Abstract A004: Broad and synergistic anti-tumor effects of small-molecule inhibitors of hypoxia inducible factors when paired with immune checkpoint blockade

Abstract Motivation: Hypoxia inducible factors (HIFs) are critical transcriptional regulators that play fundamental roles in adaptive responses to low oxygen, both in normal and disease conditions. Dysregulated activation of HIFs has been implicated in a variety of cancers due to their role in mediating a broad range of key processes including angiogenesis, glycolysis, cell survival, cancer stem cell specification, and metastasis. Methods: In this study, we utilized virtual and cell-based high-throughput screening approaches to identify compounds that disrupt the binding of HIF-1α and HIF-2α to HIF-1β, leading to the suppression of HIF target gene expression. Results: In syngeneic animal models, we observed significant tumor regression when HIF inhibitors are combined with immunotherapy agents in multiple tumor models. The combined treatment enhanced the infiltration of natural killer (NK) cells into the tumor microenvironment. Conclusion: This study highlights the anti-tumor effects of HIF inhibitors and the immune response resulting in sustained tumor regression. The promising outcomes warrant further exploration of these inhibitors as potential cancer treatment agents. Citation Format: Shaima Salman, Tina Y. Huang, Yousang Hwang, Anmol Kumar, Dominic Dordai, Alexander D. MacKerell, Gregg L. Semenza. Broad and synergistic anti-tumor effects of small-molecule inhibitors of hypoxia inducible factors when paired with immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A004.