Abstract LB164: Inducing immunogenic cell death in difficult-to-treat cancers with an orally-bioavailable GPX4 inhibitor

Abstract Recent advancements in immunotherapy have transformed cancer treatment, resulting in extended survival times for some patients. However, despite these advancements, many patients do not benefit from immunotherapy because of an immunosuppressive tumor microenvironment. Consequently, there is a need for new strategies to improve the effectiveness of immunotherapy by stimulating inflammatory immunogenic cell death in tumors. Ferroptosis is a recently-described form of non-apoptotic cell death that induces a uniquely inflammatory immunogenic cell death. Glutathione Peroxidase 4 (GPX4) is the cell’s major defense system against ferroptosis as it is the only known enzyme capable of reducing toxic lipid hydroperoxides to inert lipid alcohols. Here we describe the discovery of a series of potent and selective small molecule GPX4 inhibitors that result in significant tumor growth inhibition in several aggressive tumor CDX models. We verified induction of ferroptosis in tumors using known biomarkers of ferroptosis such as HMOX1 mRNA induction as well as with 4-HNE staining. GPX4 target engagement and degradation was confirmed by mass spectrometry and western blot in tumors. GPX4 inhibition, when combined with PDL-1 blockade in a syngeneic sarcoma model, resulted in sustained significant tumor growth inhibition throughout the course of a 28-day study at well-tolerated doses when compared to either monotherapy alone. Current studies are underway to more carefully define the unique immunogenic cell death imparted by GPX4 inhibition and resulting ferroptosis. Citation Format: Timothy J. Read, Richard Steel, Ardeshir Golialei, Jenna Rimel, Leah Damon, Joey Azofeifa. Inducing immunogenic cell death in difficult-to-treat cancers with an orally-bioavailable GPX4 inhibitor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB164.