Details

Autor(en) / Beteiligte

• Kennedy, Gregory T
• Holt, David E
• Azari, Feredun S
• Bernstein, Elizabeth
• Nadeem, Bilal
• Chang, Ashley
• Sullivan, Neil T
• Segil, Alix
• Desphande, Charuhas
• Bensen, Eric
• Santini, John T
• Kucharczuk, John C
• Delikatny, Edward J
• Bogyo, Matthew
• Egan, A J Matthew
• Bradley, Charles W
• Eruslanov, Evgeniy
• Lickliter, Jason D
• Wright, Gavin
• Singhal, Sunil

Titel

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

Ist Teil von

• Clinical cancer research, 2022-09, Vol.28 (17), p.3729-3741

Ort / Verlag

United States

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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.