Abstract 442: Developing a lipogenesis inhibitor for prostate cancer

Background: Prostate cancer (PC) is the single most common and second most lethal cancer in men. Despite therapeutic advances in androgen receptor (AR)-targeting agents, progression to lethal, drug-resistant, castration-resistant prostate cancer (CRPC) remains a major clinical problem. Thus, there is an unmet need for novel treatment approaches and novel, druggable therapeutic targets in metastatic CRPC. Profiling of PC patient samples shows increases in two master regulators of lipogenesis-sterol regulatory binding proteins 1 and 2 (SREBP1 and SREBP2)-and their transcriptional targets. Overexpression of SREBP1 and SREBP2 and their target genes has been associated with tumor aggressiveness, poor clinical outcomes, and drug resistance in PC. The activation and nuclear translocation of SREBPs is tightly regulated by SREBP cleavage-activating protein (SCAP). We propose targeting SCAP will simultaneously block the activation and subsequent activity of all three SREBPs and that this represents a promising therapeutic strategy to treat CRPC. Methods: To increase our understanding of SREBP biology in PC cells, we defined the cistrome of SREBPs across multiple PC cell lines via ChIP-Seq. We compared the transcriptomic profiles of genetic targeting of SREBP via siRNA and pharmacological targeting via the novel SCAP inhibitor, SCAPi. We evaluated the effect of SCAPi on cell viability, cell invasion, and AR-signaling in multiple PC cell lines using immunoblotting, luciferase reporters, flow cytometry, MTT, and invasion assays. Additionally, we will evaluate the anticancer activity and safety profile of our novel SCAPi using CDX mouse models. Results: We found that inhibition of SCAP via siRNA and via SCAPi both yielded similar gene signatures, particularly the perturbation of cell cycle and lipogenesis genes. SCAPi dramatically reduces cell viability, migration, invasion, and expression of both AR- and SREBP-target genes in multiple PC cell lines. Through flow cytometry (Annexin V) and western blots (cleaved PARP) we found SCAPi induces apoptosis within 48 hours in PC cells. Pilot studies in tumor-bearing mice show SCAPi significantly increases survival without inducing animal weight loss. Conclusions: There is a critical need for novel targets in PC, and dysregulated lipogenesis is an untargeted oncogenic pathway. Our work furthers the field’s understanding of hijacked lipogenesis in PC and paves the way for a first-in-class inhibitor of lipogenesis to treat lethal