For oral, oropharyngeal and oesophageal cancer, the early detection of tumours and of residual tumour after surgery are prognostic factors of recurrence rates and patient survival. Here, we report the validation, in animal models and a human, of the use of a previously described fluorescently labelled small-molecule inhibitor of the DNA repair enzyme poly(ADP–ribose) polymerase 1 (PARP1) for the detection of cancers of the oral cavity, pharynx and oesophagus. We show that the fluorescent contrast agent can be used to quantify the expression levels of PARP1 and to detect oral, oropharyngeal and oesophageal tumours in mice, pigs and fresh human biospecimens when delivered topically or intravenously. The fluorescent PARP1 inhibitor can also detect oral carcinoma in a patient when applied as a mouthwash, and discriminate between fresh biopsied samples of the oral tumour and the surgical resection margin with more than 95% sensitivity and specificity. The PARP1 inhibitor could serve as the basis of a rapid and sensitive assay for the early detection and for the surgical-margin assessment of epithelial cancers of the upper intestinal tract.
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The main data supporting the findings of this study are available within the paper and its Supplementary Information files. Associated raw data and step-by-step protocols can be made available from the corresponding author on reasonable request.
The ImageJ macro for the automated analysis of PARP1 expression on immunohistochemistry slides is available on reasonable request.
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We thank A. Sahu and R. Giese for supporting the work at MSMC; J. Budrewicz for his support of the experiments at CBSet; N. Katabi for providing expertise in histopathology; V. Dokic for assistance during clinical work with PARPi-FL; and G. Scott and L. Bassity for editing the manuscript. We thank the Molecular Cytology Core Facility, Radiochemistry and Molecular Imaging Probes Core Facility, and Flow Cytometry Core Facility at MSKCC. Finally, we thank the participants of the blinded study, including (in alphabetical order): A. Schulman, A. Sahu, A. Bolaender, C. Mason, E. Pratt, C. Andreou, F. Nicolson, J. Berry, J. Goos, J. Gonzales, K. Henry, L. Carter, M. Jain, M. McGill, N. Guru, N. Sobol, P. R. Pereira, R. Mirsafavi, S. Roberts, S. Poty, S. Jannetti, T. Crawford, V. Nagle, X. (L.) Wu and A. Sadique. This work was supported by National Institutes of Health grants R01 CA204441, P30 CA008748, R43 CA228815 and K99 CA218875 (to S.K.). We thank the Tow Foundation and the MSKCC Center for Molecular Imaging and Nanotechnology, Imaging and Radiation Sciences Program, and Molecularly Targeted Intraoperative Imaging Fund.
S.K., S.G.P., C.B. and T.R. are shareholders of Summit Biomedical Imaging. S.K., S.G.P. and T.R. are co-inventors on filed US patent (WO2016164771), held by Memorial Sloan Kettering Cancer Centre, which covers methods of use for PARPi-FL. T.R. is a co-inventor on US patent (WO2012074840), held by the General Hospital Corporation, which covers the composition of PARPi-FL. B.C. and T.R. are co-inventors on the filed US patent (WO2016033293), held by Memorial Sloan Kettering Cancer Centre, which covers methods for the synthesis of [18F]PARPi. T.R. is a paid consultant for Theragnostics. M.S. is a co-founder of Aero-Di-Namics.
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Kossatz, S., Pirovano, G., Demétrio De Souza França, P. et al. Validation of the use of a fluorescent PARP1 inhibitor for the detection of oral, oropharyngeal and oesophageal epithelial cancers. Nat Biomed Eng 4, 272–285 (2020). https://doi.org/10.1038/s41551-020-0526-9
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