Medulloblastoma (MB) is the most common malignant brain tumor in children. Although aggressive treatments have improved outcomes, many MB patients still die of their disease, and survivors suffer severe long-term side effects from the therapy. Thus, an increased understanding of the disease and improved therapeutic approaches are critical. MB is comprised of four subgroups ? WNT, Sonic hedgehog (SHH), Group 3 and Group 4 ? that differ in terms of genetics, epigenetics, clinical characteristics and outcomes. Although we have some mechanistic understanding of WNT, SHH and Group 3 tumors, the genes and pathways that underlie Group 4, the most prevalent form of the disease, remain a mystery. Identifying oncogenic drivers and using them to create animal models of Group 4 MB is critical for development and testing of new therapies. Our analysis of the genome and epigenome of >400 human Group 4 MBs has identified single nucleotide variants (SNVs) as well as chromosomal copy number alterations (CNAs). While these studies have generated lists of candidate drivers, none of these has been tested or proven necessary or sufficient to initiate tumor growth. We hypothesize that perturbing expression of candidate genes or CNAs in neural progenitors will generate models of Group 4 MB, thereby validating their functional importance. To test this hypothesis, we propose to knock out or overexpress genes in murine and human (iPS-derived) neural progenitors and evaluate tumorigenic potential in vivo. These studies will create robust models of Group 4 MB that can be used to study tumor biology and to identify novel approaches to therapy.
These studies are focused on the understanding the mechanisms underlying medulloblastoma, the most common malignant brain tumor in children. Defining the pathways that are altered in this tumor will allow us to identify new approaches to treatment, and develop animal models that can be used to test therapies before moving them forward to the clinic.
|Fan, Qi Wen; Nicolaides, Theodore P; Weiss, William A (2018) Inhibiting 4EBP1 in Glioblastoma. Clin Cancer Res 24:14-21|
|Zapotocky, Michal; Mata-Mbemba, Daddy; Sumerauer, David et al. (2018) Differential patterns of metastatic dissemination across medulloblastoma subgroups. J Neurosurg Pediatr 21:145-152|
|Mack, Stephen C; Pajtler, Kristian W; Chavez, Lukas et al. (2018) Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553:101-105|
|Guerreiro Stucklin, Ana S; Ramaswamy, Vijay; Daniels, Craig et al. (2018) Review of molecular classification and treatment implications of pediatric brain tumors. Curr Opin Pediatr 30:3-9|
|Wang, Yang; Li, Yue; Yue, Minghui et al. (2018) N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications. Nat Neurosci 21:195-206|
|Cavalli, Florence M G; Hübner, Jens-Martin; Sharma, Tanvi et al. (2018) Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol 136:227-237|
|An, Zhenyi; Aksoy, Ozlem; Zheng, Tina et al. (2018) Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene 37:1561-1575|
|Bertrand, Kelsey C; Faria, Claudia C; Skowron, Patryk et al. (2018) A functional genomics approach to identify pathways of drug resistance in medulloblastoma. Acta Neuropathol Commun 6:146|
|Waszak, Sebastian M; Northcott, Paul A; Buchhalter, Ivo et al. (2018) Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19:785-798|
|Garzia, Livia; Kijima, Noriyuki; Morrissy, A Sorana et al. (2018) A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases. Cell 172:1050-1062.e14|
Showing the most recent 10 out of 77 publications