AbstractPurposeVisual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly specific, fluorescent contrast-based approach that may fulfil the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL.Patients and MethodsTwelve patients with a histologically proven squamous cell carcinoma of the oral cavity (OSCC) gargled a PARPi-FL solution for 60 seconds (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 seconds. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application and after clearing. Blood pressure, oxygen levels, clinical chemistry and CBC were obtained before and after tracer administration.ResultsPARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of > 3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings.ConclusionsA PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity.Translational RelevanceDespite their accessible location, oral cavity cancers are often diagnosed late, especially in low-resource areas where their incidence is typically high. The high prevalence of premalignant and benign oral lesions in these populations contributes to a number of issues that make early detection of oral cancer difficult: even in experienced hands, it can be difficult to differentiate cancer from premalignant or benign lesions during routine clinical examination; and biopsy-based histopathology, the current standard of care, is invasive, prone to sampling error, and requires geographic access to appropriate health care professionals, including a highly trained pathologist. While seemingly impenetrable economic and infrastructure barriers have confounded the early diagnosis of oral cancer for most of the world’s population, these could be circumvented by a simple, in vivo, non-invasive, cost-effective, point-of-care method of diagnosis. We are attempting to address this unmet clinical need by using topically applied PARPi-FL — a molecularly specific, fluorescent contrast-based approach — to detect oral cancer.FundingThis work was supported by National Institutes of Health grants P30 CA008748, R01 CA204441 (TR) and R43 CA228815 (CB and TR). Dr. Valero was sponsored by a grant from Fundación Alfonso Martín Escudero. The funding sources were not involved in study design, data collection and analysis, writing of the report, or the decision to submit this article for publication.Disclosure of Potential Conflicts of InterestC.B., S.K., S.P. and T.R. are shareholders of Summit Biomedical Imaging, LLC. S.K., S.P. and T.R. are co-inventors on PCT application WO2016164771. T.R. is co-inventor on PCT application WO2012074840. T.R. is a paid consultant for Theragnostics, Inc. All the other authors have no relevant conflict to declare. This arrangement has been reviewed and approved by Memorial Sloan Kettering Cancer Center in accordance with its conflict of interest policies.
Non-Invasive Early Diagnosis of Oral Cavity Malignancies
