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Mentor: M. Sue O'Dorisio, MD, PhD
Year Entered Into Program: 2008 (MSTP) 2010 (PhD Program)
PhD Institution: University of Iowa, 2015 (MD, PhD)
Medulloblastoma is the most common malignant brain tumor in children. These tumors arise exclusively in the cerebellum, and represent dysregulation of cerebellar developmental pathways. Recent investigation has identified 4-5 tumor subtypes; each subtype is characterized by different initiating mutations, genetic and clinical profiles, and prognoses. The two most well-defined subtypes are characterized by overactive, uncontrolled signaling in one of two signal transduction pathways that control proliferation and migration of precursor cells in the cerebellum: the SHH- Patched- Smoothened pathway and the Wnt- Frizzled- β-catenin pathway.
G-protein coupled receptors (GPCR) are key regulators and points of control in both of these signal transduction pathways, as well as large number of other signaling pathways. While expression patterns of many proteins in human medulloblastoma subtypes have been discerned, the expression pattern of GPCRs in medulloblastoma has not been investigated. Preliminary data from the O’Dorisio lab has indicated that groups of human medulloblastoma tumors will emerge based solely on differential GPCR expression patterns. We hypothesize that significant differences in GPCR expression levels in human medulloblastoma tumors will emerge, and that these tumor groups will correlate to the known medulloblastoma subtypes.
Current imaging of pediatric brain tumors relies on CT and MRI which provide exquisite anatomical data, but do not provide molecular diagnostic or prognostic information. I hypothesize that the GPCR, Smoothened, will serve as an excellent target for molecularly-based positron emission tomography (PET) imaging of medulloblastoma to provide both diagnostic and prognostic information. My goal is to employ both pharmacogenetics and pharmacokinetics to develop a PET tracer that will enable me to exploit increased activity of the SHH pathway in a subtype of medulloblastoma. Success will provide a highly sensitive and specific imaging technique for diagnosis and staging of the SHH-subtype of medulloblastoma using a single PET/CT or PET/MRI exam, and act as a proof of principle for GPCR-targeted imaging."
Whittier, K., Boese, E., Schafer, B., Gibson-Corley, K., Ingram, W., O’Dorisio, M.S.: G-Protein Coupled Receptor Expression Patterns Delineate Medulloblastoma Groups. In preparation.
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