Sheila Singh; MD, PhD, FRCSC, Pediatric Neurosurgeon, Canada Research Chair in Human Cancer Stem Cell Biology, Associate Professor of Surgery, McMaster University
Project Title: “Therapeutic targeting of Sox2+ treatment-refractory stem cells in sonic hedgehog-dependent pediatric medulloblastoma”
Brain tumours represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumour. While MBs characterized by active sonic hedgehog (Shh) signaling have been of therapeutic interest, treatment-resistance has posed significant challenges.
Since MB brain tumour-initiating cells prospectively identify, characterize, and target treatment-refractory BTICs in Shh-dependent MB. In correlating the gene expression profile of 325 human MBs with their overall clinical outcome, we identified the stem cell gene Sox2 as an independent marker of treatment-refractory Shh MB.
By modifying the Children’s Oncology Group (COG) MB protocol for our BTIC human-mouse xenograft model, we will treat Shh-dependent MB BTIC-bearing mice with radio-and chemotherapy and assess the corresponding increase in Sox2+ cells with small molecule inhibitors identified in our pathway network analysis of these cells.
Given the current research emphasis on treatment-naïve tumours, we hope our model will account for the evolution of cells over the course of therapy and provide an opportunity to selectively target and improve the survival of treatment-resistant Group 2 MB patients.