Abstract 488: New therapeutic strategies suppressing NAD+ and ATP production in cancer metabolism specific to 3D cultured ovarian cancer cells

Abstract

Ovarian cancer is the gynecological cancer with the highest mortality rate. As resistance to treatment is acquired and many patients relapse, new treatment strategies are needed. A model that strongly reflects the features of recurrent ovarian cancer in the peritoneal cavity is the "cancer stem cells (CSCs)," which are enriched when cells are cultured in three dimensions (3D) on low-attachment plates. The unique metabolic system of the "3D CSCs" is the subject of a novel therapeutic approach. Here, we show that ovarian cancer 3D CSCs have strong NAD+ production capacity, which is particularly dependent on nicotinamide phosphoribosyl transferase (NAMPT), known as the rate-limiting enzyme in the salvage pathway of NAD+ production. We found that NAMPT inhibition blocks NADPH and ATP production as well as NAD+, and subsequently suppresses the synthesis capacity of proteins, fat droplets, and cholesterol in the 3D ovarian cancer cells. In addition, we found that the combination of NAMPT inhibitor and the ALDH inhibitor disulfiram had a pronounced synergistic effect. This synergy inhibits oxidative phosphorylation and ALDH activity and promotes reactive oxygen species and apoptosis via caspase 3/7 cleavage, which leads to death of the 3D cultured cells. Our results demonstrate that high NAMPT expression in ovarian cancer is likely to be a strong poor prognostic factor and that the combination of a NAMPT inhibitor and disulfiram could be a new treatment option to treat or prevent recurrent ovarian cancer. Our novel findings focus on NAMPT addiction as a property of ovarian cancer 3D CSCs, and strongly suggest the combined inhibition of NAMPT and ALDH as a potential therapeutic strategy. Citation Format: Kei Kudo, Brittney S. Harrington, Franklin Ning, Rahul Kamdar, Yusuke Shibuya, Soumya Korrapati, Maria Fergusson, Calen Kucera, Fantini Massimo, Christina M. Annunziata. New therapeutic strategies suppressing NAD+ and ATP production in cancer metabolism specific to 3D cultured ovarian cancer cells [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 488.