DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

SLCO2B1 and SLCO1B3 as New Targets for Enhancing Androgen Deprivation Therapy for Prostate Cancer

Principal Investigator: KANTOFF, PHILIP W
Institution Receiving Award: DANA-FARBER CANCER INSTITUTE
Program: PCRP
Proposal Number: PC130726
Award Number: W81XWH-14-1-0515
Funding Mechanism: Idea Development Award-Established Investigator
Partnering Awards:
Award Amount: $648,750.00


PUBLIC ABSTRACT

Almost all prostate cancers (PCa) depend on androgens for growth in its initial stages. We can suppress testicular androgen production with androgen deprivation therapy (ADT), which is the most effective and widely used therapy for PCa patients. However, residual androgen in patients still can active the androgen receptor (AR) and lead to castration-resistant PCa (CRPC), which is usually lethal. DHEA (dehydroepiandrosterone) and its sulfated form, DHEAS, are secreted in large amounts by the adrenal cortex and are precursors for the production of T (testosterone) and DHT (dihydrotestosterone), the most potent androgens. Therefore, blocking the uptake of adrenal androgens in the prostate could enhance the efficacy of ADT. SLCO2B1 and SLCO1B3 are two transporter genes involved in DHEAS and T uptake in the prostate. Evidence exists that SLCO2B1 and SLCO1B3 are expressed at higher levels in advanced PCa and that the expression levels and genotypes of these two genes are correlated with the uptake activity of DHEAS and T and outcomes of PCa. Since statins and estrogens have been shown to use the SLCO2B1 and SLCO1B3 transporters and have an effect on the advanced prostate cancer, we hypothesize that statins and estrogens might work by blocking the uptake of androgens via interactions with SLCO2B1 and SLCO1B3. Therefore, illustrating the role and inhibiting the transport activity of SLCO2B1 and SLCO1B3 in CRPC will ultimately lead to improved outcomes of PCa. In this study, we will determine the mechanism if statins/estrogens compete for the DHEAS/T uptake through the SLCO2B1 and SLCO1B3 transporters. We will also design specific inhibitors of SLCO2B1 and SLCO1B3. A combination treatment with ADT and statins or inhibitors of SLCO2B1 and SLCO1B3 may significantly enhance the efficacy of ADT and outcomes in PCa patients.

New Food and Drug Administration-approved agents such as abiraterone and enzalutamide successfully target the androgen pathway, but resistance in patients ultimately develops and adaptive mechanisms permitting the continued stimulation of AR by persistent ligand occurs. Novel therapeutic targets potentially improving the efficacy of ADT by further inhibition of residual androgens are needed. Based on our proposed study, we plan to develop SLCO2B1 and SLCO1B3 genotypes as biomarkers, and also improve the outcomes of PCa through inhibition of SLCO2B1 and SLCO1B3. Herein we will validate the basis of the putative benefit seen with statins and develop more potent inhibitors of this important adaptive pathway. If experimental results in our study develop as anticipated, we estimate that within 3-5 years, a clinically meaningful outcome will be achieved.

This study will reveal the mechanisms of CRPC development and enhance our understanding of molecular mechanisms underlying the impact of statins or estrogens on PCa progression. It will pave a new road to improve the efficacy of ADT by focusing on new therapeutic targets in PCa patients.