Poly ADP-ribose polymerase inhibitors (PARPi) have transformed ovarian cancer (OC) treatment, primarily for tumours deficient in homologous recombination repair. Combining VEGF-signalling inhibitors with PARPi has enhanced clinical benefit in OC. To study drivers of efficacy when combining PARP inhibition and VEGF-signalling, a cohort of patient-derived ovarian cancer xenografts (OC-PDXs), representative of the molecular characteristics and drug sensitivity of patient tumours, were treated with the PARPi olaparib and the VEGFR inhibitor cediranib at clinically relevant doses. The combination showed broad anti-tumour activity, reducing growth of all OC-PDXs, regardless of the homologous recombination repair (HRR) mutational status, with greater additive combination benefit in tumours poorly sensitive to platinum and olaparib. In orthotopic models, the combined treatment reduced tumour dissemination in the peritoneal cavity and prolonged survival. Enhanced combination benefit was independent of tumour cell expression of receptor tyrosine kinases targeted by cediranib, and not associated with change in expression of genes associated with DNA repair machinery. However, the combination of cediranib with olaparib was effective in reducing tumour vasculature in all the OC-PDXs. Collectively our data suggest that olaparib and cediranib act through complementary mechanisms affecting tumour cells and tumour microenvironment, respectively. This detailed analysis of the combined effect of VEGF-signalling and PARP inhibitors in OC-PDXs suggest that despite broad activity, there is no dominant common mechanistic inter-dependency driving therapeutic benefit.

中文翻译：

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VEGF 通路抑制增强 PARP 抑制剂在卵巢癌中的疗效，与 BRCA 状态无关

聚 ADP-核糖聚合酶抑制剂 (PARPi) 已经改变了卵巢癌 (OC) 的治疗方法，主要用于同源重组修复缺陷的肿瘤。将 VEGF 信号抑制剂与 PARPi 联合使用可增强 OC 的临床益处。为了研究结合 PARP 抑制和 VEGF 信号传导时的疗效驱动因素，一组患者衍生的卵巢癌异种移植物 (OC-PDXs)，代表患者肿瘤的分子特征和药物敏感性，用 PARPi olaparib 和 VEGFR 治疗临床相关剂量的抑制剂西地尼布。该组合显示出广泛的抗肿瘤活性，减少了所有 OC-PDX 的生长，无论同源重组修复 (HRR) 突变状态如何，在对铂和奥拉帕尼不敏感的肿瘤中具有更大的附加组合益处。在原位模型中，联合治疗减少了腹膜腔内的肿瘤扩散并延长了生存期。增强的联合益处与西地尼布靶向的受体酪氨酸激酶的肿瘤细胞表达无关，并且与与 DNA 修复机制相关的基因表达的变化无关。然而，西地尼布与奥拉帕尼的组合可有效减少所有 OC-PDX 中的肿瘤脉管系统。总的来说，我们的数据表明，奥拉帕尼和西地尼布分别通过影响肿瘤细胞和肿瘤微环境的互补机制发挥作用。对 OC-PDX 中 VEGF 信号传导和 PARP 抑制剂的联合作用的详细分析表明，尽管具有广泛的活性，但没有显着的共同机制相互依赖性驱动治疗益处。