In this Phase I STTR project, Light Switch Bio will collaborate with VirginiaCommonwealth University and the University of Pennsylvania for the early-stage development of IR-Platin, afirst-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 needmultimodal 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 andcontribute to long-term disability. For many patients, these toxicities mean that they cannot receive prolongedtreatment of cisplatin and as a result suffer worse outcomes. When combined with radiation, cisplatin is alsoknown 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 disablingmorbidities and potentially lethal side effects of systemically active cisplatin. Our strategy to address this needis IR-Platin: an inactive prodrug of cisplatin that releases activated platinum(II) species and singlet oxygen in thepresence of near-infrared (nIR) light. The dual mode of activation is expected to lead to effective treatment oflarge and hypoxic tumors, two of the main limitations of photodynamic therapy. Moreover, because the releaseof activated platinum species is directed with light, the systemic toxicity associated with platinum chemotherapyin HNSCC should be strongly diminished. Further, the demonstrated tendency for phototherapies to induce anantitumor 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 preliminarydata have established the dual mechanisms of action of IR-Platin, its in vitro stability, its low toxicity in mice, andimproved 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 ofHNSCC in orthotopic mouse models. The results of the proposed investigation are anticipated to help obtaincritical preliminary data to support larger IND-enabling studies and our Phase II STTR application. Specific Aim1 focuses on IR-Platin's tumor uptake, toxicity, efficacy, and mechanism of action for treatment in orthotopicmouse models of HNSCC. Specific Aim 2 investigates the pharmacokinetics of IR-Platin. These studies willprovide critical data to evaluate the therapeutic potential of IR-Platin for the treatment of HNSCC and will lay thefoundation for its use in the targeted treatment of other light accessible cancers (e.g. non-resectable squamouscarcinomas 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.
Public Health Relevance Statement: PROJECT NARRATIVE Head and neck cancer is the sixth leading cancer worldwide and ninth leading cause of death. A standard chemotherapy for head and neck cancer is cisplatin; however systemic administration of cisplatin causes severe side effects that limit its use, dosage and effectiveness. In order to reduce these side effects and maximize effective treatment of head and neck cancer, we propose a new therapeutic agent that delivers a potent dose of activated cisplatin and toxic oxygen species selectively to the site of the tumor with light.
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