Exploring multi-targeting strategies for the treatment of gliomas.
Molecularly targeted therapies hold the promise of providing new anticancer treatments that are more effective and less toxic than traditional cytotoxic chemotherapy. Unfortunately, results of first generation targeted therapy trials for malignant gliomas (glioblastomas and anaplastic forms of astrocytomas, oligodendrogliomas and oligoastrocytomas) have been disappointing. While combination strategies targeting angiogenesis through inhibition of the VEGFR pathway (eg, bevacizumab combined with irinotecan) have demonstrated promising activity, single-agent drugs have been largely unsuccessful when tested in recurrent disease clinical trials. These single agents include EGF receptor tyrosine kinase inhibitors (gefitinib and erlotinib), PDGF receptor inhibitors (imatinib), mTOR inhibitors (temsirolimus and everolimus), and VEGFR, protein kinase C-beta and other angiogenesis pathway inhibitors (vatalanib and enzastaurin). A new generation of trials is seeking to define whether inhibiting multiple targets simultaneously through utilization of less specific, multi-targeting drugs, or through combination of two or more single-targeted drugs, can overcome tumor resistance. In this review, the rationale and challenges of developing such multi-targeted strategies in gliomas are presented.
Omuro
Antonio Mp
AM
Memorial Sloan-Kettering Cancer Center, Department of Neurology, 1275 York Avenue, New York, NY 10065, USA. omuroa@mskcc.org
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000737:chemistry; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy*; D006801:Humans; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
D015507:Drugs, Investigational; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor