Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date

Abstract

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 2014;121:502-16.

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

“…Despite advances in all treatment modalities with aggressive surgical resection combined with irradiation and chemotherapy, the median survival remains poor. During malignant transformation, a number of genetic alterations are involved in glioma oncogenesis, including inactivation of tumor suppressor genes such as p16, Rb, p53, and phosphate and tensin homolog on chromosome 10 (PTEN), as well as amplification and overexpression of the cyclin-dependent kinase (CDK) 4 and epidermal growth factor receptor (EGFR) genes (Wen et al, 2006;Bleeker et al, 2012;Bastien et al, 2015). A specific and oncogenic EGFR mutant (EGFRviii) can be detected in about one-third of GBMs that activates the RAS/RAF/MEK/MAP kinase, phosphoinositide 3-kinase, mTOR, and STAT pathways to high levels (Tsurushima et al, 1996;Mizoguchi et al, 2006;Akhavan et al, 2010).…”

“…The cyclin-D/CDK4, CDK6/ p16INK4a/pRB/E2F pathway, a key regulator of G1 to S phase transition of the cell cycle, is disrupted in the vast majority of human malignant gliomas and is one of the hallmarks of this tumor type. Common defects include homozygous deletion of CDKN2A/2B (52%), amplification of CDK4 (18%), amplification of CDK6 (1%), and deletion or mutation of RB (12%) (Ohgaki et al, 2004;Parsons et al, 2008;Bastien et al, 2015).…”

Overcoming therapeutic resistance in glioblastoma: the way forward

“…While many patients' tumors initially respond to these treatments, no current regimen can overcome inevitable tumor recurrence, after which patient survival drops to less than 6 months. Personalized therapies against molecular targets that drive the growth of the bulk of primary tumors (5,6) have so far also been unsuccessful in clinical trials, warranting new approaches.…”

Comprehensive Genomic Profiling of Recurrent Classic Glioblastoma in a Patient Surviving Eleven Years Following Antineoplaston Therapy

“…This mutation affects the extracellular domain of the protein and produces a constitutively active receptor (Huang et al, 2007). In a clinical trial with erlotinib, which is an EGFR kinase inhibitor and has sensitivity to EGFRvIII, there was no evidence of efficacy in GBM (Mellinghoff et al, 2005;Bastien et al, 2015). PTEN tumor suppressor gene negatively regulates the phosphoinositide 3 kinase (PI3K)/ protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway.…”