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.