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Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts


Topp, MD; Hartley, L; Cook, M; Heong, V; Boehm, E; McShane, L; Pyman, J; McNally, O; Ananda, S; Harrell, M; Etemadmoghadam, D; Galletta, L; Alsop, K; Mitchell, G; Fox, SB; Kerr, JB; Hutt, KJ; Kaufmann, SH; Australian Ovarian Cancer, Study; Swisher, EM; Bowtell, DD; Wakefield, MJ; Scott, CL
2014-01-24
Molecular Oncology
Journal Article
8
3
656-668
INTRODUCTION: 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. METHODS: We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naive, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rgammanull recipient mice, completed molecular annotation and assessed platinum sensitivity. RESULTS: 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). CONCLUSIONS: 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.
BRCA1, BRCA2, DNA repair, Platinum, Serous ovarian cancer, Xenograft
Stem Cells and Cancer; Bioinformatics
10.1016/j.molonc.2014.01.008
24560445
Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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Creation Date 2014-04-16 08:43:45 Last Modified 2015-09-22 10:05:03