Abstract PO-033: Papaverine derivative smv-32 alleviates tumor hypoxia and radiosensitizes tumors by inhibiting mitochondrial metabolism

Abstract

Abstract Radiation therapy is a standard type of treatment modality used to achieve local control in more than 50% of all cancer patients. However, tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. We identified that FDA-approved phosphodiesterase 10A (PDE10A) inhibitor papaverine (PPV) has an off-target effect inhibiting mitochondrial oxygen consumption (OCR) leading to acute reduction of tumor hypoxia and significant radiosensitization of model tumors. Our data suggests that PDE10A does not contribute to the radiosensitizing effect. Based on PPV’s structure, we used biomedicinal chemistry approach to engineer its novel derivative SMV-32 with reduced PDE10A inhibition. We used Seahorse metabolic flux analyzer to determine the effect of PPV and SMV-32 on mitochondrial OCR in vitro. Near-infrared optical spectroscopy and pODD-luciferase in vivo reporter system was used for pharmacodynamics analyses and dose response evaluation. Local radiation therapy was delivered using Small Animal Radiation Research Platform (SARRP). We compared intraperitoneal (IP) and intravenous (IV) delivery and optimized dosing using pODD luciferase reporter system. SMV-32 showed superior OCR inhibition in vitro and enhanced hypoxia reduction in vivo compared to PPV. A single clinically relevant dose of PPV or SMV-32 significantly reduced the hypoxic fractions of heterotopic and orthotopic tumors in mice and sensitized the tumors to radiation therapy. PPV and SMV-32 appear to be ideal candidates for clinical radiosensitization. PPV is already in phase I clinical trial for treatment of non-small cell lung cancer combined with stereotactic body radiation therapy. Citation Format: Martin Benej, Jinghai Wu, McKenzie Kreamer, Sandip Vibhute, Ioanna Papandreou, Nicholas C. Denko. Papaverine derivative smv-32 alleviates tumor hypoxia and radiosensitizes tumors by inhibiting mitochondrial metabolism [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-033.