Investigating the antitumor efficacy of combination treatment with ONC201, Enzalutamide and Darolutamide in castration-resistant prostate cancer in vitro and in vivo

Wu, Laura Jinxuan

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Overview

Year:: 2022
Contributor:: Wu, Laura Jinxuan (creator); El-Deiry, Wafik (Advisor); Holder, Sheldon (Reader); Schell, Jacquelyn (Reader); Brown University. Biology and Medicine: Pathobiology (sponsor)
Genre:: theses
Subject:: Prostate--Cancer; Novel anti-cancer small molecules; Castration-resistant prostate cancer; ONC201; Antiandrogens; Enzalutamide; Darolutamide; combination therapy
Extent:: , None p.

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Abstract:: The androgen receptor (AR) signaling pathway plays a primary role in prostate cancer progression. Various types of second generation, non-steroidal anti-androgens (NSAA) including enzalutamide and apalutamide, and the lyase inhibitor, abiraterone, have been widely used as single agents to treat patients with advanced disease. However, despite the initial improvements, patients with metastatic castration-resistant prostate cancer (mCPRC) frequently develop resistance, resulting in limited overall survival benefit. Darolutamide is a novel next-generation androgen receptor-signaling inhibitor that is FDA approved for non-metastatic castration resistant prostate cancer (nmCRPC) currently in phase III clinical trials and has shown efficacy and tolerability in treating non-metastatic castration-resistant prostate cancer. ONC201 is an imipridone small molecule that activates the integrated stress response (ISR) pathway and upregulates TNF-related apoptosis-inducing ligand (TRAIL). ONC201 has demonstrated promising antiproliferative and proapoptotic effects in a variety of tumor types and is currently being evaluated in phase I/II clinical trials. This study investigates the integrated stress response and androgen receptor signaling as mechanisms for antitumor efficacy with ONC201 and enzalutamide or darolutamide as single agents or in combination against mCRPC in vitro and in vivo. Four mCRPC cell lines 22RV1, LNCaP, DU145 and PC3 were treated with ONC201, darolutamide, and enzalutamide as single agents or in combinations. Results show that ONC201 synergized with darolutamide and enzalutamide, decreased cell viability in vitro. Combinations of ONC201 and darolutamide reduced PSA level and demonstrated proapoptotic effects when compared to monotherapy. In vivo mouse studies indicate preliminary trends of NK cell infiltration and TRAIL activation in groups treated with ONC201 and combinations of ONC201 and darolutamide. Cytokine profiling also suggests a treatment-induced pro-inflammatory immune environment that may have contributed to partial tumor regression. Our data provide insights to improved therapeutic benefits of combination treatment that can be further developed for more efficient anticancer strategies.
Notes:: Thesis (Sc. M.)--Brown University, 2022

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Citation

Wu, Laura Jinxuan, "Investigating the antitumor efficacy of combination treatment with ONC201, Enzalutamide and Darolutamide in castration-resistant prostate cancer in vitro and in vivo" (2022). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:wjutr3tu/

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Pathobiology Theses and Dissertations

Theses and Dissertations for the Pathobiology department.
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