Project Grant R41CA281440

LIGHT-DIRECTED THERAPY OF SQUAMOUS CELL HEAD AND NECK CANCER WITH A NOVEL DUAL-ACTING CHEMOTHERAPEUTIC. - PROJECT SUMMARY. IN THIS PHASE I STTR PROJECT, LIGHT SWITCH BIO WILL COLLABORATE WITH VIRGINIA COMMONWEALTH UNIVERSITY AND THE UNIVERSITY OF PENNSYLVANIA FOR THE EARLY-STAGE DEVELOPMENT OF IR-PLATIN, A FIRST-IN-CLASS PHOTOACTIVATED CHEMOTHERAPY FOR TREATMENT OF HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC), THE SIXTH LEADING CANCER WORLDWIDE. MOST PATIENTS WITH HNSCC PRESENT WITH ADVANCED DISEASE AND NEED MULTIMODAL THERAPY INCORPORATING CISPLATIN, WHICH HAS SHOWN TO BE EFFECTIVE IN CONTROLLING LOCOREGIONAL DISEASE. HOWEVER, THE USE OF CISPLATIN IS PLAGUED BY ISSUES WITH DOSE-LIMITING TOXICITIES THAT ARE POTENTIALLY LETHAL AND CONTRIBUTE TO LONG-TERM DISABILITY. FOR MANY PATIENTS, THESE TOXICITIES MEAN THAT THEY CANNOT RECEIVE PROLONGED TREATMENT OF CISPLATIN AND AS A RESULT SUFFER WORSE OUTCOMES. WHEN COMBINED WITH RADIATION, CISPLATIN IS ALSO KNOWN TO EXACERBATE RADIATION-INDUCED MUCOSITIS THAT CREATES A SPECTRUM OF LONG-TERM SWALLOWING DISABILITIES. THESE CHALLENGES PRESENT AN OPPORTUNITY FOR STRATEGIES THAT CAN DELIVER CISPLATIN LOCALLY, AVOIDING THE DISABLING MORBIDITIES AND POTENTIALLY LETHAL SIDE EFFECTS OF SYSTEMICALLY ACTIVE CISPLATIN. OUR STRATEGY TO ADDRESS THIS NEED IS IR-PLATIN: AN INACTIVE PRODRUG OF CISPLATIN THAT RELEASES ACTIVATED PLATINUM(II) SPECIES AND SINGLET OXYGEN IN THE PRESENCE OF NEAR-INFRARED (NIR) LIGHT. THE DUAL MODE OF ACTIVATION IS EXPECTED TO LEAD TO EFFECTIVE TREATMENT OF LARGE AND HYPOXIC TUMORS, TWO OF THE MAIN LIMITATIONS OF PHOTODYNAMIC THERAPY. MOREOVER, BECAUSE THE RELEASE OF ACTIVATED PLATINUM SPECIES IS DIRECTED WITH LIGHT, THE SYSTEMIC TOXICITY ASSOCIATED WITH PLATINUM CHEMOTHERAPY IN HNSCC SHOULD BE STRONGLY DIMINISHED. FURTHER, THE DEMONSTRATED TENDENCY FOR PHOTOTHERAPIES TO INDUCE AN ANTITUMOR IMMUNE RESPONSE, IN COMBINATION WITH THE ADJUVANT CAPACITY OF ACTIVE PLATINUM(II) SPECIES, GRANTS IR- PLATIN THE POTENTIAL TO PROVIDE CONTROL OF DISTANT DISEASE AND RECURRENT DISEASE. OUR PUBLICATIONS AND PRELIMINARY DATA HAVE ESTABLISHED THE DUAL MECHANISMS OF ACTION OF IR-PLATIN, ITS IN VITRO STABILITY, ITS LOW TOXICITY IN MICE, AND IMPROVED TUMOR CONTROL IN MICE BEARING HNSCC TUMORS TREATED WITH IR-PLATIN PLUS NIR LIGHT COMPARED TO CISPLATIN. THE GOAL OF THIS PROPOSAL IS TO ESTABLISH THE FEASIBILITY AND THERAPEUTIC POTENTIAL OF IR-PLATIN FOR THE TREATMENT OF HNSCC IN ORTHOTOPIC MOUSE MODELS. THE RESULTS OF THE PROPOSED INVESTIGATION ARE ANTICIPATED TO HELP OBTAIN CRITICAL PRELIMINARY DATA TO SUPPORT LARGER IND-ENABLING STUDIES AND OUR PHASE II STTR APPLICATION. SPECIFIC AIM 1 FOCUSES ON IR-PLATIN'S TUMOR UPTAKE, TOXICITY, EFFICACY, AND MECHANISM OF ACTION FOR TREATMENT IN ORTHOTOPIC MOUSE MODELS OF HNSCC. SPECIFIC AIM 2 INVESTIGATES THE PHARMACOKINETICS OF IR-PLATIN. THESE STUDIES WILL PROVIDE CRITICAL DATA TO EVALUATE THE THERAPEUTIC POTENTIAL OF IR-PLATIN FOR THE TREATMENT OF HNSCC AND WILL LAY THE FOUNDATION FOR ITS USE IN THE TARGETED TREATMENT OF OTHER LIGHT ACCESSIBLE CANCERS (E.G. NON-RESECTABLE SQUAMOUS CARCINOMAS OF THE SKIN AND ESOPHAGUS; LUNG CANCER; BLADDER CANCER). AS A FIRST-IN-CLASS TREATMENT STRATEGY, IR- PLATIN WILL ALSO PAVE THE WAY FOR LIGHT SWITCH BIO'S DEVELOPMENT OF OTHER LIGHT-TARGETED DRUGS THAT MITIGATE OFF- TARGET TOXICITIES BY PHYSICALLY TARGETING THEIR ACTIVITY.