Developmental Origins of Therapeutic Response in Medulloblastoma
Despite intensive treatment with radiation and chemotherapy, the heterogeneity of outcomes for medulloblastoma, the most common malignant brain tumor in children, remains a persistent problem. At present there is neither a predictive marker for patients with curable disease, nor a mechanistic understanding of treatment resistance. We have developed a novel mouse model of medulloblastoma in which an oncogenic allele of Smo can be activated during brain development in either early stem cells or later stage progenitors. Oncogene activation at either stage causes rapid formation of histologically identical tumors after birth, but tumors arising from early oncogene activation are resistant to radiation whereas those arising from later activation are sensitive. This striking variation in tumor response based on developmental stage at oncogenic event suggests the provocative hypothesis that epigenomic features present at the time of oncogene activation result in persistent clinically-relevant differences in the resulting tumors. We will investigate this hypothesis by: 1. examining the link between the cell-of-origin, chromatin variation and transcriptional response to radiation in sensitive and resistant tumors; 2. determining the role of 53BP1, a radiation-responsive protein differentially expressed in resistant tumors, as a mediator of treatment outcome. This project synergizes a unique mouse model, clinically relevant treatment and cutting-edge high-throughput genomic techniques. Linking chromatin variation, transcriptional responsiveness and clinical outcome will impact neuro-oncology as well as developmental neurobiology and extend new relevance to the growing appreciation of the role of epigenetic deregulation in brain and childhood tumors.
PI: Timothy Gershon, MD, PhD
Category: Basic Science