Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma.
BACKGROUND
Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Aberrant PDGFR signaling is observed in approximately 25-30% of human GBMs, which are frequently molecularly classified as the proneural subclass. It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition.


RESULTS
Using genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM that closely mimic the histology and genetics of the human PDGF subgroup, we investigated the effect of inhibiting Akt and mTOR alone or in combination in vitro and in vivo. We used perifosine and CCI-779 to inhibit Akt and mTOR, respectively. Here, we show in vitro data demonstrating that the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null primary glioma cell cultures is obtained when using both inhibitors in combination. We next investigated if the effects we observed in culture could be duplicated in vivo by treating mice with gliomas for 5 days. The in vivo treatments with the combination of CCI-779 and perifosine resulted in decreased Akt and mTOR signaling, which correlated to decreased proliferation and increased cell death independent of PTEN status, as monitored by immunoblot analysis, histology and MRI.


CONCLUSIONS
These findings underline the importance of simultaneously targeting Akt and mTOR to achieve significant down-regulation of the PI3K pathway and support the rationale for testing the perifosine and CCI-779 combination in the human PDGF-subgroup of GBM.
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Kenneth L
KL
Pitter
Craig J
CJ
Galbán
Stefanie
S
Galbán
Omid Saeed
OS
Tehrani
Omid
O
Saeed-Tehrani
Fei
F
Li
Nikki
N
Charles
Michelle S
MS
Bradbury
Oren J
OJ
Becher
Thomas L
TL
Chenevert
Alnawaz
A
Rehemtulla
Brian D
BD
Ross
Eric C
EC
Holland
Dolores
D
Hambardzumyan
D000818:Animals; D000970:Antineoplastic Agents; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D010767:Phosphorylcholine; C105905:perifosine; C401859:temsirolimus; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus
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