High-grade serous ovarian cancer (HGSOC) has the highest mortality rate among all gynecological cancers. Patients are generally diagnosed in an advanced stage with the majority of cases displaying platinum resistant relapses. Recent genomic interrogation of large numbers of HGSOC patient samples indicated high complexity in terms of genetic aberrations, intra- and intertumor heterogeneity and underscored their lack of targetable oncogenic mutations. Sub-classifications of HGSOC based on expression profiles, termed 'differentiated', 'immunoreactive', 'mesenchymal' and 'proliferative', were shown to have prognostic value. In addition, in almost half of all HGSOC patients, a deficiency in homologous recombination (HR) was found that potentially can be targeted using PARP inhibitors. Developing precision medicine requires advanced experimental models. In the current review, we discuss experimental HGSOC models in which resistance to platinum therapy and the use of novel therapeutics can be carefully studied. Panels of better-defined primary cell lines need to be established to capture the full spectrum of HGSOC subtypes. Further refinement of cell lines is obtained with a 3-dimensional culture model mimicking the tumor microenvironment. Alternatively, ex vivo ovarian tumor tissue slices are used. For in vivo studies, larger panels of ovarian cancer patient-derived xenografts (PDXs) are being established, encompassing all expression subtypes. Ovarian cancer PDXs grossly retain tumor heterogeneity and clinical response to platinum therapy is preserved. PDXs are currently used in drug screens and as avatars for patient response. The role of the immune system in tumor responses can be assessed using humanized PDXs and immunocompetent genetically engineered mouse models. Dynamic tracking of genetic alterations in PDXs as well as patients during treatment and after relapse is feasible by sequencing circulating cell-free tumor DNA and analyzing circulating tumor cells. We discuss how various models and methods can be combined to delineate the molecular mechanisms underlying platinum resistance and to select HGSOC patients other than BRCA1/2-mutation carriers that could potentially benefit from the synthetic lethality of PARP inhibitors. This integrated approach is a first step to improve therapy outcomes in specific subgroups of HGSOC patients.

中文翻译：

---

研究铂对高度浆液性卵巢癌的敏感性和耐药性：针对不同问题的不同模型。

在所有妇科癌症中，高级别浆液性卵巢癌（HGSOC）死亡率最高。通常将患者诊断为晚期，大多数病例表现出铂耐药性复发。最近对大量HGSOC患者样品的基因组研究表明，在遗传畸变，肿瘤内和肿瘤间异质性方面具有很高的复杂性，并强调了它们缺乏可靶向的致癌突变。HGSOC基于表达谱的亚分类被称为具有预后价值，被称为“分化的”，“免疫反应性”，“间质性”和“增生性”。另外，在几乎所有的HGSOC患者中，发现同源重组（HR）不足，可以使用PARP抑制剂靶向。开发精密医学需要先进的实验模型。在当前的审查中，我们讨论了实验性HGSOC模型，在该模型中可以仔细研究对铂疗法的耐药性和新疗法的使用。需要建立更好定义的原代细胞系，以捕获HGSOC亚型的全部光谱。用模仿肿瘤微环境的3维培养模型可以获得细胞系的进一步细化。或者，使用离体卵巢肿瘤组织切片。为了进行体内研究，正在建立更大范围的卵巢癌患者异种移植物（PDXs），包括所有表达亚型。卵巢癌PDX大致保留了肿瘤异质性，并且保留了对铂疗法的临床反应。目前，PDX用于药物筛查和用作患者反应的化身。免疫系统在肿瘤反应中的作用可以使用人源化的PDX和具有免疫能力的基因工程小鼠模型进行评估。通过对无细胞循环肿瘤DNA测序并分析循环肿瘤细胞，可以动态跟踪PDX以及治疗期间和复发后患者的遗传变化。我们讨论了如何结合各种模型和方法来描述潜在的铂耐药分子机制，并选择除BRCA1 / 2突变携带者以外的可能从PARP抑制剂的合成杀伤力中受益的HGSOC患者。这种综合方法是改善HGSOC患者特定亚组治疗效果的第一步。