Abstract 3067: Exploring strategies to modulate mitochondrial metabolism to alleviate tumor hypoxia

Radiation therapy is a standard type of treatment modality used as a part of curative or palliative treatment in more than 50% of all cancer patients. However, tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. Here, we explore and compare strategies to alleviate hypoxia by modifying the oxygen supply or demand within mouse tumor models. We used pODD-Luc, a dynamic in vivo luciferase reporter system that monitors relative levels of tumor hypoxia in real time. We show that in mouse tumor models, contrary to the reported results of human clinical trials, acute manipulation of systemic oxygen delivery significantly reduces the level of hypoxia. We then examined pharmacological manipulation of oxygen demand, which is an emerging trend in therapeutic efforts to sensitize tumors to anti-cancer therapy. Mitochondrial oxygen consumption (OCR) constitutes more than 90% of cellular oxygen demand by coupling carbon source oxidation with ATP generation in a series of redox reactions transferring electrons from reduced cofactors to molecular oxygen. Mechanistically, a decrease in mitochondrial OCR would lead to increased oxygen availability within the tumor, allowing initially hypoxic areas to become re-oxygenated. We found that strategies that directly stimulate mitochondrial OCR exacerbate levels of hypoxia while OCR suppression in turn promotes tumor re-oxygenation. We have previously shown that papaverine, an FDA-approved phosphodiesterase 10A (PDE10A) inhibitor effectively reduces hypoxic tumor fractions in vivo by an off-target effect that inhibits mitochondrial complex I. Here we show that its novel derivative SMV-32 that acts as complex I inhibitor with reduced PDE10A effect mediates superior OCR inhibition in both orthotopic and heterotopic mouse tumor models. These findings further establish the direct impact of OCR manipulation on tumor hypoxia and support the role of mitochondrial metabolism as an attractive target to alleviate tumor hypoxia and overcome treatment resistance. Citation Format: Martin Benej, Jinghai Wu, McKenzie Kreamer, Sandip Vibhute, Ioanna Papandreou, Nicholas C. Denko. Exploring strategies to modulate mitochondrial metabolism to alleviate tumor hypoxia [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 3067.