Kelsey L. Whittier


G-Protein Coupled Receptor Expression in Medulloblastoma Subgroups: Identifying and Exploiting Molecular Targets


Medulloblastoma (MB) is the most common malignant brain tumor in children. These tumors arise exclusively in the cerebellum, and represent dysregulation of cerebellar developmental pathways.  Recent genetic profiling 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.  Mouse models of these two subtypes have been developed; the ND2:SmoA1 mouse recapitulates human SHH-driven MB, while the Cttnb1-mutant mouse mimics the WNT-subtype of MB.  We hypothesize that groups of human MB tumors will emerge based on differences in G-protein coupled receptor (GPCR) expression patterns and that these groups will correlate to the known MB subtypes.  GPCRs are key regulators and points of control in both the SHH and WNT signal transduction pathways, as well as a large number of other signaling pathways.   GPCRs also possess characteristics that make them ideal targets for molecular imaging and therapeutics; including that they are membrane-bound, their ligands bind with high affinity and specificity, and that the receptor-ligand complex is endocytosed carrying the ligand into the tumor cell. While expression patterns of many proteins in human MB subtypes have been discerned, the expression pattern of GPCRs in MB has not been investigated.  My work thus far has shown that sub-groups of human MB tumors emerge based solely on differential GPCR expression patterns. Further, immunohistochemical analysis to differentiate the known MB subtypes demonstrates a high correlation between our GPCR expression-based groups and the known MB subtypes.  Differential GPCR expression patterns could lead to the identification of GPCRs with potential to act as targets for both imaging and therapeutics.  With this overall goal in mind, the development of targeted agents is largely dependent on accurate mouse models of the MB subtypes.  GPCR expression data from tumors of the ND2:SmoA1 and Ctnnb1-mutant mice has shown significantly different GPCR expression patterns, as compared to cerebellum of age-matched murine controls.   Additionally, certain over-expressed GPCRs in these mouse models are consistent with those observed to be over-expressed in sub-groups of human MB.  The next step in my project will be to develop a PET imaging agent that targets key over-expressed GPCRs in specific sub-types of medulloblastoma.

Recent publications

Dept. Obstetrics and Gynecology, Washington University
Kelsey L. Whittier
Sammamish, WA
Sue O'Dorisio