Project Grant R43DE031464

PRECLINICAL ASSESSMENT OF A NOVEL COMPOUND FOR TREATING RADIATION-INDUCED ORAL MUCOSITIS - PROJECT SUMMARY INFLAMMATION AND ULCERATION OF MUCOSAL TISSUE, CALLED MUCOSITIS, IS A SEVERE SIDE EFFECT OF MANY COMMON TREATMENTS IN ONCOLOGY, INCLUDING CHEMO- AND RADIOTHERAPY. MUCOSITIS DEVELOPMENT IS COSTLY TO THE HEALTH CARE SYSTEM AND CAN LEAD TO POORER OUTCOMES FOR PATIENTS. MUCOSITIS OF THE MOUTH AND ESOPHAGUS, CALLED ORAL MUCOSITIS, IS PARTICULARLY COMMON IN HEAD AND NECK CANCER PATIENTS RECEIVING RADIATION THERAPY, WHERE ROUGHLY 80% OF PATIENTS DEVELOP THIS SIDE EFFECT. TREATING ORAL MUCOSITIS REMAINS A LARGE CLINICAL UNMET NEED WITH NO FDA APPROVED TREATMENTS FOR PATIENTS WITH SOLID TUMORS. USING SINOPIA BIOSCIENCES' COMPUTATIONAL PLATFORM, WE IDENTIFIED A UNIQUE TARGET CLASS AND AN ASSOCIATED SMALL MOLECULE FOR PREVENTING AND/OR TREATING MUCOSITIS. THE TARGET CLASS HAS AN ESTABLISHED SAFETY PROFILE IN PATIENTS WITH SOLID TUMORS. IN TWO STUDIES WITH THE ACUTE RADIATION- INDUCED HAMSTER MODEL OF ORAL MUCOSITIS, WE OBSERVED PROMISING RESULTS THAT ORAL ADMINISTRATION OF THE COMPOUND SIGNIFICANTLY DECREASED THE DURATION OF ULCERATIVE MUCOSITIS AND IN SOME ANIMALS COMPLETELY PREVENTED THE DEVELOPMENT OF ULCERS. THE OBSERVED EFFECT SIZE WAS AS LARGE OR LARGER THAN OTHER COMPOUNDS CURRENTLY IN THE CLINIC TESTED IN THE SAME MODEL. THE TEST COMPOUND IS A PAN-INHIBITOR OF SEVERAL TARGETS IN THE TARGET CLASS, EACH WITH MULTIPLE BINDING DOMAINS. IN THIS PHASE I PROPOSAL, WE WILL TEST THREE ADDITIONAL COMPOUNDS WITH DIFFERENT SELECTIVITY TO THESE TARGETS AND DOMAINS IN ORDER TO UNDERSTAND THE PHARMACOLOGY OF THIS TARGET CLASS TO DETERMINE THE TARGET THAT MOST CONTRIBUTES TO MUCOSITIS AMELIORATION. IF SUCCESSFUL, IN PHASE II OF THIS PROPOSAL WE WILL DEVELOP A NOVEL COMPOUND SELECTIVE FOR THE MOST EFFECTIVE TARGET. WE WILL THEN CHARACTERIZE THIS NEW COMPOUND IN THE FRACTIONATED RADIATION MODEL OF ORAL MUCOSITIS AND THE CHEMOTHERAPY-INDUCED GASTROINTESTINAL MUCOSITIS TO ADVANCE TOWARDS THE CLINIC.