Targeting TGFb Pathway Dependencies in Group 3 Medulloblastoma
Neurons are nerve cells that populate the brain and are responsible for transmitting chemical signals to regulate several human functions. A deadly form of pediatric cancer, known as medulloblastoma, occurs when these neurons start to proliferate uncontrollably. Developing nerve cells, known as neural stem cells, can transform and get ‘stuck’ at a certain stage in brain development. Medulloblastoma is hypothesized to arise from alterations to the DNA template of such neural stem cells, known as mutations. These mutations result in gene expression changes to escalate cellular growth, migration, and invasion. Recent work has identified alterations in the developmental pathway TGFβ, however the functional significance and how it cooperates with other cancer driving events, such as MYC amplification, is currently unclear.
This study aims to mechanistically characterize clinically relevant TGFβ driven genes/pathways in medulloblastoma. I will map the localization of these factors and how they affect gene expression in a panel of tumor cells derived from genetically manipulated neural stem cells driven by MYC alone and/or in combination with TGFβ effectors. I will also investigate how a single cell develops to medulloblastoma and the pathways that mediate this transformation. Finally, I will investigate novel targeted strategies against TGFβ and MYC, some of which are in clinical trials for other cancers. The prognosis for children with this aggressive and treatment resistant medulloblastoma is exceptionally poor. I anticipate that my studies will provide insight on the mechanism(s) of how TGFβ promote tumor progression and new therapies to overcome resistance to improve patient outcomes.