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

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163227-02
Application #
8765213
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$322,955
Indirect Cost
$44,010
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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
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
Chen, Sen; Cai, Changmeng; Sowalsky, Adam G et al. (2018) BMX-Mediated Regulation of Multiple Tyrosine Kinases Contributes to Castration Resistance in Prostate Cancer. Cancer Res 78:5203-5215
Lam, Hung-Ming; Corey, Eva (2018) Supraphysiological Testosterone Therapy as Treatment for Castration-Resistant Prostate Cancer. Front Oncol 8:167
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

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