TY - JOUR
T1 - Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts
AU - Topp, Monique D.
AU - Hartley, Lynne
AU - Cook, Michele
AU - Heong, Valerie
AU - Boehm, Emma
AU - McShane, Lauren
AU - Pyman, Jan
AU - McNally, Orla
AU - Ananda, Sumitra
AU - Harrell, Marisol
AU - Etemadmoghadam, Dariush
AU - Galletta, Laura
AU - Alsop, Kathryn
AU - Mitchell, Gillian
AU - Fox, Stephen B.
AU - Kerr, Jeffrey B.
AU - Hutt, Karla J.
AU - Kaufmann, Scott H.
AU - Australian Ovarian Cancer Study, Ovarian Cancer Study
AU - Swisher, Elizabeth M.
AU - Bowtell, David D.
AU - Wakefield, Matthew J.
AU - Scott, Clare L.
N1 - Funding Information:
This work was supported by fellowships and grants from the National Health and Medical Research Council (NHMRC Australia; Fellowships JKF (#441101), KJH (#494836)); the Cancer Council Victoria (Sir Edward Dunlop Fellowship in Cancer Research to CLS); the Victorian Cancer Agency (Clinical Fellowship to CLS); Monash University (PhD Scholarship to MT); CRC for Cancer Therapeutics (PhD top-up scholarship to MT), Ovarian Cancer Australia (PhD Scholarship to VH) and the National Institute of Health (2P50CA083636) (EMS) and the Wendy Feuer Ovarian Cancer Research Fund (EMS) . This work was made possible through the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. We thank Clovis Oncology for funding Foundation Medicine analyses. The Australian Ovarian Cancer Study was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Tasmania and The Cancer Foundation of Western Australia and the National Health and Medical Research Council of Australia (NHMRC; ID400413). The Australian Ovarian Cancer Study gratefully acknowledges the cooperation of the participating institutions in Australia and also acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org . We would like to thank all of the women who participated in these research programs.
PY - 2014/5
Y1 - 2014/5
N2 - 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 IL2Rγnull 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. Invivo cisplatin response, determined as platinum sensitive (progression-free interval ≥100d, n=4), resistant (progression-free interval <100d, 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.
AB - 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 IL2Rγnull 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. Invivo cisplatin response, determined as platinum sensitive (progression-free interval ≥100d, n=4), resistant (progression-free interval <100d, 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.
KW - BRCA1
KW - BRCA2
KW - DNA repair
KW - Platinum
KW - Serous ovarian cancer
KW - Xenograft
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U2 - 10.1016/j.molonc.2014.01.008
DO - 10.1016/j.molonc.2014.01.008
M3 - Article
C2 - 24560445
AN - SCOPUS:84899475102
SN - 1574-7891
VL - 8
SP - 656
EP - 668
JO - Molecular Oncology
JF - Molecular Oncology
IS - 3
ER -