Poster Presentation 32nd Lorne Cancer 2020

  A functional blood brain barrier is required for the effective translation of novel therapeutic agents for paediatric brain tumours (#162)

Laura A Genovesi 1 , Simon Puttick 2 , Amanda Miller 1 , Marija Kojic 1 , Pengxiang Ji 1 , Anne K Lagendijk 1 , Caterina Brighi 3 4 , Christelle Adolphe 1 , Brandon J Wainwright 1
  1. Institute for Molecular Bioscience, St Lucia, QUEENSLAND, Australia
  2. Australian e-Health Research Centre, Commoonwealthh Scientific and Industrial Research Organisation, Herston, Queensland, Australia
  3. Australian Institute of Biotechnology and Nanotechnology, St Lucia, Brisbane, Australia
  4. ARC Centre of Excellence for Convergent Bio-Nano Ccience and Technology, St Lucia, Queensland, Australia

Background.  Novel targeted therapies for children diagnosed with medulloblastoma (MB), the most common malignant brain tumour diagnosed in children, is urgently required.  A major hurdle in the development of novel therapies is the blood-brain barrier (BBB), a restrictive barrier that impedes the delivery of therapies to tumour cells and as such, an essential consideration in the development of any novel therapeutic.  This study sought to assess the functional integrity of the BBB in several preclinical mouse models of MB. Methods. Dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) was used to characterize BBB permeability in a murine spontaneous genetically engineered model (GEMM) of MB and patient derived xenograft (PDX) models of MB.  We established an orthotopic transplantation model of the GEMM to evaluate the direct effect of transplantation on the integrity of the BBB.  Immunofluorescence was performed to assess the vascular phenotype at the histological level.Results.  Contrast enhancement was observed in all transplantation models of MB, with greater BBB disruption in transplanted murine allograft model and one PDX model of MB.  No contrast enhancement was observed in the GEMM despite significant tumour burden.  Vascular phenotyping revealed significant BBB aberrancies in all transplantation models, with these differences correlated to the varying levels of BBB breakdown observed by MRI in these models.Conclusions. These results not only highlight functional differences in the integrity of the BBB and tumour vessel phenotype between commonly utilised preclinical models of MB, but have important implications for the preclinical evaluation of novel therapeutic agents MB.