Project Summary/Abstract Counterintuitively, the incidence and societal impact of oral and oropharyngeal cancer are increasing in the US despite the markedly decreased use of tobacco products. This trend is exacerbated by the fact that almost two- thirds of patients have lymph node or distant metastases at the time of diagnosis, dramatically reducing 5-year survival rates. Oral cavity cancers are overwhelmingly diagnosed late despite their superficial location, often because they remain asymptotic – and early lesions are erroneously considered benign. The current standard of care for detecting oral cancer is still visual examination in combination with biopsy-based histopathology, which is not only labor-intensive but also requires highly trained personnel and a sophisticated infrastructure – impenetrable economic barriers for most of the world’s population, and precisely the unmet clinical need we have chosen to address. We recently reported very encouraging first-in-human Phase I clinical trial data with PARPi-FL, a small molecule with high specificity for PARP1. PARP1 is a quantitative and highly overexpressed biomarker for in vivo imaging of oral cancer, and we showed that PARPi-FL identifies tumors with sensitivities and specificities >95%. Taking our drug to the next level and validating its clinical value in a Phase II trial, we have partnered with Memorial Sloan Kettering Cancer Center (MSK) and assembled three Specific Aims (SAs). In SA1, we will redesign the formulation and manufacturing of PARPi-FL, making it easier to formulate for the clinicians as well as improving the taste of the gargling solution for the patient. In SA2, we will optimize workflows, thresholding and image analysis, based on and informed by our Phase I clinical data. In SA3, we will test intraoperative PARPi-FL imaging of the oral cavity to determine sensitivity and specificity in discriminating benign and malignant lesions. If successfully, this project will provide a solid foundation for a multicenter Phase III clinical trial and ultimately raise the clinical standard of care for oral cavity cancer.