? Project 4 Medulloblastoma encompasses four molecular subtypes that have different prognoses (WNT, Sonic Hedgehog [SHH], Group-3 and Group-4). Despite these differences, all children with medulloblastoma receive the same surgery, radiation, and chemotherapy. This treatment fails to cure most cases of Group-3 disease, and inflicts debilitating long-term side effects on children with WNT-medulloblastoma. Therefore, future efforts to cure all children with medulloblastoma must provide an understanding of disease biology that can guide the development of curative, relatively non-toxic, subtype-specific therapies. During the last funding cycle we focused on understanding WNT-medulloblastoma, complementing studies by our P01 colleagues of the other disease subtypes. We identified progenitor cells of the lower rhombic lip as the origin of WNT- medulloblastoma, and generated the first mouse model of this disease subtype. In addition, using whole genome sequencing (WGS), we identified over 40 novel mutations in medulloblastoma, including highly recurrent mutations in a new candidate oncogene of WNT and SHH-tumors, DDX3X. The proposed studies will build on these data, and through three new Specific Aims will address our central hypothesis: `Medulloblastoma subtypes are driven by distinct cell signals that can be targeted for therapeutic gain.' Through a comprehensive series of in vitro and in vivo phenotype and tumorigenesis assays, Aim 1 will determine the role of DDX3X in hindbrain development and medulloblastoma.
Aim 2 will employ an innovative, multiplatform approach that integrates high-throughput drug screening, cell biology assays, and genomics to pinpoint key molecular therapeutic targets and matched inhibitors of WNT-medulloblastoma, including DDX3X.
Aim 3 will test the subtype-specificity of potential new therapies identified in Aim 2 in the context of novel, combination, neurosurgical, irradiation, and chemotherapy trials in mice with WNT, SHH and Group-3 tumors. In this manner we will perform the most rigorous preclinical testing of new subtype-specific treatments of medulloblastoma to date, and thereby optimize the selection of combination treatments for translation to clinical trial.
? Project 4 Our inability to advance the treatment of children with medulloblastoma has resulted from a lack of tractable drug targets, accurate preclinical models, and a drug development process that fails to account for the discrete subtypes of the disease. Our proposal address each of these obstacles by developing new treatment strategies of WNT and other medulloblastomas through accurate combination preclinical trials.
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