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

Autor:	Boudreau MW; Department of Chemistry, University of Illinois at Urbana-Champaign.; Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, Illinois., Tonogai EJ; Department of Chemistry, University of Illinois at Urbana-Champaign.; Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, Illinois., Schane CP; Department of Chemistry, University of Illinois at Urbana-Champaign.; Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, Illinois., Xi MX; HealthPartners Institute, Minneapolis, Minnesota., Fischer JH; Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago., Vijayakumar J; HealthPartners Institute, Minneapolis, Minnesota., Ji Y; HealthPartners Institute, Minneapolis, Minnesota., Tarasow TM; Vanquish Oncology, Inc, Champaign., Fan TM; Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, Illinois.; Vanquish Oncology, Inc, Champaign.; Cancer Center at Illinois, University of Illinois at Urbana-Champaign.; Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois., Hergenrother PJ; Department of Chemistry, University of Illinois at Urbana-Champaign.; Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, Illinois.; Vanquish Oncology, Inc, Champaign.; Cancer Center at Illinois, University of Illinois at Urbana-Champaign., Dudek AZ; HealthPartners Institute, Minneapolis, Minnesota.; Vanquish Oncology, Inc, Champaign.; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.
Jazyk:	angličtina
Zdroj:	Melanoma research [Melanoma Res] 2023 Dec 01; Vol. 33 (6), pp. 514-524. Date of Electronic Publication: 2023 Sep 22.
DOI:	10.1097/CMR.0000000000000927
Abstrakt:	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. Clinical trial registration: Clinical Trials.gov: NCT04589832. (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
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