Abstract 1565: A novel therapeutic target in lethal prostate cancer in African American males

Abstract

Abstract Background: The largest US cancer health disparity exists in prostate cancer (PC), with African American (AA) men having a 1.6-fold increased risk of developing PC; younger age and more advanced stage at diagnosis; increased risk for recurrence; and a 2.5-fold increased mortality rate relative to Caucasian American (CA) men. In addition to important socioeconomic and environmental factors, this disparity is linked to incompletely understood genetic and other intrinsic biological factors. Consequently, there is an unmet need to identify actionable targets in AA PC in order to develop more effective therapeutics and, ultimately, improve clinical outcomes for AA PC patients. Rationale/Hypothesis: The p160 Steroid Receptor Coactivator (SRC) family (SRC-1, SRC-2, and SRC-3), are master regulators of transcriptional activity. They cooperate with several oncogenic transcription factors to mediate their gene expression programs, thus representing a critical connecting signaling node in PC. We have hypothesized that the p160 SRCs underlie the higher aggressiveness of AA PC and proposed that the inhibition of the p160 SRCs can target the oncogenic transcriptional programs of AA PC, suppress AA PC cell proliferation, survival, and metastasis, and improve outcomes for AA PC patients. Data from the three p160 SRC knockout mouse models (Src1, Src2, or Src3 knockout mice) show no negative effect on mouse lifespan, suggesting the possibility of a therapeutic window. Experimental approach: We utilized state-of-the-art in vitro assays and multi-Omics datasets to examine these hypotheses and shed light onto the role of the p160 SRCs in the intrinsic biological aggressiveness of AA PC. Recently, our BCM group synthesized an innovative panel of small molecule inhibitors (SMIs) of the p160 SRCs. We examined the efficacy of our novel p160 SRC SMIs against AA PC cell lines and patient-derived xenografts (PDXs). Results: The p160 SRCs exhibit increased activity in AA PC compared to CA PC. They are important regulators of the transcriptional programs that drive AA PC cell proliferation, metabolism, invasion, and metastasis. Importantly, our novel p160 SRC SMIs potently suppress multiple oncogenic signaling programs in AA PC cells and inhibit cell proliferation. They also potently suppress key AA PC driver transcription factors, including AR, SREBP1, and MNX1. The latter two are - so far - undruggable oncogenic transcription factors that our extended BCM group recently discovered to be specifically overexpressed in AA PC. Furthermore, our lead SMI is well tolerated in mice and can inhibit PC cell proliferation and tumor growth in vivo. Conclusions: We propose pharmacologic inhibition of the p160 SRC as an innovative treatment opportunity that will target several signaling pathways simultaneously and improve clinical outcomes in AA PC. Citation Format: Salma Kaochar, Michael Ittmann, Matthew Robertson, Jin Wang, Darlene Skapura, Christel Davis, Erik Ehli, Matthew Freedman, Cristian Coarfa, Bert O'Malley, Nicholas Mitsiades. A novel therapeutic target in lethal prostate cancer in African American males [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1565.