1. Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts
- Author
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David D.L. Bowtell, Lauren McShane, Stephen B. Fox, Karla J. Hutt, Valerie Heong, Sumitra Ananda, Scott H. Kaufmann, Matthew Wakefield, Jan Pyman, Michele Cook, Orla McNally, Emma Boehm, Dariush Etemadmoghadam, Gillian Mitchell, Marisol Harrell, Kathryn Alsop, Jeffrey B. Kerr, Elizabeth M. Swisher, Lynne Hartley, Laura Galletta, Clare L. Scott, and Monique Topp
- Subjects
Cancer Research ,endocrine system ,endocrine system diseases ,medicine.medical_treatment ,Transplantation, Heterologous ,Ovary ,Antineoplastic Agents ,Mice, SCID ,Biology ,digestive system ,Mice ,Genetics ,medicine ,Carcinoma ,Animals ,Humans ,Research Articles ,Cisplatin ,BRCA2 Protein ,Ovarian Neoplasms ,Chemotherapy ,BRCA1 Protein ,Cancer ,General Medicine ,DNA Methylation ,medicine.disease ,female genital diseases and pregnancy complications ,Transplantation ,medicine.anatomical_structure ,Oncology ,Mutation ,Cancer research ,Molecular Medicine ,Female ,Ovarian cancer ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
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.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.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 interval100 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).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.
- Published
- 2013