Molecular correlates of platinum response in human high‐grade serous ovarian cancer patient‐derived xenografts
Year: 2014
Type: 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-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. 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.
Source: Molecular Oncology
Authors: Monique D. Topp, Lynne Hartley, Michele Cook, Valerie Heong, Emma Boehm, Lauren McShane, Jan Pyman, Orla McNally, Sumitra Ananda, Marisol Harrell, Dariush Etemadmoghadam, Laura Galletta, Kathryn Alsop, Gillian Mitchell, Stephen B. Fox, Jeffrey B. Kerr, Karla J. Hutt, Scott H. Kaufmann, Australian Ovarian Cancer Study, Elizabeth M. Swisher, David D. Bowtell, Matthew J. Wakefield, Clare L. Scott
Institutions: Walter and Eliza Hall Institute of Medical Research, Monash University, Royal Women's Hospital, The University of Melbourne, University of Washington, Peter MacCallum Cancer Centre, Mayo Clinic, Mayo Clinic Comprehensive Cancer Center (Minnesota), The University of Sydney, QIMR Berghofer Medical Research Institute, Westmead Hospital, Westmead Institute
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2020240832