Poster Presentation 26th Lorne Cancer Conference 2014

Using personalized xenograft models to improve treatment for women with epithelial ovarian cancer (#269)

Monique D Topp 1 2 , Lynne Hartley 1 , Michele Cook 1 , Valerie Heong 1 3 4 , Emma Boehm 1 , Lauren McShane 1 , Jan Pyman 3 , Orla McNally 3 , Sumi Ananda 3 , Maria I Harrell 5 , Dariush Etemadmoghadam 6 7 8 , Laura Galetta 6 , Kathryn Alsop 6 , Gillian Mitchell 6 , Stephen B Fox 6 8 , Jeff B Kerr 2 , Karla J Hutt 2 9 , Scott H Kaufmann 10 , AOCS Australian Ovarian Cancer Study 6 11 12 , Elizabeth M Swisher 5 , David D Bowtell 6 8 13 , Matthew Wakefield 1 4 14 , Clare L Scott 1 3 4
  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  2. Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
  3. The Royal Women's Hospital, Melbourne, Victoria, Australia
  4. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  5. Department of Obstetrics and Gynaecology, School of Medicine, University of Washington, Seattle, Washington, United States of America
  6. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  7. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
  8. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
  9. Prince Henry's Institute of Medical Research, Melbourne, Victoria, Australia
  10. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America
  11. Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, and Departments of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
  12. Queensland Institute of Medical Research, Brisbane, Queensland, Australia
  13. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia
  14. Departments of Genetics, University of Melbourne, Melbourne, Victoria, Australia

Background: Treatment options for women with ovarian cancer remain very limited. Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) 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. In vitro drug screening studies utilizing this well annotated cohort will guide future in vivo studies to determine drivers of individual cancers.

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 <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, provide outstanding utility for studies of novel therapies and mechanisms of resistance. This will improve the design of clinical trials for women.