Abstract 1672: Synergistic combination therapy with ONC201/TIC10, Enzalutamide and Darolutamide in castration-resistant prostate cancer
Authors: Wu Jinxuan Laura , Zhou Lanlan , Zhang Leiqing , Huntington Kelsey E. , Malpass Ryan , Seyhan Attila , Carneiro Benedito , El-Deiry Wafik S. 
Published: June 2023

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, have been widely used as single agents to treat patients with advanced disease. However, despite 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 nmCRPC. ONC201/TIC10 is a first-in-class small molecule that activates the integrated stress response (ISR) and upregulates TNF-related apoptosis-inducing ligand (TRAIL). Our study investigates the ISR and AR 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. We previously reported that ONC201 synergizes with daroluatmide in inhibiting cell viability, upregulating ISR, inducing apoptosis, reducing prostate specific antigen (PSA) and AR signaling in CRPC cell lines 22RV1, LNCaP, DU145 and PC3. To test the novel combinatorial treatment in vivo, we established a subcutaneous CRPC mouse xenograft model with luciferase expressing 22RV1 cells, 22RV1-LUC. Tumors were routinely measured with a digital caliper and bioluminescence imaging. After tumor size reached 150mm3, mice were randomly assigned to control and treatment groups with ONC201 (50mg/kg or 100mg/kg, p.o., t.i.w or b.i.w.) and/or darolutamide (50mg/kg, p.o., b.i.d) and/or enzalutamide (20mg/kg, p.o., q.d.) for 36 days. Preliminary results demonstrated significant antitumor efficacy in the high-dose ONC201 group (100mg/kg, t.i.w.) and partial tumor regression in the combination groups. Flow cytometric analysis indicated preliminary trends of increased intratumor NK cells in mice treated with ONC201 and combination of ONC201 and darolutamide. Trends of increased TRAIL activation within NK cells were also observed in treatment groups. We are exploring the antitumor immune-modulatory effects of the combinatorial therapy that may have contributed to the partial reduction of tumor growth of 22RV1-LUC in an immunodeficient mouse model and biomarkers from the in vivo tissue samples. Our data provide insights to improved therapeutic benefits of combination treatment that can be further studied and developed for more efficient anticancer strategies.
Citation Format: Jinxuan Laura Wu, Lanlan Zhou, Leiqing Zhang, Kelsey E. Huntington, Ryan Malpass, Attila Seyhan, Benedito Carneiro, Wafik S. El-Deiry. Synergistic combination therapy with ONC201/TIC10, Enzalutamide and Darolutamide in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1672.