Medulloblastoma (MB) is the most common malignant pediatric brain tumour. Global gene expression arrays performed on human MBs have divided this tumour entity into 4 distinct molecular subgroups. Out of all the subgroups, Group 3 patients face the highest incidence of leptomeningeal spread and overall patient survival of less than 50%. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumours, provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumors. By adapting the existing COG (Children’s Oncology Group) Protocol for children with newly diagnosed high-risk MB for treatment of immuno-deficient mice intracranially engrafted with human MB brain tumour initiating cells (BTICs), we aim to identify and characterize the rare treatment-refractory cell population in Group 3 MBs. MB cell populations recovered separately from brains and spines at (i) engraftment; (ii) post-radiation; (iii) post-radiation and chemotherapy; and (iv) recurrence, during the course of tumor development and therapy were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy to relapse. One of the most intriguing observations from our gene expression data was consistent over-expression of proteins belonging to Inhibitor of DNA-binding/differentiation (ID) family, transcription factors with a basic helix-loop-helix motif that act as suppressors cellular differentiation and a longevity associated protein bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) in our refractory population. The persistent upregulation of genes preserving undifferentiated state and cellular longevity further strengthens the hypothesis of stem-cell like cells driving tumor relapse in MB. We then set out to determine whether genes upregulated at relapse correlated with patient outcome in our therapy-adapted patient-derived xenograft model. Interestingly, the upregulation of the top 90 genes in our relapse cohort was predictive of worse overall survival in patients with group 3 MB. In the next set of experiments, through application of cellular barcoding technology we determined how MB BTICs evolve in response to therapy by tracking unique vector DNA sequences integrated at a single copy level into individual cells. Our differential genomic profile of the “treatment-responsive” tumors against those that fail therapy will thus contribute to discovery of novel therapeutic approaches for the most aggressive subgroup of MB.
Citation Format: David Bakhshinyan, Thusyanth Vijayakumar, Chitra Venugopal, Mohini Singh, Maleeha Qazi, Sujeivan Mahendram, Sujeivan Mahendram, Branavan Manoranjan, Nicole McFarlane, Ashley Adile, Sheila Singh. Clonal evolution of medulloblastoma BTICs in response to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3870. doi:10.1158/1538-7445.AM2017-3870