A Cathepsin-Targeted Quenched Activity-Based Probe Facilitates Enhanced Detection of Human Tumors during Resection.

Autor:	Kennedy GT; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Holt DE; Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania., Azari FS; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Bernstein E; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Nadeem B; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Chang A; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Sullivan NT; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Segil A; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Desphande C; Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Bensen E; Vergent Bioscience, Minneapolis, Minnesota., Santini JT; Vergent Bioscience, Minneapolis, Minnesota., Kucharczuk JC; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Delikatny EJ; Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Bogyo M; Department of Pathology, Stanford University, Palo Alto, California., Egan AJM; Department of Pathology, St. Vincent's Hospital, Melbourne, Australia., Bradley CW; Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania., Eruslanov E; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania., Lickliter JD; Nucleus Network, Melbourne, Australia., Wright G; Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia.; Victorian Comprehensive Cancer Centre Alliance, Melbourne, Australia., Singhal S; Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Sep 01; Vol. 28 (17), pp. 3729-3741.
DOI:	10.1158/1078-0432.CCR-22-1215
Abstrakt:	Purpose: Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity-based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity-based probe (VGT-309) for fluorescence-guided surgery. Experimental Design: We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of lung cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing lung cancer surgery. Results: In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine tumors, we found that the probe selectively labeled tumors and demonstrated high tumor-to-background ratio (TBR; range: 2.15-3.71). In the Phase I human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase II trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs = 2.83 and 7.18) in real time to illustrate its successful clinical translation and potential to improve surgical management. Conclusions: This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary tumors during resection. These results may be generalizable to other cancers due to cathepsin overexpression in many solid tumors. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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