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

Abstract

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 1 human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase 2 trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs= 2.83 & 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.

Bioinspired color-near infrared endoscopic imaging system for molecular guided cancer surgery

“…Enzyme-or pH-activated probes have the potential to address some of these shortcomings as demonstrated by results from phase 2 and phase 3 clinical trials, though none of these probes are FDA-approved at this time. 46,47 Since there is still no universal molecular probe that works for all types of cancers, the next frontier for FGS will involve a cocktail of carefully selected tracers to highlight all tumors and involved lymph nodes.…”

“…However, about ∼20% of adenocarcinoma patients and the majority of squamous cell and non-small cell lung cancer patients will not benefit from the pafolacianine probe due to a lack of folate alpha receptors in the primary tumors. Enzyme- or pH-activated probes have the potential to address some of these shortcomings as demonstrated by results from phase 2 and phase 3 clinical trials, though none of these probes are FDA-approved at this time 46 , 47 . Since there is still no universal molecular probe that works for all types of cancers, the next frontier for FGS will involve a cocktail of carefully selected tracers to highlight all tumors and involved lymph nodes.…”

Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery

“…The previously described cathepsin-targeted probe VGT-309 is currently under investigation in a phase II clinical trial in 40 patients undergoing surgery for primary lung cancer or lung metastases (NCT05400226). The preliminary results in two patients have already been published and illustrate the successful clinical translation of VGT-309 and its potential to improve surgical management of patients undergoing cancer resection [144]. However, VGT0309 has not yet been tested in breast cancer patients.…”

Chemical Tools to Image the Activity of PAR-Cleaving Proteases

“…In a Phase I clinical trial, VGT-309 was demonstrated to be safe for human use. It is currently in Phase II clinical trials for fluorescence-guided detection of lung cancers . Reports from the first patients were extremely encouraging, with VGT-309 aiding in the identification of nonpalpable lung nodules that were not visually detected by the surgeons.…”