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Mol Oncol. 2014 May;8(3):656-68. doi: 10.1016/j.molonc.2014.01.008. Epub 2014 Jan 24.

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

Author information

1
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.
2
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Royal Women's Hospital, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
4
Royal Women's Hospital, Parkville, Victoria 3052, Australia.
5
University of Washington, Seattle, WA, USA.
6
Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria 3010, Australia; Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
7
Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia.
8
Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia; Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
9
Department of Medicine and Health Sciences, Monash University, Clayton, Victoria 3168, Australia.
10
Department of Medicine and Health Sciences, Monash University, Clayton, Victoria 3168, Australia; Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia.
11
Mayo Clinic Cancer Centre, Rochester, MN, USA.
12
Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia; Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, NSW, Australia; Department of Gynaecological Oncology, Westmead Hospital, NSW, Australia; Queensland Institute of Medical Research, Brisbane, QLD, Australia.
13
Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria 3010, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 8006, Australia.
14
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia; Department of Genetics, University of Melbourne, Melbourne, Victoria 8006, Australia.
15
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Royal Women's Hospital, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia. Electronic address: scottc@wehi.edu.au.

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.

KEYWORDS:

BRCA1; BRCA2; DNA repair; Platinum; Serous ovarian cancer; Xenograft

PMID:
24560445
PMCID:
PMC4400120
DOI:
10.1016/j.molonc.2014.01.008
[Indexed for MEDLINE]
Free PMC Article

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