Targeted molecular therapy of GBM.
Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand-independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.
Mischel
Paul S
PS
Department of Pathology and Laboratory Medicine, The David Geffen UCLA School of Medicine, Los Angeles, Calif. 90095-1732, USA.
Cloughesy
Timothy F
TF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D015316:Genetic Therapy; D005909:Glioblastoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines / Q000037:antagonists & inhibitors; D008967:Molecular Biology / Q000639:trends; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors