Grant: Operating Grant

Brain tumors represent the leading cause of childhood cancer mortality, due to their highly aggressive and often incurable nature. For medulloblastoma, the most frequent malignant pediatric brain tumor, a stem cell origin has long been implicated. The current project examines the molecular factors governing stem cell regulation that may be disrupted to result in medulloblastoma formation and tumor recurrence despite best current therapy. Self-renewal, a unique property of stem cells, is defined as the ability of the parental stem cell to generate another daughter stem cell, along with a second cell. We will examine how genes that regulate self-renewal of normal neural stem cells may be disrupted to give rise to abnormal brain cancer stem cells, known as brain tumor initiating cells (BTICs). BTIC populations are known to be resistant to both radiotherapy and chemotherapy, and higher fractions of BTICs escaping therapy may explain why some patients relapse despite current best therapy. We will study the function of these BTIC self-renewal genes and their molecular pathways in regulating stem cell populations in human medulloblastoma, using stem cell biology experimental approaches and animal models. Using an animal model that adapts current radiation and chemotherapy for medulloblastoma patients to mice, we can profile BTIC self-renewal throughout therapy to discover how BTICs evolve and change to evade therapy and cause tumor relapse. Currently, a specific subset of medulloblastoma patients still suffers from poor outcomes and relapse leading to death. Discovery of stem cell self-renewal pathways activated in these subtypes could provide much-needed BTIC-specific therapeutic targets, leading to an improved risk-benefit profile for current survivors, and an overall improved survivorship for all medulloblastoma patients.