Abstract 38: Using molecularly characterized patient-derived models to delineate underlying drivers and vulnerabilities of epithelial ovarian cancer
Authors: Topp Monique D. , Hartley Lynne , Cook Michele , Heong Valerie , Boehm Emma , McShane Lauren , Pyman Jan , McNally Orla , Ananda Sumi , Harell Maria I. , Etemadmoghadam Dariush , Galletta Laura , Alsop Kathryn , Mitchell Gillian , Fox Stephen B. , Kerr Jeff B. , Hutt Karla J. , Kaufmann Scott H. ,   Australian Ovarian Cancer Study (AOCS), Swisher Elizabeth M. , Bowtell David D. , Wakefield Matthew M. , Scott Clare L. 
Published: May 2015

Background: Treatment options for women with ovarian cancer remain very limited and acquired resistance to current therapies is very common. Altered DNA repair capability in epithelial ovarian cancer (EOC) may underlie response to both standard therapy and novel treatments, such as PARP inhibitors. Molecular sub-classification of high-grade serous ovarian cancer (HG-SOC) may uncover potential drug targets and possible mechanisms of drug resistance. Understanding the contribution of DNA repair and other driver mutations to drug response and resistance requires the development of molecularly annotated preclinical models reflective of the clinic.

Methods: A patient derived xenograft (PDX) cohort has been generated from consecutive, chemotherapy-naïve human HG-SOC and stratified according to in vivo response to standard chemotherapy, DNA repair capability and molecular characteristics, including next generation sequencing by Foundation Medicine. Resistance to therapy is driven by re-treating relapsed PDX in vivo providing invaluable “paired samples” (pre and post drug treatment), which are difficult to obtain from patients, to allow clonal evolution analysis of mechanisms of drug response and resistance.

Results: The xenograft success rate was 83%. Of ten HG-SOC PDX, all exhibited mutations in TP53, five in BRCA1/2 (two of which were germline) and two were methylated for BRCA1. In vivo cisplatin response, determined as platinum sensitive (progression-free interval (PFI) ≥100 d, n=4), platinum resistant (PFI &lt;100 d, n=3) or platinum refractory (n=3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDX contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDX overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2). Molecular analysis of this cohort has revealed actionable targets for novel therapeutic strategies. In vivo studies, including with PARP inhibitors, are underway.

Conclusion: PDX with histologic, molecular and therapeutic annotation, as well as clinical outcome data allow interrogation of molecular aberrations and drug resistance in vivo. This will inform targeting of novel therapies and the design of clinical trials for women.

Citation Format: Monique D. Topp, Lynne Hartley, Michele Cook, Valerie Heong, Emma Boehm, Lauren McShane, Jan Pyman, Orla McNally, Sumi Ananda, Maria I. Harell, Dariush Etemadmoghadam, Laura Galletta, Kathryn Alsop, Gillian Mitchell, Stephen B. Fox, Jeff B. Kerr, Karla J. Hutt, Scott H. Kaufmann, Australian Ovarian Cancer Study (AOCS), Elizabeth M. Swisher, David D. Bowtell, Matthew M. Wakefield, Clare L. Scott. Using molecularly characterized patient-derived models to delineate underlying drivers and vulnerabilities of epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 38. doi:10.1158/1538-7445.CANSUSC14-38