New Directions in the Treatment of Glioblastoma

Zachary J. Reitman, MD, PhD; Frank Winkler, MD, PhD; Andrew E. H. Elia, MD, PhD


Semin Neurol. 2018;38(1):50-61. 

In This Article

Abstract and Introduction


Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. The current standard of care for GBM is maximal resection followed by postoperative radiation with concomitant and adjuvant temozolomide. Despite this multimodality treatment, the median survival for GBM remains marginally better than 1 year. In the past decade, genome-wide analyses have uncovered new molecular features of GBM that have refined its classification and provided new insights into the molecular basis for GBM pathogenesis. Here, we review these molecular features and discuss major clinical trials that have recently defined the field. We describe genetic alterations in isocitrate dehydrogenase, ATRX, the telomerase promoter, and histone H3 variants that promote GBM tumorigenesis and have altered GBM categorization. We also discuss intratumoral genetic heterogeneity as one explanation for therapeutic failures and explain how ultra-long extensions of glioma cells, called tumor microtubes, mediate therapeutic resistance. These findings provide new insights into GBM biology and offer hope for the development of next-generation therapies.


Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system (CNS). It accounts for 14.9% of primary CNS tumors and 46.6% of all malignant CNS tumors, with 12,390 cases projected for 2017 in the United States.[1] The World Health Organization (WHO) grades CNS tumors from I to IV based on histologic and molecular features, with GBM classified as grade IV glioma. Adult patients with GBM have a poor prognosis despite multimodality treatment, with a median survival of 15 to 17 months and 5-year overall survival of 5.5%.[1] GBM is more common in the elderly with a median age of 64 years at diagnosis. Pediatric GBM also has a poor prognosis yet represents a clinically and biologically distinct entity.

Most cases of GBM occur in the absence of identifiable risk factors. Prior cranial irradiation is the only well-established environmental risk factor.[2] Hereditary cancer susceptibility syndromes are present in <5% of GBMs and include disorders such as Li–Fraumeni syndrome (TP53 mutation), Turcot syndrome (biallelic mutation of mismatch repair genes), and neurofibromatosis type 1 (NF1 mutation).[3] Germline risk loci identified through genome-wide association studies account for <30% of GBM risk and include polymorphisms in the genes TP53, TERT, EGFR, CDKN2B-AS1, and RTEL1.[4] Genomic analyses of tumors over the past decade have uncovered mutational, copy number, gene expression, and epigenetic alterations in GBMs.[5–8] Integration of these data provides deeper understanding of GBM pathogenesis and has led to the identification of new molecular subtypes whose evaluation has become routine in GBM diagnosis. Such advances hold promise for the development of new therapeutic strategies in GBM.