PTEN loss does not predict for response to RAD001 (Everolimus) in a glioblastoma orthotopic xenograft test panel.
OBJECTIVE
Hyperactivation of the phosphatidylinositol 3-kinase/Akt signaling through disruption of PTEN function is common in glioblastoma multiforme, and these genetic changes are predicted to enhance sensitivity to mammalian target of rapamycin (mTOR) inhibitors such as RAD001 (everolimus).


METHODS
To test whether PTEN loss could be used as a predictive marker for mTOR inhibitor sensitivity, the response of 17 serially transplantable glioblastoma multiforme xenografts was evaluated in an orthotopic therapy evaluation model. Of these 17 xenograft lines, 7 have either genomic deletion or mutation of PTEN.


RESULTS
Consistent with activation of Akt signaling, there was a good correlation between loss of PTEN function and elevated levels of Akt phosphorylation. However, of the 7 lines with disrupted PTEN function, only 1 tumor line (GBM10) was significantly sensitive to RAD001 therapy (25% prolongation in median survival), whereas 1 of 10 xenograft lines with wild-type PTEN was significantly sensitive to RAD001 (GS22; 34% prolongation in survival). Relative to placebo, 5 days of RAD001 treatment was associated with a marked 66% reduction in the MIB1 proliferation index in the sensitive GBM10 line (deleted PTEN) compared with a 25% and 7% reduction in MIB1 labeling index in the insensitive GBM14 (mutant PTEN) and GBM15 (wild-type PTEN) lines, respectively. Consistent with a cytostatic antitumor effect, bioluminescent imaging of luciferase-transduced intracranial GBM10 xenografts showed slowed tumor growth without significant tumor regression during RAD001 therapy.


CONCLUSIONS
These data suggest that loss of PTEN function is insufficient to adequately predict responsiveness to mTOR inhibitors in glioblastoma multiforme.
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Lin
L
Yang
Michelle J
MJ
Clarke
Brett L
BL
Carlson
Ann C
AC
Mladek
Mark A
MA
Schroeder
Paul
P
Decker
Wenting
W
Wu
Gaspar J
GJ
Kitange
Patrick T
PT
Grogan
Jennie M
JM
Goble
Joon
J
Uhm
Evanthia
E
Galanis
Caterina
C
Giannini
Heidi A
HA
Lane
C David
CD
James
Jann N
JN
Sarkaria
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D000068338:Everolimus; D005909:Glioblastoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011379:Prognosis; D011494:Protein Kinases / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D016042:Transplantation, Heterotopic; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D020123:Sirolimus