Poster Presentation 25th Lorne Cancer Conference 2013

Designing targeted therapies for High-Grade Serous Ovarian Cancer (HG-SOC) utilising a novel xenograft cohort stratified according to molecular defects (#384)

Monique D Topp 1 , Lynne Hartley 1 , Michele Cook 1 , Dariush Etemadmoghadam 2 , Laura Galetta 2 , Jan Pyman 3 , Orla M McNally 3 , Jeff B Kerr 4 , Karla J Hutt 5 , Stephen B Fox 2 , Scott H Kaufmann 6 , Elizabeth M Swisher 7 , David D Bowtell 2 , Matthew Wakefield 1 , Australian Ovarian Cancer Study Group (AOCS) , Clare L Scott 1
  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. The Royal Women's Hospital, Melbourne, Victoria, Australia
  4. Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
  5. Prince Henry's Institute of Medical Research, Melbourne, Victoria, Australia
  6. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America
  7. Department of Obstetrics and Gynaecology, School of Medicine, University of Washington, Seattle, Washington, United States of America
Background: Molecular sub-classification of HG-SOC has the potential to uncover drug targets and mechanisms of drug resistance. DNA repair capability may predict treatment response in HG-SOC for both platinum agents and some novel therapeutics. We have generated a well annotated, human HG-SOC xenograft cohort stratified according to in vivo drug response and molecular characteristics. This allows us to perform pre-clinical analysis of novel therapies and to explore the molecular basis of drug resistance allowing targeted therapeutic approaches.
Methods:
Transplantation of whole fragments of consecutive, clinically annotated, chemotherapy-naive HG-SOC into NOD/SCID IL2Rγnull mice has been performed with no prior in vitro culture. Each has been characterised (at baseline and following xenotransplantation) according to histologic, functional and molecular features. Analysis includes histological review, documentation of in vivo platinum response; classification according to molecular subtype (Tothill classifier1); BRCA1/2 status2 and other DNA repair gene status (BROCA analysis)3, RNASeq analysis and documentation of NHEJ pathway status4.

Results: A novel xenograft cohort comprising 10 individual HG-SOC (out of 15 HG-SOC transplanted; two failed by 300d; 3 under observation; xenograft success rate 77%) has been generated, including proven successful cryopreservation ensuring xenograft supply. BROCA analysis3 of tumour samples has revealed 3 HG-SOC with BRCA2 mutations and 2 with BRCA1 mutations (the germline status of these mutations is being determined) and for five other HG-SOC, no DNA repair gene mutations were found (apart from in the p53 pathway, which is presumed mutated in all). In vivo platinum response data is available for 7 individual HG-SOC, three were platinum sensitive (Progressive Disease (PD)≥100 d post platinum), two were platinum resistant (PD<100 d) and two were platinum refractory (PD on platinum). Relapsed tumours are retreated in vivo or harvested for molecular analysis and serial transplantation followed by re-treatment.

Conclusions: We will report correlation of molecular characteristics with drug response outcome. The invaluable “paired” samples (pre and post drug treatment) will allow clonal evolution analysis of mechanisms of drug response and resistance.
  1. Tothill et al, Clinical Cancer Research.2008 Aug 15;14(16):5198-5208
  2. Norquist B et al, J Clin Oncol. 2011 Aug 1;29(22):3008-15
  3. Walsh T et al, Proc Natl Acad Sci 108(44):18032-7
  4. Patel A et al, Proc Natl Acad Sci 108(8):3406-11