Related Experiment Video
Updated: Sep 5, 2025
Computed Tomography-guided Time-domain Diffuse Fluorescence Tomography in Small Animals for Localization of Cancer Biomarkers
Published on: July 17, 2012
A Cathepsin-Targeted Quenched Activity-Based Probe Facilitates Enhanced Detection of Human Tumors during Resection
Gregory T Kennedy1, David E Holt2, Feredun S Azari1
1Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
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.
Insights
A novel cathepsin activity-based probe (VGT-309) has been successfully translated for human use in fluorescence-guided surgery. This probe safely and effectively labels lung tumors, improving surgical precision for better oncologic outcomes.
Area of Science:
- Oncology
- Surgical Innovation
- Molecular Imaging
Background:
- Fluorescence-guided surgery enhances oncologic resection completeness.
- Activity-based probes offer improved specificity by targeting tumor enzymes.
- Clinical translation of such probes for human use is limited.
Purpose of the Study:
- To report the clinical translation of a cathepsin activity-based probe, VGT-309, for fluorescence-guided surgery.
- To evaluate the safety and feasibility of VGT-309 in human subjects undergoing lung cancer surgery.
Main Methods:
- VGT-309 specificity, dosing, and timing were optimized in preclinical lung cancer models.
- Canine pulmonary tumor resections assessed VGT-309 feasibility and tumor-to-background ratio (TBR).
- A Phase I human study evaluated VGT-309 safety in healthy volunteers, followed by testing in lung cancer patients.
Main Results:
- Preclinical models showed specific tumor cell labeling blocked by cathepsin inhibitors.
- Canine studies demonstrated selective tumor labeling with high TBR (2.15-3.71).
- Phase I trials confirmed VGT-309 safety across all doses. Two human cases showed real-time localization of occult tumors (TBRs = 2.83 and 7.18).
Conclusions:
- First-in-human study confirms VGT-309 safety and feasibility for labeling pulmonary tumors during resection.
- VGT-309 shows potential to improve surgical management by visualizing non-palpable tumors.
- Findings may extend to other cancers with cathepsin overexpression.
