A phase 0 pilot study to determine if papaverine increases oxygenation in spontaneous canine soft tissue sarcoma

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ABSTRACT Tumor hypoxia reduces the effectiveness of radiotherapy by reducing the effective dose delivered to the tumor. Cells that are severely hypoxic require 2.8-fold greater dose to achieve the same cell kill as those that are fully oxygenated. For this reason, many groups have tried to deliver more oxygen to tumors as a therapy to reduce hypoxia and increase radiosensitivity. These strategies did effectively radiosensitize model tumors in rodents, but did not prove successful in human trials. We have looked at tumor oxygenation differently from the biological perspective and the evaluation of success perspective. In terms of biology, if we could clinically reduce oxygen demand rather than increase its supply, we could effectively reduce hypoxia and produce tumor radiosensitization. We have identified papaverine as an FDA-approved molecule with the ability to inhibit mitochondrial function at clinical doses. Studies in mouse tumors support the idea that papaverine can radiosensitize through regulation of oxygen consumption, producing “Metabolic Radiosensitization”. In terms of the evaluation of papaverine, we propose to test its potential as a clinical radiosensitizer in a heterogeneous population of spontaneous canine soft tissue sarcomas being treated at OSU Veterinary Medical School. The heterogeneous host- and tumor genetics generate a clinical trial that we hypothesize will be much more predictive of human success than a rodent study. Papaverine is not targeted to a specific cancer mutation, and should be effective as a radiosensitizer in any solid tumor where hypoxia exists. The proposed study will be a phase 0 pharmacodynamics study that will determine if papaverine can increase oxygenation in canine soft tissue sarcoma as measured by near infrared spectroscopy (FD-NIRS) technology in real time. We propose to test 10 animals with 1 mg/kg and 10 animals with 2 mg/kg papaverine. Correlative biological studies will determine if baseline tumor hypoxia or other biological variables can predict response to papaverine. These studies will determine if canine soft tissue sarcoma is a feasible system to test new hypoxic tumor radiosensitizers, and if papaverine should be considered as a potential radiosensitizer in future interventional trials.