Abstract A029: Targeting neural transcription factor BRN2 in neuroendocrine prostate tumors

Abstract

Abstract Introduction: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as enzalutamide (ENZ), rapidly emerges and patients generally die within two years. In particular, a subset of patients who relapse following ARPI therapy exhibit lineage switching whereby tumors shed their dependence on AR signaling and emerge with neuroendocrine features. These tumors, termed treatment-induced neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and to date treatment remains decades-old cytotoxic chemotherapy, which carries a short-lived response at the cost of significant toxicity. Thus, the need to develop targeted treatments for this devastating disease is of paramount importance. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of NEPC and aggressive tumor growth, both in vitro and in vivo, suggesting that targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC. Methods: Using the integrated power of computational drug discovery platform and biologic testing we identified first-in-field inhibitors for BRN2. Results: One of the most potent inhibitors identified, Cpd 18, binds to BRN2 using a Drug Affinity Responsive Target Stability (DARTS) assay, decreases the expression of the neuroendocrine genes SOX2, NCAM1, CGA, NSE, PEG10, and N-Myc in BRN2Hi NCI-H660 cells with similar effect in 42DENZR cells. Moreover, Cpd18 displays pronounced antiproliferative activity in NCI-H660 and 42DENZR without any effect on BRN2 low/neg 16DCRPC and LNCaP cells. Combination treatment of Cpd 18 with ENZ prevents the trans-differentiation of 16DCRPC cells into NEPC-like morphology and downregulates the expression of NEPC markers. These outcomes confirmed that the BRN2 is a novel drug target that can help address the problem of ENZ-resistant form of NEPC. Conclusion: No therapies exist for highly lethal NEPC. Hence, the described work will identify first-in-field inhibitors for BRN2, a central driver of NEPC, and lay the preclinical foundation for the integration of such drugs into the treatment landscape to improve survival and quality of life for patients suffering from deadly form of prostate cancer. Citation Format: Ravi Shashi Nayana Munuganti, Daksh Thaper, Amina Zoubeidi. Targeting neural transcription factor BRN2 in neuroendocrine prostate tumors [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A029.