Small-molecule and antibody approaches to molecular chemotherapy of primary brain tumors.
High-grade primary brain tumors remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of these malignant tumors and identify oncogenic pathways that might be amenable to small-molecule and antibody 'targeted' therapy. Growth factor signaling pathways are often upregulated in these tumors and contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the downstream Ras signaling pathway. Other internal signal transduction pathways that may become dysregulated during transformation include Raf, MEK, PI3K, Akt (protein kinase B), and mTOR (mammalian target of rapamycin). In addition, overactivity of VEGF and other effectors leads to neoplastic angiogenesis. 'Targeted' therapy against the growth factor signaling and Ras pathways include tyrosine kinase inhibitors (eg, imatinib and erlotinib) and farnesyltransferase inhibitors (eg, tipifarnib). Molecular therapeutic small molecules specific to Raf, PI3K, and mTOR include sorafenib, LY-294002, and temsirolimus, respectively. 'Targeted' anti-angiogenesis approaches include mAbs to VEGF (eg, bevacizumab) and VEGF receptor tyrosine kinase inhibitors (eg, vatalanib and sunitinib). Further development of 'targeted' therapies designed to modulate the activity of these pathways, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality-of-life for patients with malignant brain tumors.
Newton
Herbert B
HB
Dardinger Neuro-Oncology Center, Division of Neuro-Oncology, 465 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA. newton.12@osu.edu
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000145:classification / Q000187:drug effects; D005544:Forecasting; D011905:Genes, ras; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020123:Sirolimus / Q000627:therapeutic use; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D020123:Sirolimus