Molecular Strategies to Widen the Therapeutic Index of Radiotherapy

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Abstract (Overall) The central hypothesis of this program project grant is that our knowledge of tumor genomics and the microenvironment, combined with our understanding of normal tissue biology, can be exploited to protect normal tissues from radiation (RT) damage while selectively killing tumor cells, leading to an improved therapeutic index. The projects and cores that comprise this grant represent a highly integrated effort with a single focus of widening the therapeutic index of radiotherapy. Project 1 (Giaccia) will modulate the radiosensitivity of tumors and radioprotection of normal tissues via the complement pathway and will aim to understand the mechanistic basis of how inhibition of C5aR1 serves to sensitize gastrointestinal (GI) tumors and protect abdominal tissues from RT. They will also explore the role of C5aR1 inhibition in other normal tissues in collaboration with the other projects and cores. Project 2 (Le) will focus on activating Aldehyde Dehydrogenase- 3A1 (ALDH3A1) to mitigate RT-induced severe dry mouth in head and neck cancer (HNC) patients by testing d- limonene, a novel ALDH3A1 activator identified by their group, in a phase I clinical trial. While focusing on HNC, they will evaluate the effect of d-limonene in radioprotecting other normal tissues in collaboration with the other projects and cores. Project 3 (Diehn) will develop a personalized radiosensitization strategy for patients with KEAP1/NFE2L2 mutant non-small cell lung cancer (NSCLC) based on their prior work that identified mutations in this pathway as key determinants of radioresistance in NSCLC patients. They will test the hypothesis that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant NSCLC without enhancing normal lung tissue toxicity. While concentrating on NSCLC, they will also evaluate the effects of glutaminase inhibition in other KEAP1/NFE2L2 mutant tumors and its effect on normal tissues in collaboration with other projects and cores. Project 4 (Rankin) tests the hypothesis that inhibition of FTO (Fat mass and obesity-associated protein), an RNA demethylases, would enhance the efficacy of RT in multiple solid tumors. This is based on their preliminary data showing that FTO is overexpressed in many cancers including cervical, lung and HN cancers, that FTO inhibition reduces cancer cell growth and enhances RT sensitivity through the inhibition of glutamine metabolism. They will determine the therapeutic effects and mechanism of action of FTO inhibition in combination with RT in multiple cancer models in collaboration with the other projects and cores. They will also study the effect of FTO inhibition on normal tissue response to RT. If successful, D-limonene, a nutraceutical, can be rapidly tested in larger phase II and III clinical trials for future clinical use. Similarly, PMX 205 (a C5aR1 inhibitor) and CB-839 (a glutaminase inhibitor) are currently being evaluated in clinical trials for other clinical indications while drugs targeting FTO are in active development. Thus the proposed projects could rapidly lead to clinical studies that could impact the management of cancer patients.