Abstract 1011: Disulfiram superior to ALDH1A1 inhibitor analogs in targeting ovarian cancer stem cells

Abstract

Abstract Epithelial ovarian cancer (EOC) is a global health burden and remains the fifth leading cause of cancer related death in women worldwide with the poorest five-year survival rate of the gynecological malignancies. Disease recurrence is the major cause of morbidity and mortality of EOC, considered to be driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs). TIC populations in EOC can be identified by the expression of molecular markers such as aldehyde dehydrogenase (ALDH), CD133, Nanog and Sox2. Although the TICs have been characterized, little progress has been made in finding drugs to specifically target this population, which has driven the research and development of novel therapies to prevent relapse. We previously showed that disulfiram, an ALDH inhibitor, effectively targeted TICs in terms of viability, spheroid formation, oxidative stress and also prevented relapse in an in vivo model of EOC. In this study we sought to determine whether specific targeting of ALDH isoenzyme ALDH1A1 would provide similar benefit as the broader pathway inhibition by disulfiram. NCTs 505 and 506 are isoenzyme specific ALDH1A1 inhibitors whose activity was compared to the effects of disulfiram. Following treatment with either the NCTs or disulfiram, the viability of TICs versus adherent cells, sphere formation, oxidative stress and cell death in our in vitro relapse model were measured and compared in OC cell lines. We found that disulfiram decreased the viability of TICs significantly more effectively versus non-TIC cells, while no trend was observed when the cells were treated with the NCTs. Disulfiram also induced greater amounts of ROS than the NCTs and affected the expression of proteins associated with the NFkB and JNK signaling pathways. Comparison of disulfiram to the direct targeting of ALDH1A1 with the NCTs suggests that disulfiram's broader cellular effects are more suitable as a therapeutic to eradicate TICs from tumors and prevent OC relapse. In addition to providing insight into a fitting treatment for TICs, the comparison of disulfiram to NCTs 505 and 506 has increased our understanding of disulfiram's mechanism of action. Further elucidation of disulfiram's mechanism has the potential to reveal additional targets to treat OC TICs and prevent disease recurrence. Citation Format: Michael Caminear, Brittney Harrington, Christina Annunziata. Disulfiram superior to ALDH1A1 inhibitor analogs in targeting ovarian cancer stem cells [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 1011.