Combining molecular targeted agents with radiation therapy for malignant gliomas

Abstract

The expansion in understanding the molecular biology that characterizes cancer cells has led to the rapid development of new agents to target important molecular pathways associated with aberrant activation or suppression of cellular signal transduction pathways involved in gliomagenesis, including epidermal growth factor receptor, vascular endothelial growth factor receptor, mammalian target of rapamycin, and integrins signaling pathways. The use of antiangiogenic agent bevacizumab, epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib, mammalian target of rapamycin inhibitors temsirolimus and everolimus, and integrin inhibitor cilengitide, in combination with radiation therapy, has been supported by encouraging preclinical data, resulting in a rapid translation into clinical trials. Currently, the majority of published clinical studies on the use of these agents in combination with radiation and cytotoxic therapies have shown only modest survival benefits at best. Tumor heterogeneity and genetic instability may, at least in part, explain the poor results observed with a single-target approach. Much remains to be learned regarding the optimal combination of targeted agents with conventional chemoradiation, including the use of multipathways-targeted therapies, the selection of patients who may benefit from combined treatments based on molecular biomarkers, and the verification of effective blockade of signaling pathways.

Keywords: glioblastoma; high-grade glioma; radiation therapy; targeted therapy; temozolomide.

Figure 1

Schematic representation of the effects of radiation and targeted agents on EGFR, VEGFR, and integrin-signaling pathways. Notes: After stimulation by irradiation, activation of EGFR, VEGFR, and integrin receptors results in stimulation of downstream signaling pathways that can promote cell survival and proliferation, DNA repair, and angiogenesis in both glioma and endothelial cells. Targeted agents that block at various steps the interaction of EGF (cetuximab), VEGF (bevacizumab), and extracellular proteins containing the RDG-peptide (cilengitide) with their receptor and downstream effectors (EGFR inhibitor erlotinib and gefitinib, VEGFR inhibitor vandetanib, vatalanib and sorafenib, PKC-B inhibitor enzastaurin, and mTOR inhibitors everolimus and temsirolimus) may enhance the damaging effects of irradiation. Abbreviations: EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; RDG-peptide, Arg-Gly-Asp peptide; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor; integrin-R, integrin receptor; PTEN, phosphatase and tensin homologue; PI3K, phosphoinositide 3-kinase; Ras, Ras GTPase; mTOR, mammalian target of rapamycin; AKT, protein kinase B; Raf, rapidly accelerated fibrosarcoma; p53, tumor protein 53; MDM2, mouse double minute 2 homologue; BAD, Bcl-2-associated death promoter; MEK, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; PLC, phospholipase C; IP3, inositol trisphosphate; PKC, protein kinase C; DNA, deoxyribonucleic acid.