Background Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease. Objectives To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC. Design and methods Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was BRCA2 mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either BRCA1 or BRCA2 (BRCA1/2), four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and in vivo treatment studies were undertaken. Results Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with p < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX p < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary BRCA2 mutations, two BRCA2-mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the SLC25A40-ABCB1 fusion, known to upregulate drug efflux via MDR1. Conclusion The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy.

中文翻译：

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微管抑制剂艾日布林在铂类耐药和难治性高级别浆液性卵巢癌患者来源的异种移植模型中显示出疗效。

背景 尽管对铂类化疗和 PARP 抑制剂治疗 (PARPi) 有初步反应，但几乎所有复发性高级别浆液性卵巢癌 (HGSC) 都会获得致命的耐药性；事实上，大约 15% 的人患有新发的铂难治性疾病。目的 通过评估 HGSC 患者来源的异种移植 (PDX) 模型中的反应，确定抗微管剂 (AMA) 疗法（紫杉醇、长春瑞滨和艾日布林）在铂类耐药或难治性 (PRR) HGSC 中的潜力。设计和方法 在 13 个 PRR HGSC PDX 中，6 个是原发性 PRR，源自未经化疗的样本（1 个是 BRCA2 突变体），7 个来自临床化疗后获得的样本（5 个是 BRCA1 或 BRCA2 突变体（BRCA1/ 2），其中四人之前曾暴露于 PARPi），概括了临床上患有侵袭性治疗耐药 HGSC 的个体群体。进行了分子分析和体内治疗研究。结果 13 名 PRR PDX 中的 7 名 (54%) 对 AMA、艾日布林治疗敏感（从治疗开始到疾病进展 (PD) 的时间≥100 天），13 名 PRR 中的 11 名 (85%) 获得了显着获益来自艾日布林 [每个 PDX 的收获时间 (TTH)，p < 0.002]。在 10 例铂类难治性 HGSC PDX 中，有 5 例 (50%) 和三分之一的铂类耐药 PDX (33%) 中，艾日布林比顺铂更有效，PD 时间更长，TTH 显着延长（每个 PDX p < 0.02）。此外，其中四个模型对所有三种测试的 AMA 都极其敏感，保持反应直到实验结束（治疗开始后 120 天）。尽管存在继发性 BRCA2 突变，但源自经过大量预处理的个体的两种 BRCA2 突变 PDX 模型对 AMA 敏感。PRR HGSC PDX 模型对 AMA 表现出更高的敏感性，具有高增殖指数和癌基因表达。两种 PDX 模型（均接受过化疗和/或 PARPi 暴露）对所有 AMA 均无效，其中一种含有 SLC25A40-ABCB1 融合体，已知可通过 MDR1 上调药物流出。结论 艾日布林在 PRR HGSC PDX 中观察到的疗效与紫杉醇相似，改变了卵巢癌的临床实践。因此，艾日布林值得在临床试验中进一步考虑，特别是卡铂/紫杉醇化疗早期失败的卵巢癌。