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

IF 1.5 4区 医学 Q3 DERMATOLOGY Melanoma Research Pub Date : 2023-12-01 Epub Date: 2023-09-22 DOI:10.1097/CMR.0000000000000927
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
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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. Clinical trial registration: Clinical Trials.gov: NCT04589832.

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PAC-1和恩特替尼联合治疗转移性葡萄膜黑色素瘤。
转移性葡萄膜黑色素瘤的治疗仍然是一个主要的临床挑战。原凋亡蛋白酶-3是一种促凋亡蛋白,也是关键凋亡执行子胱天蛋白酶-3的前体,在多种恶性肿瘤中过表达,药物PAC-1利用这种过表达选择性杀死癌症细胞。在此,我们研究了PAC-1对葡萄膜黑色素瘤细胞系的疗效,并报道了PAC-1和恩特替尼的协同组合。这种临床前活性、小鼠耐受性数据以及这些药物在人类癌症患者中的已知临床有效性导致了对转移性葡萄膜黑色素瘤患者的小型1b期研究。PAC-1和恩曲替尼的联合用药在这些患者中具有耐受性,且无治疗相关等级≥3的毒性。恩曲替尼的药代动力学不受PAC-1治疗的影响。在这个经过大量预处理的小型初始队列中,六分之四的患者病情稳定,中位无进展生存期为3.38个月(95%CI 1.6-6.5个月)。这项研究初步证明,PAC-1和恩特替尼的组合可能需要进一步的临床研究。临床试验注册:Clinical Trials.gov:NCT04589832。
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来源期刊
Melanoma Research
Melanoma Research 医学-皮肤病学
CiteScore
3.40
自引率
4.50%
发文量
139
审稿时长
6-12 weeks
期刊介绍: ​​​​​​Melanoma Research is a well established international forum for the dissemination of new findings relating to melanoma. The aim of the Journal is to promote the level of informational exchange between those engaged in the field. Melanoma Research aims to encourage an informed and balanced view of experimental and clinical research and extend and stimulate communication and exchange of knowledge between investigators with differing areas of expertise. This will foster the development of translational research. The reporting of new clinical results and the effect and toxicity of new therapeutic agents and immunotherapy will be given emphasis by rapid publication of Short Communications. ​Thus, Melanoma Research seeks to present a coherent and up-to-date account of all aspects of investigations pertinent to melanoma. Consequently the scope of the Journal is broad, embracing the entire range of studies from fundamental and applied research in such subject areas as genetics, molecular biology, biochemistry, cell biology, photobiology, pathology, immunology, and advances in clinical oncology influencing the prevention, diagnosis and treatment of melanoma.
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