Project Grant R21DE034106

TARGETING TRPV1-CONTAINING NERVES FOR RADIATION-INDUCED PAIN AND ORAL MUCOSITIS - PROJECT SUMMARY PAIN DURING AND AFTER RADIATION THERAPY (RT) FOR HEAD AND NECK CANCER (HNC) IS A MAJOR CLINICAL CHALLENGE DUE TO ITS MULTIFACTORIAL ETIOLOGY AND VARIABLE MANAGEMENT. IN A RECENT CLINICAL RETROSPECTIVE STUDY OF 351 HNC PATIENTS, THE MAJORITY (61%) UNDERGOING RT REPORTED ONGOING "BURNING" PAIN BY THE END OF TREATMENT SUGGESTING A NEUROPATHIC PAIN PHENOTYPE. HOWEVER, RADIATION-INDUCED PAIN TYPICALLY CO-DEVELOPS WITH ORAL MUCOSITIS (OM), AN INFLAMMATORY CONDITION DEFINED AS TISSUE DAMAGE TO THE ORAL MUCOSA RESULTING IN HIGHLY SYMPTOMATIC LESIONS THAT AFFECT PATIENTS' FUNCTION, QUALITY OF LIFE, AND ABILITY TO TOLERATE TREATMENT. EFFECTIVE PAIN TREATMENT IN HNC PATIENTS RECEIVING RT REMAINS AN IMPORTANT UNMET CLINICAL NEED; INTERMITTENT BREAKS TAKEN DUE TO PAIN OFTEN RESULT IN POOR THERAPEUTIC RESPONSE AND RECURRENCE. PRECLINICAL RESEARCH EFFORTS ARE NEEDED TO DEVELOP AND EVALUATE NEW THERAPEUTIC OPTIONS; HOWEVER, STANDARDIZED PRECLINICAL RT-INDUCED PAIN MODELS ARE SEVERELY LACKING. SENSORY INNERVATION OF THE ORAL CAVITY IS DENSE AND TRPV1-EXPRESSING PEPTIDERGIC AFFERENTS HAVE BEEN STRONGLY IMPLICATED IN PAIN ASSOCIATED WITH BOTH ORAL CANCER AND RT-INDUCED OM. A RECENT STUDY BY MENESES ET AL. FOUND THAT SYSTEMIC TRPV1 DENERVATION REDUCED THE SEVERITY OF RADIATION-INDUCED OM IN A NON-TUMOR BEARING MOUSE, HOWEVER PAIN WAS NOT ASSESSED. FURTHERMORE, THE IMPETUS FOR THIS APPLICATION IS OUR PRELIMINARY FINDING OF A SIGNIFICANT INCREASE IN S100-IMMUNOREACTIVE NERVE DENSITY IN TUMOR TISSUE 2 WEEKS AFTER MICE RECEIVED A SINGLE FOCAL RT DOSE COMPARED TO SHAM RADIATION IN 3 DIFFERENT HNC TUMOR MODELS. THESE RESULTS SUGGEST THAT RADIATION BY ITSELF CAN INDUCE NEURONAL SPROUTING IN THE ORAL CAVITY. THIS DATA COMBINED WITH PREVIOUS EVIDENCE LED TO OUR HYPOTHESIS THAT BOTH THE PAIN AND MUCOSITIS SEVERITY ARE DUE TO THE NEGATIVE SYNERGY OF RADIATION-INDUCED SPROUTING ACTING ON EXISTING HYPERINNERVATION INDUCED BY THE TUMOR. THE CRITICAL PREDICTION THAT FOLLOWS FROM THIS HYPOTHESIS IS THAT PROPHYLACTIC DENERVATION OF THE TUMOR PRIOR TO RT WILL REDUCE BOTH POST-TREATMENT PAIN AND MUCOSITIS SEVERITY. TO TEST THIS HYPOTHESIS, WE WILL USE A SYNGENEIC ORTHOTOPIC TRANSPLANT MOUSE MODEL IN TANDEM WITH SINGLE AND MULTI-FRACTION RT TO CHARACTERIZE NOCICEPTIVE BEHAVIOR AND OM AS WELL AS RT-INDUCED PRIMARY AFFERENT SPROUTING IN VIVO (AIM 1) AND IN VITRO (AIM 2). ADDITIONALLY, WE WILL USE ULTRAPOTENT RESINIFERATOXIN TO DENERVATE TRPV1-EXPRESSING SENSORY NEURONS PRIOR TO RT TO INVESTIGATE IF PROPHYLACTIC DENERVATION OF THE TUMOR PRIOR TO RT CAN REDUCE SUBSEQUENT PAIN AND OM SEVERITY (AIM 3). WE BELIEVE THIS PROPOSAL WILL BEGIN TO FILL AN IMPORTANT GAP IN KNOWLEDGE IN THE CANCER PAIN FIELD AND ALLOW FOR THE DEVELOPMENT OF NEW STRATEGIES TO TREAT RADIATION-ASSOCIATED PAIN.