Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit large cell/anaplastic (LCA) histology usually fail therapy and die from their disease. Improved approaches to treating these patients are likely to come from a deeper understanding of LCA tumors, including their aggressive growth properties and their invasive and metastatic behavior. Unfortunately, human LCA MB tissue is difficult to obtain, and existing genetically engineered mouse (GEM) models of MB rarely display anaplasia or metastasis. To address this problem, we have collected >100 human LCA MBs, including paired samples of primary/metastatic tumors. In addition, we have generated GEM and transplant-based models of LCA MB, and mobilized the transposable element Sleeping Beauty (SB) to promote anaplasia and metastasis in these models. Through analysis of our human and murine datasets, we propose to identify the cells and genes that drive progression in LCA medulloblastoma. This application brings together investigators from three institutions, with collective experience in neural development, stem cell biology and genomics of both human and murine MB. Our complementary backgrounds and expertise uniquely position us to investigate the cellular and molecular basis of LCA MB, and will ultimately allow us to develop more effective approaches to targeting these aggressive tumors.
The proposed studies focus on large cell/anaplastic medulloblastoma, a highly malignant pediatric brain tumor with an extremely poor prognosis. By identifying the cells and genes responsible for the aggressive behavior of this tumor, we hope to develop more effective approaches to therapy.
|Thompson, Eric M; Hielscher, Thomas; Bouffet, Eric et al. (2016) Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol 17:484-95|
|Pei, Yanxin; Liu, Kun-Wei; Wang, Jun et al. (2016) HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. Cancer Cell 29:311-23|
|Morrissy, A Sorana; Garzia, Livia; Shih, David J H et al. (2016) Divergent clonal selection dominates medulloblastoma at recurrence. Nature 529:351-7|
|Mack, Stephen C; Hubert, Christopher G; Miller, Tyler E et al. (2016) An epigenetic gateway to brain tumor cell identity. Nat Neurosci 19:10-9|
|Lafay-Cousin, Lucie; Smith, Amy; Chi, Susan N et al. (2016) Clinical, Pathological, and Molecular Characterization of Infant Medulloblastomas Treated with Sequential High-Dose Chemotherapy. Pediatr Blood Cancer 63:1527-34|
|Wen, J; Lee, J; Malhotra, A et al. (2016) WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma. Oncogene 35:5552-5564|
|Ramaswamy, Vijay; Hielscher, Thomas; Mack, Stephen C et al. (2016) Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34:2468-77|
|Ramaswamy, Vijay; Remke, Marc; Adamski, Jennifer et al. (2016) Medulloblastoma subgroup-specific outcomes in irradiated children: who are the true high-risk patients? Neuro Oncol 18:291-7|
|Mack, Stephen C; Agnihotri, Sameer; Bertrand, Kelsey C et al. (2015) Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype. Clin Cancer Res 21:3750-8|
|Wang, Xin; Dubuc, Adrian M; Ramaswamy, Vijay et al. (2015) Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta Neuropathol 129:449-57|
Showing the most recent 10 out of 57 publications