Abstract A070: Determining gene expression regulated by androgen receptor variant 7 in co-loss of MAP3K7/CHD1 prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the second leading cancer diagnosis in men. The ACS estimates 268,490 new cases of PCa and 34,500 deaths in 2022. Most patients with local PCa are disease free at the 5-year mark. Patients with metastatic PCa only have a 31% 5-year disease-free survival rate. While these patients may initially respond to androgen deprivation therapy, many will progress to castration-resistant prostate cancer (CRPC) and fail treatment. There is a need to develop new therapies to treat CRPC. The Cramer lab studies the dual deletion of MAP3K7 and CHD1 PCa subtype. In MAP3K7/CHD1-depleted PCa cell lines the ratio of AR splicing variants shifts to enrich for the constitutively active variant AR-v7, a known driver of CRPC. Other studies demonstrated that AR-v7 has unique target genes and can alter canonical AR target gene expression. I hypothesize that gain of AR-v7 signaling activates atypical gene targets which alter the gene expression of MAP3K7/CHD1-depleted PCa. I will determine the chromatin-binding targets and identify AR-v7 specific candidate genes. Patients with loss of MAP3K7 and CHD1 also enrich in the spliceosome protein U2AF2, therefore I will also perform transcriptomics with/without AR-FL and AR-v7 to characterize the larger impacts of AR-variant signaling at the RNA level. To this end, I will develop an inducible knockdown system in dual shMAP3K7/shCHD1 cells targeting AR-FL, AR-v7, and AR-Total. This will provide insight into the role of AR-v7 in two stages of gene expression and identify candidate therapeutic genes/pathways in loss of MAP3K7 and CHD1 PCa. Citation Format: Claire Gillette, Lauren Jillson, Scott Cramer. Determining gene expression regulated by androgen receptor variant 7 in co-loss of MAP3K7/CHD1 prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A070.