The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma

Matthew W. Boudreau, Emily J. Tonogai, Claire P. Schane, Min X. Xi, James H. Fischer, Jayanthi Vijayakumar, Yan Ji, Theodore M. Tarasow, Timothy M. Fan, Paul J. Hergenrother, Arkadiusz Z. Dudek

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)514-524
Number of pages11
JournalMelanoma research
Issue number6
StatePublished - Dec 1 2023


  • PAC-1
  • entrectinib
  • procaspase-3
  • uveal melanoma

ASJC Scopus subject areas

  • Dermatology
  • Oncology
  • Cancer Research


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