Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
The Wistar Institute, Philadelphia, Pennsylvania, USA.
JCI Insight. 2017 Jan 12;2(1):e89760. doi: 10.1172/jci.insight.89760.
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., /). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models with mutations () were established with a 93% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. A PDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in the PDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies for HGSOC.
约 50% 的高级别浆液性卵巢癌 (HGSOC) 存在同源重组 (HR) 相关基因缺陷（即 /）。缺乏用于优化 HR 缺陷 (HRD) HGSOC 治疗策略的临床前模型。我们开发了一种用于 HRD HGSOC 的临床前平台，包括原代肿瘤培养物、患者来源的异种移植物 (PDX) 和分子成像。通过免疫组织化学、靶向测序和反相蛋白阵列分析对模型进行了表征。我们还测试了 PDX 肿瘤对 PARP、CHK1 和 ATR 抑制剂的反应。建立了 14 个具有 突变 () 的同源性卵巢癌 PDX 模型，成功率为 93%。该同基因 PDX 模型模拟了 HGSOC 的自然进展，包括原发性卵巢肿瘤的发展和腹部内脏转移。PDX 对标准化疗的反应与患者的反应相关。在多次小鼠传代后，致病性突变和 HGSOC 标志物得以保留，表明致癌发生的潜在分子机制得以保留。一个高 p-CHK1 的 PDX 对 PARP、CHK1 和 ATR 抑制剂的肿瘤生长延迟表现出类似的反应。多聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂示踪剂与 PARP1 活性相关，并显示出对 PDX 模型中 PARP 抑制的反应。总之，同基因 HGSOC PDX 是一种强大且可靠的模型，可用于优化 HRD HGSOC 的治疗策略。
