Molecular Characterizations of Glioblastoma, Targeted Therapy, and Clinical Results to Date

During the last decade, extensive multiplatform genome-wide analysis has yielded a wealth of knowledge regarding the genetic and molecular makeup of glioblastoma multiforme (GBM). These profiling studies support the emerging view that GBM comprises a group of highly heterogeneous tumor types, each with its own distinct molecular and genetic signatures. This heterogeneity complicates the process of defining reliable intertumor/intratumor biological states, which will ultimately be needed for classifying tumors and for designing effective customized therapies that target resultant disease pathways. The increased understanding of the molecular pathogenesis of GBM has brought the hope and expectation that such knowledge will lead to better and more rational therapies directed toward specific molecular targets. To date, however, these expectations have largely been unrealized. This review discusses some of the principal genetic and epigenetic aberrations found in GBM that appear promising for targeted therapies now and in the near future, and it offers suggestions for future directions concerning the rather disappointing results of clinical trials to date. Cancer 2015;121:502-516. (c) 2014 American Cancer Society. The last decade has seen an explosion of data elucidating the molecular and genetic drivers of glioblastoma, but clinical trials of molecularly targeted agents have been largely disappointing to date. This article reviews the most important genetic and epigenetic changes found in glioblastoma and the trials that have attempted to target those lesions, and it offers some potential reasons for their current lack of clinical efficacy.