Poster Presentation 25th Lorne Cancer Conference 2013

Developing Polyomic Personalised Therapeutic Strategies for Pancreatic Cancer: Molecular Phenotyping for Treating “One Patient at a Time”. (#120)

Andrew V Biankin 1 , Sean M Grimmond 2
  1. Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, QLD, AUSTRALIA

Pancreatic Cancer (PC) is the fourth leading cause of cancer death with few effective therapies. Our increasing appreciation of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive phenotypes. As a consequence, novel strategies to approach this disease are required. Here we show that through a combined bench-to-bedside, and bedside-to-bench strategy using appropriate well-characterized model systems we can identify molecular phenotypes with significant responses to specific therapies. We identify candidate actionable phenotypes using a combination of assays including global analysis of gene expression, copy number alteration, structural variation and mutation using next-generation sequencing. These data either directly inform patient treatment decisions or are initially tested in well-characterized pre-clinical models. Outliers that express high levels of molecules involved in gemcitabine activity (hENT1, hCNT1 and hCNT3) demonstrate robust and sustained responses to gemcitabine. Similarly, high frequency structural variation seen on whole genome sequencing, termed “chromoaluminus”, is associated with mutations in many genes involved in DNA damage repair and confers responses to DNA damaging agents. In addition, we identify HER2 amplification in 2% of cases, whom appear to have a distinct clinical phenotype. We also observe individuals with dramatic responses to emerging therapies and attempt to define corresponding molecular phenotypes. Although these actionable phenotypes individually constitute a mean prevalence of 2%, together they add up to as much as 28% of pancreatic cancers.

This approach of tackling heterogeneous cancers “one patient at a time” and grouping responders that are likely to have different molecular biomarkers can start to build a library, or knowledge bank of responsive phenotypes to inform clinical decision-making, create opportunities for the rescuing and repurposing of existing therapeutics, and the development of novel therapeutic strategies.