Abstract 979: Bcl-2 inhibitor enhances anti-androgen therapy induced regression of castration sensitive prostate cancer
Authors: Hirani Rahim , Nandakumar Subhiksha , Kalidindi Teja , Fidele Deborah , Rajanala Harisha , Mazzu Ying , Yoshikawa Yuki , Jehane Lina , Lee Gwo-Shu Mary , de Stanchina Elisa , Sowalsky Adam , Morris Michael J. , Schoder Heiko , Pillarsetty Naga Vara Kishore , Mucci Lorelei A. , Danila Daniel , Chakraborty Goutam , Kantoff Philip W. 
Published: July 2021

Abstract
Prostate cancer (PC) is the second most common cause of cancer-related deaths in males in the United States (U.S.). In the United States, an estimated 191,930 new cases will be diagnosed in 2020, resulting in 33,330 deaths, representing 10.4% of all cancer-related deaths in men in the U.S. Over the past decade, preclinical studies have demonstrated that androgen receptor (AR) signaling is a principal driver of prostate cancer, and androgen deprivation therapy (ADT) has been a mainstay in the treatment of PC. Although most PCs are initially sensitive to ADT, the duration of response is variable, and relapse invariably occurs in the transition to metastatic castration-resistant prostate cancer (mCRPC) the most lethal form of the disease. A significant proportion of mCRPCs exhibit alteration (amplification and mutation) of the AR gene. Notably, localized castration sensitive prostate cancer (CSPC) rarely demonstrates alterations of AR. This observation indicates that the alteration of AR likely results from exposure to systemic therapies rather than acting as a driver from primary CSPC to more aggressive disease. For mCRPC patients, many initially respond to second-line AR inhibitors (eg. enzalutamide and abiraterone) or docetaxel-based chemotherapy, however durable responses are rare. Therefore, it is vital to investigate additional therapeutic strategies to delay or prevent the transition of CSPC to mCRPC.
Earlier studies showed that the survival of malignant cells after anti-cancer therapies could be due to increase expression in anti-apoptotic proteins, such as the Bcl-2 family of proteins. In our current study, we observed that treatment with androgen inhibits but AR inhibitors (eg enzalutamide, apalutamide) restore Bcl2 expression in human CSPC cell lines indicating possible direct negative-regulation of the Bcl2 by the AR-signaling pathway. Experimentally we also showed that overexpression of BCL2 in human CSPC cells acts as an early mediator of ADT resistance in CSPC. Cell growth assays showed an overall strong additive effect on growth inhibition with enzalutamide in-combination with the Bcl-2 inhibitor (venetoclax) on human CSPC cells. Our in-vivo isograft tumor growth results were consistent with the in-vitro data where we observed a significant decrease in tumor volume and an increase of overall survival when mice treated with enzalutamide and venetoclax in combination as compared to either of the drugs when treated alone. Our current study for the first time develops a rationale for combining ADT with Bcl2 targeted therapies for CSPC. We believe this combination will show great potential for future clinical trials of high-risk CSPC patients and may block or delay the ADT-induced shift from CSPC to mCRPC.
Citation Format: Rahim Hirani, Subhiksha Nandakumar, Teja Kalidindi, Deborah Fidele, Harisha Rajanala, Ying Mazzu, Yuki Yoshikawa, Lina Jehane, Gwo-Shu Mary Lee, Elisa de Stanchina, Adam Sowalsky, Michael J. Morris, Heiko Schoder, Naga Vara Kishore Pillarsetty, Lorelei A. Mucci, Daniel Danila, Goutam Chakraborty, Philip W. Kantoff. Bcl-2 inhibitor enhances anti-androgen therapy induced regression of castration sensitive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 979.