Poster Presentation 26th Lorne Cancer Conference 2014

Improving targeted therapy in oncogene expressing High-Grade Serous Ovarian Cancer using novel xenografts (#167)

Valerie Heong 1 2 3 4 , Monique Topp 4 , Sumi Ananda 2 5 , Shirley Wong 5 , Elizabeth Swisher 6 , Geoffrey Lindeman 4 , Michelle Haber 7 , Murray Norris 7 , paul Haluska 8 9 , Matthew Wakefield 4 , David Bowtell 10 , Clare Scott 2 3 4
  1. University of Melbourne, parkville, Victoria, Australia
  2. Oncology, Royal Women's Hospital, parkville, Victoria, Australia
  3. University of Melbourne, parkville, Victoria, Australia
  4. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  5. Oncology, Western Hospital, Parkville, Victoria, Australia
  6. University of Washington, Seattle, USA
  7. Experimental therapeutic, Children's Cancer Institute Australia, Randwick, NSW, Australia
  8. Mayo Clinic, Rochester, Minesota, USA
  9. Mayo Clinic, Rochester, Minesota, USA
  10. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

Background:Epithelial ovarian cancer (EOC) mortality rates have not changed in 30 years.1 The most common high-grade serous ovarian carcinoma (HG-SOC) subtype can be divided into four sub-groups based on molecular characteristics2,3 The C5 or “mesenchymal” subgroup is defined by MYCN pathway activation2. However, more research into the MYCN pathway is required to ascertain whether molecular targeting leads to improved outcomes. Patient derived xenografts (PDX) from primary HG-SOC retain pathological and immunohistochemical features of the primary tumour4,5 and provide a valuable pre-clinical model for therapeutic exploration.

Methods:A cohort of 12 “C5-like” HG-SOC PDX were generated from tumour tissue transplanted into NOD/SCIDIL2Rγnull mice. Molecular analysis includes qRT-PCR for MYCN, HMGA2 and LIN28B as well as sequencing of DNA repair genes.6 As response to platinum agents is prognostic,7in vivo response to cisplatin is being determined for all 12 PDX  (I.P. cisplatin on D1, D8 and D18). Tumour volume is measured twice a week and mice with tumours larger than 0.7cm3 are euthanased. PDX are deemed sensitive to cisplatin if response is maintained for ≥ 100 days; resistant if they had stable disease or relapsed < 100 days and refractory if they progressed whilst on therapy.Results:Preliminary data revealed seven of this cohort of 12 "C5-like" PDX expressed higher levels of LIN28B and seven over-expressed MYCN. Three over-expressed CCNE1. One contains a mutation in BRCA2 and another in the DNA repair gene, CHEK2. Preliminary cisplatin response showed one PDX was sensitive while two were resistant to cisplatin, three were refractory and one showed a mixed response.

Conclusion:Analysis of this cohort of “C5-like” HG-SOC PDX reveals molecular complexity and cisplatin response heterogeneity.  With detailed molecular analysis and drug response, we aim to demonstrate novel effective therapies for each PDX, using agents targeting the MYCN pathway, CCNE1 and the DNA repair machinery. This information will be useful in understanding how to treat women with this sub-type of HG-SOC
  1. 1Vaughan et al, Nat Rev Cancer, 2011;
  2. 2Tothill et al, Clin Cancer Res, 2008
  3. 3TCGA Nature, 2011
  4. 4Lee et al, Gynecol Oncol, 2005
  5. 5Stewart et al, Proc Natl Acad Sci USA, 2011
  6. 6Walsh et al, PNAS, 2011
  7. 7Bookman et al, J Clin Oncol, 2009