Poster Presentation 29th Lorne Cancer Conference 2017

A network-based druggable genome analysis identifies novel therapeutic targets for non-WNT medulloblastoma (#163)

Laura A Genovesi 1 , Michelle L Cook Sangar 2 , Beryl A Hatton 3 , William S Kerwin 3 , Emily Beirne 3 , Joseph R Casalini 3 , Pengxiang Ji 1 , Christelle Adolphe 1 , James M Olsen 2 , Melissa J Davis 4 , Brandon J Wainwright 1
  1. Institute for Molecular Bioscience, St Lucia, QUEENSLAND, Australia
  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  3. Presage Biosciences,, Seattle, WA, United States of America
  4. Division of Bioinformatics, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities. Clearly, there is an urgent need for improved, more targeted therapies that minimise harmful side effects. Here, we sought to identify drug candidates for MB by examining the broader systems level impact of perturbations in genomic data and transcriptomic regulatory mechanisms underlying MB. Using an integrative “omics” approach, we exploited the protein regulatory networks established from our previously published transposon mutagenesis mouse MB model and created a drug-target network, overlaying drugs and their known targets with significantly over-expressed genes obtained from human MB expression data. We restricted our analyses to non-WNT MB since the WNT subgroup is associated with greater than 95% long-term survival and are by some margin the least frequent subgroup. Several proteins were identified as novel drug targets for non-WNT MB, including CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Our analyses also identified CDK4, CDK6 and AURKA, potential targets that are well validated in other tumour types. We then demonstrated that PI3K/mTOR pathway inhibition induced apoptosis and reduced proliferation in vivo in mice bearing Group 3 MB PDX tumours. Combined, our findings confirm this strategy as a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment.