Androgen receptor (AR) is a ligand-activated transcription factor and a key driver for prostate cancer (PCa) growth and progression. While the new generation of AR pathway inhibitors have shown efficacy against castration-resistant prostate cancer (CRPC), the improvement in survival is measured in months. There continues to be an urgent need for novel means of AR pathway inhibition without involving AR ligand binding. It is well-known that the transcriptional activity of the AR is prominently dictated by the protein FOXA1, which acts as a ‘pioneer’ factor opening the compacted chromatin and facilitating the recruitment of AR to specific genomic sites. Inhibition of AR through targeting FOXA1 is an attractive therapeutic approach when direct AR-targeting fails. We recently reported that critical to the function of FOXA1 is its modulation by poly-(ADP-ribose) polymerase 2 (PARP-2). PARP-2 is one of the PARP family of enzymes that uses NAD+ as a substrate to synthesize and transfer ADP-ribose polymers onto target proteins. Our studies have demonstrated that PARP-2 is a critical component in AR signaling through interacting with FOXA1. Disruption of FOXA1 function by targeting of PARP-2 is an alternative therapeutic strategy to inhibit AR signaling. Our long-term goal is to develop novel targeted therapies for CRPC patients when direct AR-targeted therapies fail. The goal of this project is to determine the molecular mechanisms by which selective targeting of PARP-2 inhibits CRPC growth through disruption of FOXA1 function and define PARP-2 as an alternative therapeutic target for CRPC.
(Supported by NCI R01)
Genomic studies have revealed a variety of actionable molecular targets with underlying genomic alterations beyond the AR. Alterations in genes involved in DNA damage response (DDR) are among the most common genetic events and enriched in metastatic CRPC. Importantly, these alterations have been correlated with therapeutic vulnerabilities. Specifically, defects in homologous recombination repair (HRR) would predict sensitivity to inhibition of Poly (ADP-ribose) polymerase (PARP). The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for the treatment of mCRPC patients with HRR mutations (largely deleterious BRCA1/2 mutations). Clinical studies have shown that tumors harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DDR genes have not been consistently predictive of clinical response to PARP inhibition. Importantly, current clinical use of PARP inhibitors is largely guided by mutations of a single gene and overlooks concurrent genomic alterations. To this end, we performed genome-wide CRISRP screening in PCa cells and discovered genes that mediate cellular response and resistance to PARPis. The goal of this project is to mechanistically define novel genes (such as RNASEH2B and MMS22L), loss of which confers BRCA-like synthetic lethality to PARP inhibition.
(Supported by DoD and NCI R01)
The Wnt gene family is known to play a critical role in development and oncogenesis. Recent genomic studies have identified β-catenin-activating genomic alteration (APC and β-catenin) in metastatic CRPC. Mutations in Wnt negative regulators (RNF43 and ZNRF3) and gain of function gene fusion involving RSPO2 have also been observed. These mutations in upstream components (RNF43, ZNRF3, and RSPO2) lead to increased cell surface abundance of Frizzled and LRP5/6 co-receptors and consequently enhanced Wnt signaling through both β-catenin-dependent (canonical) and β-catenin-independent (non-canonical) pathways. CRPC is often associated with bone metastasis, which is responsible for most prostate cancer mortality and morbidity. We are interested in understanding the molecular mechanisms of WNT signaling in promoting CRPC cell growth in bone using in vitro and in vivo models. Inhibition of WNT signaling may allow targeting both CRPC cells and bone microenvironment.
(Supported by American Cancer Society)