title: Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition.
abstract: Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.
authors.affiliation: Department of Pathology, Duke University Medical Center, P.O. Box 2900, Durham, NC 27710, USA.
authors.forename: Ranjit K
authors.initials: RK
authors.lastname: Goudar
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hjelmeland
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Wikstrand
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Reese
authors.forename: Charles A
authors.initials: CA
authors.lastname: Conrad
authors.forename: Peter
authors.initials: P
authors.lastname: Traxler
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Lane
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011494:Protein Kinases / Q000378:metabolism*; D011687:Purines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases; D014183:Transplantation, Heterologous
chemical_list: D011687:Purines; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases; C489254:AEE 788