Motivated by the bleak situation of oral cancer in India and encouraged by our successes in the UH2/UH3 mechanism for diagnosing and treating pre- and early cancers, a new integrated “Screen, Image and Treat Optical System” (SITOS) is proposed in the current application which combines the expertise of 3 US sites in collaboration with 2 clinical Indian teams. All sites were participants in the previous NCI awards as 2 individual UH2/UH3 projects focused on either detection or therapy. The treatment continues to be photodynamic therapy (PDT), a photochemistry-based, FDA approved modality while the detection is based on fluorescence and white light imaging combined with a cloud-based deep-learning AI approach for image classification. The SITOS enables image guided PDT, while a topical application of the dual property flourophore/photosensitizer precursor to the oral cavity, more suitable for LMICs and designed to achieve better tumor penetration than previous topical deliveries, is also developed. The goals will be accomplished in 3 Specific Aims. Aim 1 builds on previous successful development and clinical validation of separate low-cost devices for intraoral imaging, and intraoral PDT to produce a new, handheld, low-cost, easy-to-use, SITOS. The integrated platform enables the use of the same hardware for initial imaging, and a single thernostic molecule for image-guided PDT and online monitoring during therapy. Incorporated is an ergonomic intraoral light delivery for PDT and preliminarily validated in optical phantoms and in vitro 3D tumor models. Aim 2A establishes conditions for topical photosensitization using an adhesive ALA patch provided by Photonamic GmbH in ex vivo porcine mucosa model. Based on data from 2A, Aim 2B establishes optimal PDT parameters in a murine xenograft model. Aim 2C validates the best of these parameters in a carcinogen-induced hamster cheek pouch model which recapitulates transition from pre- malignant to malignant lesions. Aim 3 applies SITOS to identify and treat high-risk oral potentially malignant lesions (OPML), and early-stage oral cancer using broad guidance from the preclinical studies. Screening of patients will take place at camps and remote villages led by the clinical teams in India as in the UH effort. Patients with histologically confirmed HGD/OPML (and meeting other inclusion criteria) will be eligible. Patients will be treated using the ALA topical patch, (after a small cohort establishes safety and optimal contact time, based on Aim 2). Finally, PDT of high-risk OPML and early cancer in patients using light delivery and simultaneous image guidance with the new intraoral probe will be performed. Impact and relevance: The study provides, for the first time, a comprehensive low-cost approach that enables not only detection of pre-malignant/malignant oral lesions, but also an effective, monitored therapy in LMIC settings. The SITOS platform is mobile, handheld and appropriate for point of care applications. It brings together collaborators (scientists, oral cancer surgeons, oncologists and industry) to help with FDA clearance of ALA patch and SITOS. Capacity building: a new clinical modality and a platform for AI/engineering development.

Narrative A new platform is envisioned that combines two existing technologies to produce a low cost, simple to use, handheld device that can screen patients for high-risk oral cancer, image the location of the cancer, and treat it using this same device at point of care. It includes testing therapeutic efficacy both pre-clinically and clinically in patients, along with identification of an easy-to-use topical application of the therapeutic agent well suited for low-income settings. The impact of these studies could be substantial in the low-income settings such as rural areas and can avoid deaths in the regions where oral cancer is highly prevalent in India as well as other countries including regions of the U.S.A.