Antitumor Activity and Molecular Effects of Vemurafenib in Dogs with BRAF-mutant Bladder Cancer

A phase I/II clinical trial of vemurafenib was performed in dogs with naturally-occurring invasive urothelial carcinoma which harbored the BRAF V595E mutation (canine homologue of the BRAF V600E mutation in human cancer). The purpose was to determine the suitability of the canine cancer in serving as a model to improve BRAF-targeted therapies in humans. The objectives were to determine the: (1) safety and maximum tolerated dose of vemurafenib, (2) pharmacokinetic profile, (3) antitumor activity and clinical case follow-up, and (4) analysis of RNA-seq data from tumor samples collected prior to vemurafenib, at approximately one month into treatment, and at relapse. The findings confirmed good initial antitumor activity followed by consistent relapse in the dogs, similar to that reported in BRAF-driven cancer in humans, and provided new information concerning some of the mechanisms involved in drug sensitivity and resistance.

本研究针对携带BRAF V595E突变（人类癌症中BRAF V600E突变的犬类同源突变体）的自发性浸润性尿路上皮癌犬只，开展了维莫非尼的I/II期临床试验。本研究旨在评估该犬类癌症模型用于优化人类BRAF靶向治疗的适用性。本次试验的核心目标包括：(1) 明确维莫非尼的安全性与最大耐受剂量；(2) 解析其药代动力学特征；(3) 评估抗肿瘤活性并开展临床病例随访；(4) 对维莫非尼治疗前、治疗约1个月时以及肿瘤复发时采集的肿瘤样本的RNA测序（RNA-seq）数据进行分析。研究结果证实，受试犬只在初始阶段展现出良好的抗肿瘤活性，随后出现持续的肿瘤复发，这与人类BRAF驱动型癌症的已有报道高度相符，同时为阐明药物敏感性与耐药性的部分潜在机制提供了新的实验依据。