Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts
Details
Publication Year 2014-01-24, Volume 8, Issue #3, Page 656-668
Journal Title
Molecular Oncology
Publication Type
Journal Article
Abstract
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.
Keywords
BRCA1, BRCA2, DNA repair, Platinum, Serous ovarian cancer, Xenograft
WEHI Research Division(s)
Stem Cells And Cancer; Bioinformatics
PubMed ID
24560445
Rights Notice
Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


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