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Abstract 5795: Functional and mechanistic interrogation of BET Bromodomain degraders for the treatment of metastatic castration resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC), a lethal disease primarily driven by androgen receptor (AR) signaling, results in approximately 30,000 annual deaths in the U.S. While the AR is necessary for the function, survival, and differentiation of normal prostatic tissue, AR function and signaling shift from tumor suppressive to tumor promoting during prostate carcinogenesis. Surgical or chemical castration targeting the AR signaling axis has been the mainstay of prostate cancer (PCa) treatment. Unfortunately, despite castration, PCa will inevitably progress into castration resistant prostate cancer (CRPC) in which AR remains an important oncogene. Current CRPC therapeutics, such as second-generation AR antagonists, elicit only temporary responses and patients eventually succumb to the disease. Therefore, new therapeutics against the AR axis in CRPC are urgently needed. One such novel strategy for targeting the AR-pathway and inhibiting the growth of CRPC has been the use of bromodomain and extraterminal (BET) protein inhibitors such a JQ1, which disrupt AR and oncogenic c-MYC transcriptional activity. While BET inhibitors may seem to be attractive candidate drugs for clinical translation, their off-target effects, such as binding to other proteins, toxicity, and the rapid development of treatment resistance, limit their translation. However, a new class of molecules that target BET proteins through proteasomal degradation can improve efficacy and specificity over standard inhibitors. Based on our preliminary findings, we have hypothesized that pharmacologic BET degradation represents an important advance in CRPC treatment and may provide a novel therapeutic strategy that can enhance efficacy and disrupt resistance to AR-targeted therapy. Utilizing prostate cancer cell lines, organoids, and patient derived xenografts, we performed RNA-seq, ChIP-seq, and proteomic studies to assay the effects of BET inhibitors and degrader compounds in preclinical models. These inhibitors affected AR-positive prostate cancer cells preferentially over AR-negative cells, and proteomic and genomic mechanistic studies confirmed the disruption of oncogenic AR and MYC signaling both in vivo and in vitro. In conclusion, we are developing highly potent, small molecules that lead to the proteasomal-degradation of BET proteins. With optimized in vivo properties, BET degraders promise to be a novel potential therapeutic strategy for patients with mCRPC. Citation Format: Steven Kregel, Rohit Malik, Irfan A. Asangani, Ester Fernandez-Salas, Kari Wilder-Romans, Xia Jiang, Thekkelnaycke Rajendiran, Xuhong Cao, Corey Speers, Shaomeng Wang, Arul M. Chinnaiyan. Functional and mechanistic interrogation of BET Bromodomain degraders for the treatment of metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5795.