Tumor-Selective Radiosensitization by Targeting Hypoxia in Rectal Cancer

PROJECT SUMMARY The paradigm for treatment of locally advanced rectal cancer (LARC) has shifted to total neoadjuvant therapy (TNT), where preoperative chemotherapy and radiation therapy (RT) are delivered prior to surgery. Utilizing this approach, pathologic complete response rates of ~30% have been reported. In addition, non-operative management (NOM), where watchful waiting with serial imaging and endoscopic assessments are performed, is possible in ~30-50% of patients who complete chemotherapy and RT. NOM allows patients to avoid a potentially life-altering surgery, but local recurrence occurs in 25-30% of patients. Thus, about two-thirds of patients ultimately require surgery due to ineligibility for NOM or failure after treatment for NOM. Innovative treatment approaches are needed to enhance response rates to make NOM feasible in the majority of LARC patients. One factor contributing to lack of response is tumor hypoxia, which has been shown to contribute to radiation resistance in multiple cancer types including rectal cancer, but has not been effectively reversed to date. Hypoxia-related resistance to radiation is particularly more noticeable in higher dose per fractions of radiation. We have found that targeting mitochondrial oxygen consumption (MOC) can effectively sensitize tumor cells to radiation therapy using an FDA-approved mitochondrial complex I (papaverine) inhibitor. In this patient study, we will characterize the biology driving the response of LARC to standard of care (SOC) TNT therapy with RT followed by chemotherapy, and determine if intervention with a mitochondrial inhibitor in this context may represent a safe, and effective approach worthy of further investigation. In Aim 1, we will determine whether papaverine (PPV) a mitochondrial complex I inhibitor can be safely combined with RT using a two- cohort phase I study. This innovative study will incorporate a control cohort and a cohort combining PPV with short course RT over 1 week, which employs a larger radiation dose per fraction than conventional radiation, and thus stands to benefit most from hypoxia-directed strategies. We will also perform longitudinal collection of tumor and normal rectal biopsies, and peripheral blood, (before, during, and after RT) in order to comprehensively determine how papaverine and RT alters tumor molecular profiles and the immune contexture, through transcriptomic, and tumor and peripheral (blood) compartment immune profiling. In Aim 2, we will test whether treatment with PPV directly results in reduced tumor hypoxia. We will use state-of-the-art functional MR imaging techniques to measure blood oxygenation and use our longitudinal tissue collections obtained during the phase I trial to measure changes in established hypoxia gene expression signatures. In Aim 3, we will examine the impact of papaverine in combination with radiation on the immune microenvironment. Results from these studies will lead to a deeper understanding of the biological basis of response to radiation therapy for rectal cancer, develop molecular and imaging biomarkers of response to therapy, and will rationalize the innovative strategy of targeting hypoxia through a reduction in MOC in order to improve response rates in LARC.