Neuro-Oncology, 11/01/2016, 11/01/2016, Vol.18(suppl_6), pp.vi154-vi155
Medulloblastoma (MB) is the most common malignant brain tumor in children. Even with an intensive regimen of surgery, radiation and chemotherapy, one-third of patients still die from their disease, and survivors suffer devastating side effects from the therapy. Thus, more effective and less toxic therapies are desperately needed. Genomic analyses have identified 4 major subgroups of MB – WNT, SHH, Group 3 and Group 4 – that differ in terms of mutations, gene expression and patient outcomes. Despite this heterogeneity, all MB patients currently receive the same therapy. To identify novel therapies for each subgroup of MB, we have assembled a panel of patient-derived xenograft (PDX) lines. These lines, established by orthotopic transplantation of tumor cells obtained from surgery, recapitulate the properties of patients’ tumors more accurately than cultured cell lines. We are using these lines to screen small molecule libraries for compounds that can inhibit tumor growth and survival. To date we have completed 19 lines, including 10 representing Group 3, the most aggressive and lethal form of the disease. Among ~7800 compounds tested, 22 were effective against all Group 3 lines. Ongoing studies are focused on validating the activity of these compounds and moving the most promising ones forward into in vivo efficacy studies. Similar approaches will be pursued for each of the other subgroups of MB. Drug response data will also be compared with genomic and epigenomic data (whole exome and low coverage whole genome DNA sequencing, DNA methylation analysis, and gene expression profiling) to identify biomarkers of drug responsiveness and key pathways that may be exploited for therapy. Based on these studies, we hope to move away from a one-size-fits-all approach, and begin to treat each patient with therapies that are likely to be effective against their tumor.
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