@article{5b04440ef83f4b19b1faab542f6a7dec,
title = "The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma",
abstract = "The treatment of metastatic uveal melanoma remains a major clinical challenge. Procaspase-3, a proapoptotic protein and precursor to the key apoptotic executioner caspase-3, is overexpressed in a wide range of malignancies, and the drug PAC-1 leverages this overexpression to selectively kill cancer cells. Herein, we investigate the efficacy of PAC-1 against uveal melanoma cell lines and report the synergistic combination of PAC-1 and entrectinib. This preclinical activity, tolerability data in mice, and the known clinical effectiveness of these drugs in human cancer patients led to a small Phase 1b study in patients with metastatic uveal melanoma. The combination of PAC-1 and entrectinib was tolerated with no treatment-related grade ≥3 toxicities in these patients. The pharmacokinetics of entrectinib were not affected by PAC-1 treatment. In this small and heavily pretreated initial cohort, stable disease was observed in four out of six patients, with a median progression-free survival of 3.38 months (95% CI 1.6-6.5 months). This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation.",
keywords = "PAC-1, entrectinib, procaspase-3, uveal melanoma",
author = "Boudreau, {Matthew W.} and Tonogai, {Emily J.} and Schane, {Claire P.} and Xi, {Min X.} and Fischer, {James H.} and Jayanthi Vijayakumar and Yan Ji and Tarasow, {Theodore M.} and Fan, {Timothy M.} and Hergenrother, {Paul J.} and Dudek, {Arkadiusz Z.}",
note = "We thank patients, clinical research staff of Early Phase Therapeutic Program at Regions Hospital in St. Paul, MN, HealthPartners Institute (especially, we thank Joanna Hill and Lisa Wahowske), and research support from Hoosier Cancer Research Network. We thank Genentech for providing entrectinib and we thank Vanquish Oncology for providing PAC-1 and financial support for this study. We would like to thank Martine Jager for providing all uveal melanoma cell lines (Leiden University Medical Center). We would like to extend our gratitude to the Cancer Center at Illinois (CCIL), and this work was partially supported by the University of Illinois, the NIH (R01CA120439), and the Melanoma Research Alliance (412305). M.W.B. was a member of the NIH Chemistry-Biology Interface Training Program (T32-GM136629), an ACS Medicinal Chemistry Predoctoral Fellow, and he is supported by an NCI F99/K00 predoctoral fellowship (F99-CA253731; K00-CA253731). We also would like to thank Engdahl Family Foundation that provided partial financial support for the study.",
year = "2023",
month = dec,
day = "1",
doi = "10.1097/CMR.0000000000000927",
language = "English (US)",
volume = "33",
pages = "514--524",
journal = "Melanoma research",
issn = "0960-8931",
publisher = "Lippincott Williams and Wilkins",
number = "6",
}