Department of Chemistry, University of Illinois at Urbana-Champaign.
Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, Illinois.
Melanoma Res. 2023 Dec 1;33(6):514-524. doi: 10.1097/CMR.0000000000000927. Epub 2023 Sep 22.
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.
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。Procaspase-3 是一种促凋亡蛋白，也是关键凋亡执行者 caspase-3 的前体，在广泛的恶性肿瘤中过度表达，药物 PAC-1 利用这种过度表达来选择性地杀死癌细胞。在此，我们研究了 PAC-1 对葡萄膜黑色素瘤细胞系的疗效，并报告了 PAC-1 和恩曲替尼的协同组合。这种临床前活性、在小鼠中的耐受性数据以及这些药物在人类癌症患者中的已知临床疗效，导致了转移性葡萄膜黑色素瘤患者的一项小规模 1b 期研究。在这些患者中，PAC-1 和恩曲替尼联合使用时无治疗相关的≥3 级毒性。PAC-1 治疗并未影响恩曲替尼的药代动力学。在这个小型且预处理较多的初始队列中，6 名患者中有 4 名观察到疾病稳定，中位无进展生存期为 3.38 个月（95%CI，1.6-6.5 个月）。这项研究初步表明，PAC-1 和恩曲替尼的联合可能值得进一步的临床研究。临床试验注册：ClinicalTrials.gov：NCT04589832。
