Details

Autor(en) / Beteiligte

• Topp, Monique D.
• Hartley, Lynne
• Cook, Michele
• Heong, Valerie
• Boehm, Emma
• McShane, Lauren
• Pyman, Jan
• McNally, Orla
• Ananda, Sumitra
• Harrell, Marisol
• Etemadmoghadam, Dariush
• Galletta, Laura
• Alsop, Kathryn
• Mitchell, Gillian
• Fox, Stephen B.
• Kerr, Jeffrey B.
• Hutt, Karla J.
• Kaufmann, Scott H.
• Australian Ovarian Cancer Study
• Swisher, Elizabeth M.
• Bowtell, David D.
• Wakefield, Matthew J.
• Scott, Clare L.

Titel

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

Ist Teil von

• Molecular oncology, 2014-05, Vol.8 (3), p.656-668

Ort / Verlag

United States: Elsevier B.V

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• 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 IL2Rγnull 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 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). 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. •High-grade serous ovarian cancer patient-derived xenografts from fragments (83% success).•In vivo platinum response (sensitive ≥ 100 d) consistent with patient outcome.•Three of four platinum-sensitive PDX contained mutations in BRCA1 or BRCA2.•All three platinum refractory PDX overexpressed dominant oncogenes.•These annotated PDX will enhance preclinical testing of novel therapies.