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

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.

Gleason grade accuracy of transperineal and transrectal prostate biopsies in MRI-naïve patients.

PURPOSE: Accurate assessment of Gleason grade is essential to guiding prostate cancer management. Not all healthcare systems have universal access to prostate MRI. We investigated whether transperineal (TP) prostate biopsies provide more accurate Gleason grading than transrectal (TR) biopsies in MRI-naïve patients. METHODS: Consecutive patients undergoing TP and TR systematic prostate needle biopsies from 2011 to 2018 were analysed. Patients who underwent radical prostatectomy (RP) within 180 days of biopsies were included. Patients undergoing MRI prior to biopsies were excluded. Pathological concordance, incidence of Gleason upgrading, and correlation coefficients among biopsies and RP Gleason grade were compared. A sub-analysis for concordance in anterior prostate tumours was conducted. RESULTS: 262 patients were included (112 TP; 150 TR), the median age was 63 years, and median time from biopsy to RP was 68 days. Concordance with RP histology for TP was 65% compared to 49% for TR (p = 0.011). Biopsy technique predicted RP concordance independent of the number of cores. Gleason upgrading occurred following 24% of TP versus 33% of TR biopsies. In anterior and apical tumours, upgrading occurred in 19% of TP biopsies and 38% of TR biopsies (p = 0.027). CONCLUSION: This study suggests TP approach to prostate biopsies result in improved histological grade accuracy in men whom MRI is not available, even after controlling for number of cores. TP approach also resulted in less upgrading for lesions in the anterior and apical prostate compared to TR.