Pathway inhibition: emerging molecular targets for treating glioblastoma

Abstract

Insights into the molecular pathogenesis of glioblastoma have not yet resulted in relevant clinical improvement. With standard therapy, which consists of surgical resection with concomitant temozolomide in addition to radiotherapy followed by adjuvant temozolomide, the median duration of survival is 12-14 months. Therefore, the identification of novel molecular targets and inhibitory agents has become a focus of research for glioblastoma treatment. Recent results of bevacizumab may represent a proof of principle that treatment with targeted agents can result in clinical benefits for patients with glioblastoma. This review discusses limitations in the existing therapy for glioblastoma and provides an overview of current efforts to identify molecular targets using large-scale screening of glioblastoma cell lines and tumor samples. We discuss preclinical and clinical data for several novel molecular targets, including growth factor receptors, phosphatidylinositol-3 kinase, SRC-family kinases, integrins, and CD95 ligand and agents that inhibit these targets, including erlotinib, enzastaurin, dasatinib, sorafenib, cilengitide, AMG102, and APG101. By combining advances in tumor screening with novel targeted therapies, it is hoped that new treatment options will emerge for this challenging tumor type.

Fig. 1.

Genetic alterations in glioblastoma signal transduction pathways (adapted from Parsons et al). (A) Proliferation and survival signaling is altered in 88% of glioblastomas. (B) p53 signaling is altered in 87% of glioblastomas. (C) RB signaling is altered in 78% of glioblastomas. CCND2 indicates cyclin-D2; CDK indicates cyclin-dependent kinase; CDKN indicates cyclin-dependent kinase inhibitor; EGFR indicates epidermal growth factor receptor; FOXO indicates forkhead box-O; HER2 indicates human epidermal growth factor receptor-2; NF1 indicates neurofibromin; PDGFR indicates platelet-derived growth factor receptor; PI3K indicates phosphatidylinositol 3-kinase; PTEN indicates phosphatase and tensin homolog; RB1 indicates retinoblastoma protein-1; and SRC* indicates activated (phosphorylated) SRC. Figure 1 is adapted from The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455(7216):1061–1068.

Fig. 2.

Molecular targets of antiangiogenic therapies investigated in glioblastoma. ANG indicates angiopoietin; CKII indicates casein kinase II; eNOS indicates endothelial nitric oxide synthase; ERK indicates extracellular signal-regulated kinases; FAK indicates focal adhesion kinase; GSK3β indicates glycogen synthase kinase 3β; MEK indicates mitogen-activated protein kinase kinase; mTOR indicates mammalian target of rapamycin; PDGF(R) indicates platelet-derived growth factor (receptor); PI3K indicates phosphatidylinositol 3-kinase; PKC indicates protein kinase C; PLCγ indicates phopholipase Cγ; and VEGF(R) indicates vascular endothelial growth factor (receptor).