Drug Development for Prostate Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Our understanding of the biology of CRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. We are interested in the preclinical and clinical development of novel therapeutics with efforts on characterizing their molecular and clinical pharmacology as well as evaluating for potential biomarkers of treatment response and resistance. Cancer organoids are three-dimensional culture systems derived from patient tumor tissues that closely recapitulate the histological architecture and molecular characteristics of the original tumor. These models provide a physiologically relevant platform for high-throughput drug screening and the identification of novel therapeutic targets. Tumor organoids have demonstrated utility in predicting patient-specific responses to chemoradiotherapy, targeted therapies, and immunotherapies, thereby supporting their role in guiding personalized cancer treatment. We have developed prostate cancer organoid models and utilized them in comprehensive drug screening to identify novel synergistic drug combinations. Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge, with patients often developing resistance to androgen receptor (AR)-axis-targeted therapies such as abiraterone and enzalutamide. A key resistance mechanism involves the clinically validated biomarker, AR splice variant AR-V7, which drives tumor progression and poor prognosis. To address the need for novel, effective treatment strategies, we conducted unbiased high-throughput screening (HTS) to discover highly synergistic drug combinations that improve therapeutic efficacy, overcome resistance mechanisms, and minimize toxicity. Leveraging a robotic automation platform, we quantitatively screened 2,480 mechanistically annotated compounds from an oncology-focused library, targeting over 800 biological pathways, across 8 prostate cancer cell lines representing various stages of disease progression. Single-agent cytotoxicity was evaluated using an area under the 11-point dose-response curve (AUC) metric, identifying therapeutically vulnerable targets in mCRPC. Utilizing the Excess Highest Single Agent (HSA) model to quantify synergy/antagonism, this large-scale analysis revealed highly synergistic combinations. We are currently testing promising combinations in various preclinical prostate cancer models with the goal of selecting the best treatment combination to move towards clinical development. One of these combinations target the apoptosis pathways. Bcl-xL (A-1331852 and navitoclax) and Mcl-1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7 expressing CRPC cell lines (LNCaP95, VCaP-CR, 22Rv1) and a patient-derived organoid model (LuCaP 167 CR). We also explored the use of a Bcl-xL-specific PROTAC degrader to minimize platelet toxicity associated with Bcl-xL inhibitors. We showed similar synergistic efficacy with the Bcl-xL targeting PROTAC in combination with S63845 in the 3D spheroid models. Our findings support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC. We are currently investigating other promising combinations in patient-derived mCRPC organoid models and performing high-throughput RNA sequencing and proteomics to elucidate the mechanisms driving the treatment combination synergy.