Monday, October 2, 2023
10/2/2023
ABSTRACT Among pediatric brain tumors, medulloblastoma is the most common form. While most children with medulloblastoma can be cured, ~25% of these kids will die, and those that survive will live with severe long-term side effects as a result of the devastating effects of current therapies on the developing brain. In patients with medulloblastoma, prognosis depends heavily on the molecular makeup of the tumor. New genomic approaches have enabled to classify medulloblastoma into molecular subgroups, allowing physicians to better predict patient outcome and design treatment adequately. Among these subgroups, patients having alterations in the developmental pathway SONIC HEDGEHOG (SHH), along with mutations in the tumor suppressor gene P53 have a poor outcome. These tumors are resistant to therapy what results in rapid tumor relapse, which almost uniformly leads to patient death. Loss of P53 activity results in significant genomic instability and, consequently, large scale alterations in the signaling networks that drive cellular proliferation, survival, differentiation and/or stemness are created. Subsequently, a smaller number of these networks are selected for during the tumorigenic process and behave as tumor drivers. Here, I hypothesize that the growth of TRP53 mutant medulloblastoma will be abrogated by targeting this P53-specific set of signaling pathways. My previous work allowed me to identify two distinct drivers of these tumors, controlling independently tumor growth and propagation. The goal of this proposal is to understand how these identified tumor drivers control overall medulloblastoma viability, and to further validate them in murine and human derived TRP53 mutant SHH medulloblastoma models.
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