015) Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. Mol Cancer Res 13:98-106|
|Tamae, Daniel; Mostaghel, Elahe; Montgomery, Bruce et al. (2015) The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chem Biol Interact 234:332-8|
|Jehle, Katja; Cato, Laura; Neeb, Antje et al. (2014) Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif. J Biol Chem 289:8839-51|
|Hsieh, Chen-Lin; Fei, Teng; Chen, Yiwen et al. (2014) Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci U S A 111:7319-24|
|Cao, Bo; Qi, Yanfeng; Zhang, Guanyi et al. (2014) Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget 5:1646-56|
|He, Housheng Hansen; Meyer, Clifford A; Hu, Sheng'en Shawn et al. (2014) Refined DNase-seq protocol and data analysis reveals intrinsic bias in transcription factor footprint identification. Nat Methods 11:73-8|
|Penning, Trevor M (2014) Androgen biosynthesis in castration-resistant prostate cancer. Endocr Relat Cancer 21:T67-78|
|Thadani-Mulero, Maria; Portella, Luigi; Sun, Shihua et al. (2014) Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res 74:2270-82|
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