Topp Monique D, Hartley Lynne, Cook Michele, Heong Valerie, Boehm Emma, McShane Lauren, Pyman Jan, McNally Orla, Ananda Sumitra, Harrell Marisol, Etemadmoghadam Dariush, Galletta Laura, Alsop Kathryn, Mitchell Gillian, Fox Stephen B, Kerr Jeffrey B, Hutt Karla J, Kaufmann Scott H, Swisher Elizabeth M, Bowtell David D, Wakefield Matthew J, Scott Clare L
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medicine and Health Sciences, Monash University, Clayton, Victoria 3168, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Mol Oncol. 2014 May;8(3):656-68. doi: 10.1016/j.molonc.2014.01.008. Epub 2014 Jan 24.
Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses.
We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγ(null) recipient mice, completed molecular annotation and assessed platinum sensitivity.
The success rate of xenografting was 83%. Of ten HG-SOC PDXs, all contained mutations in TP53, two were mutated for BRCA1, three for BRCA2, and in two, BRCA1 was methylated. In vivo cisplatin response, determined as platinum sensitive (progression-free interval ≥ 100 d, n = 4), resistant (progression-free interval <100 d, n = 3) or refractory (n = 3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDXs contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDXs overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2).
Because PDX platinum response reflected clinical outcome, these annotated PDXs will provide a unique model system for preclinical testing of novel therapies for HG-SOC.
要提高针对高级别浆液性卵巢癌（HG-SOC）潜在驱动因素和脆弱性的能力，需要开发能够反映临床反应的分子注释临床前模型。
我们通过将新鲜的人类HG-SOC片段移植到NOD/SCID IL2Rγ（缺失）受体小鼠的皮下和卵巢囊内位点，从连续的、未经化疗的人类HG-SOC中生成患者来源的异种移植模型（PDX），完成分子注释并评估铂敏感性。
异种移植成功率为83%。在十个HG-SOC PDX中，所有模型的TP53均有突变，两个BRCA1突变，三个BRCA2突变，两个BRCA1甲基化。体内顺铂反应分为铂敏感（无进展生存期≥100天，n = 4）、耐药（无进展生存期<100天，n = 3）或难治（n = 3），这在很大程度上与患者预后一致。四个铂敏感的HG-SOC PDX中有三个含有DNA修复基因突变，第四个BRCA1甲基化。相比之下，所有三个铂难治性PDX均过表达主要癌基因（CCNE1、LIN28B和/或BCL2）。
由于PDX的铂反应反映了临床结果，这些注释的PDX将为HG-SOC新型疗法的临床前测试提供一个独特的模型系统。
