The Role of Cdc20 in Cerebellar Granule Cell Precursor and Medulloblastoma Biology

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Dr. Albert H. Kim, MD, PhD
Primary brain tumors represent the most common solid tumor of childhood. Among these, medulloblastoma is the most frequently observed, accounting for nearly 20% of all pediatric brain tumors. Despite recent overall improvements in patient survival with current treatments, the five-year event-free survival rate remains 20% in a substantial number of patients severely afflicted with this disease. An emerging theme in cancer biology is that the dysregulation of normal developmental signaling pathways contributes to cell transformation. Consequently, elucidation of the pathways controlling proliferation, differentiation, and survival of the medulloblastoma cell-of-origin is likely to provide insights into tumor pathogenesis. Pathological and microarray evidence suggests that the cell-of-origin for medulloblastoma is the cerebellar granule cell precursor (GCP).

Dr. Kim has recently uncovered a novel role for Cdc20, a component of the major mitotic regulator, the anaphase-promoting complex (APC), in the development of postmitotic neurons along the GCP lineage. Using an RNA interference-based approach, he has discovered in cerebellar granule cells in vivo that Cdc20 is required for the formation of dendrites, the critical receptive limb of neuronal circuits. Dr. Kim’s current project will not only investigate the molecular basis for Cdc20’s essential function in dendrite morphogenesis but also test the role of Cdc20 in GCP and medulloblastoma proliferation.

The underlying hypothesis of this project is that insights into normal GCP development will reveal mechanisms of medulloblastoma pathogenesis. An improved molecular understanding of medulloblastoma tumorigenesis is required for the development of specific signaling pathway-targeted therapies and patient-tailored treatment.