Molecularly Targeted Radiosensitization of Locally Advanced Cancers

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PROJECT SUMMARY (OVERALL) Cancer cannot be cured unless the primary tumor is cured. For patients with locally advanced or unresectable disease for whom initial surgery is not an option, radiation therapy (RT) combined with a systemic agent has become the standard treatment. This is because systemic therapy alone can rarely cure gross disease, but can significantly improve the efficacy of RT and eliminate microscopic disease. Therefore, as systemic therapies continue to improve, the need for effective local control becomes increasingly important. Although technical improvements in planning and delivery have decreased the toxicity of RT, RT dose escalation trials have, in general, failed to improve outcome. The overarching hypothesis of this SPORE proposal is that combining RT with systemic therapy that targets the molecular drivers of locally advanced cancers will improve the outcome of treatment. The goal of this SPORE proposal is to test this hypothesis through in vitro and in vivo preclinical studies targeting key mechanisms of radiation resistance. Our studies will motivate pilot clinical trials that will define the conditions for phase II trials, yield an initial assessment of response, and test the preclinical hypotheses through correlative studies. This goal will be achieved through three specific aims. Aim 1 will determine if primary radiation resistance, the presence of occult metastatic disease, and a lack of immunogenicity can be targeted by increasing radiation-induced DNA damage using a PARP inhibitor with immune checkpoint blockade (ICB). We test this strategy in preclinical and clinical studies combining olaparib, RT, and durvalumab in pancreatic cancer. Aim 2 will determine if the radiation resistance due to unique tumor metabolism, specifically, elevated purine levels, can be targeted. We test this hypothesis in preclinical and clinical studies of glioblastoma using the purine depleting CNS-penetrant FDA approved agent mycophenolate mofetil (MMF). Aim 3 will determine if the radiation resistance due to aberrant cell cycle control and activated DNA repair can be targeted in tumor cells with intact retinoblastoma protein (RB) using CDK4/6 inhibitors. We test this hypothesis in preclinical studies and in a clinical trial treating women with locally advanced ER+ (and, in the future, if supported by preclinical data, triple negative) breast cancer using RT with concurrent abemaciclib. These projects will be supported by the five cores: Administrative, Translational Pathology, Biostatistics & Computational Biology, Clinical Trials, and Radiosensitization. We have a strong history of vertical translation: our prior early phase trials in these three disease have progressed to multi-institutional trials We do not know of another group that can carry out integrated preclinical and clinical studies which have a significant chance of decreasing the morbidity and mortality of three common and difficult to treat cancers by increasing the RT sensitivity and immunogenicity of tumors through targeting their molecular drivers using clinically available agents.