PMID- 15657358
OWN - NLM
STAT- MEDLINE
DCOM- 20050512
LR  - 20211203
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 4
IP  - 1
DP  - 2005 Jan
TI  - 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.
PG  - 101-12
AB  - 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.
FAU - Goudar, Ranjit K
AU  - Goudar RK
AD  - Department of Pathology, Duke University Medical Center, P.O. Box 2900, Durham, 
      NC 27710, USA.
FAU - Shi, Qing
AU  - Shi Q
FAU - Hjelmeland, Mark D
AU  - Hjelmeland MD
FAU - Keir, Stephen T
AU  - Keir ST
FAU - McLendon, Roger E
AU  - McLendon RE
FAU - Wikstrand, Carol J
AU  - Wikstrand CJ
FAU - Reese, Elizabeth D
AU  - Reese ED
FAU - Conrad, Charles A
AU  - Conrad CA
FAU - Traxler, Peter
AU  - Traxler P
FAU - Lane, Heidi A
AU  - Lane HA
FAU - Reardon, David A
AU  - Reardon DA
FAU - Cavenee, Webster K
AU  - Cavenee WK
FAU - Wang, Xiao-Fan
AU  - Wang XF
FAU - Bigner, Darell D
AU  - Bigner DD
FAU - Friedman, Henry S
AU  - Friedman HS
FAU - Rich, Jeremy N
AU  - Rich JN
LA  - eng
GR  - 1 P20 CA096890/CA/NCI NIH HHS/United States
GR  - CA11898/CA/NCI NIH HHS/United States
GR  - CA14236/CA/NCI NIH HHS/United States
GR  - CA94231-02/CA/NCI NIH HHS/United States
GR  - M01 RR 30/RR/NCRR NIH HHS/United States
GR  - NS047409/NS/NINDS NIH HHS/United States
GR  - NS20023/NS/NINDS NIH HHS/United States
GR  - NS30245-15/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Purines)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - F9JLR95I3I (AEE 788)
SB  - IM
MH  - Animals
MH  - Cell Division/*drug effects
MH  - Cell Line, Tumor
MH  - DNA Replication/drug effects
MH  - ErbB Receptors/antagonists & inhibitors
MH  - Glioma/drug therapy/*pathology
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Protein Kinases/*metabolism
MH  - Purines/*therapeutic use
MH  - Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
MH  - TOR Serine-Threonine Kinases
MH  - Transplantation, Heterologous
EDAT- 2005/01/20 09:00
MHDA- 2005/05/13 09:00
CRDT- 2005/01/20 09:00
PHST- 2005/01/20 09:00 [pubmed]
PHST- 2005/05/13 09:00 [medline]
PHST- 2005/01/20 09:00 [entrez]
AID - 4/1/101 [pii]
PST - ppublish
SO  - Mol Cancer Ther. 2005 Jan;4(1):101-12.