Poster Presentation 35th Lorne Cancer Conference 2023

Developing and characterising a novel age-appropriate preclinical model for paediatric medulloblastoma (#101)

Zahra Abbas 1 2 , Omar Elaskalani 2 , Iley Johnson 2 , Jenny Truong 2 , Allison Wan 2 , Hilary Hii 2 , Meegan Howlett 1 2 , Merridee Wouters 2 , Timo Lassmann 1 2 , Terrance Johns 1 2 , Joost Lesterhuis 1 2 , Raelene Endersby 1 2
  1. The University of Western Australia, Perth, Western Australia
  2. Telethon Kids Institute, Nedlands, WESTERN AUSTRALIA, Australia

Background: Childhood cancers have fewer treatment options than adult cancers, especially in the relapsed setting. Medulloblastoma is the most common childhood brain cancer, and survival outcomes for children with aggressive subtypes have plateaued over recent decades. Preclinical models are critical for the identification of therapeutic targets and the development of new clinical trials for rare childhood brain cancers. Despite the significant biological differences between children and adults, almost all preclinical research on paediatric cancer is carried out using adult mouse models, overlooking age-related differences in the immune system, metabolism, and growth factor signalling. Methods: We have developed a novel mouse model of Group 3 medulloblastoma that recapitulates tumour growth within the context of the paediatric cerebellum which continues to develop in mammals postnatally. MRI, in vivo bioluminescence imaging, flow cytometry, immunohistochemistry, and both bulk and single cell RNA sequencing was applied to understand the impact of the developing brain microenvironment on these cancers. Results: Myc-amplified medulloblastomas grow faster in juvenile hosts than adult hosts. Gene set enrichment analysis suggests that enhanced Myc signalling drives accelerated tumour growth in paediatric mice, and that altered immune transcriptional profiles may contribute to tumour growth in our paediatric model. Differences in tumour immune microenvironment were also detected between juvenile and adult mice using flow cytometry and immunohistochemistry. Conclusion: The differences observed in medulloblastoma growth kinetics and microenvironment in our novel paediatric model highlights the importance of using biologically accurate preclinical models for childhood medulloblastoma. This, and other new paediatric brain cancer models currently being developed, will allow for the identification of novel therapeutic targets specific for the paediatric setting. Moreover, with these paediatric models developmental-specific side effects of treatment can be rigorously assessed, enabling design of more appropriate clinical trials to improve outcomes for children with brain cancer.