The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas.
OBJECTIVE
The objectives of this study were to examine activation patterns of the phosphatidylinositol 3-kinase (PI3K) pathway in gliomas and to examine the prognostic significance of PI3K pathway activation using snap-frozen clinical specimens.


METHODS
Levels of expression of PI3K pathway members were assessed in 92 prospectively collected gliomas through quantitative Western analysis using total and phospho-specific antibodies for PI3K, Akt, and p70(s6k). Both expression and expression levels of these PI3K pathway members were correlated with histology, markers of apoptosis (cleaved caspase 3), and with clinical outcome (eg, overall survival).


RESULTS
It was determined that activation of all three PI3K pathway members were significantly more frequent in glioblastoma multiforme than in non-glioblastoma multiforme tumors. Levels of phospho-PI3K, phospho-Akt, and phospho-p70(s6k) were all found to be inversely associated with cleaved caspase 3 levels, suggesting PI3K pathway activation is associated with reduced levels of apoptosis. Perhaps most importantly, activation of PI3K pathway members was found to be significantly associated with reduced survival times when all glioma cases were considered in aggregate. When glioblastoma cases were considered separately, the prognostic value of PI3K activation remained significant, suggesting that PI3K activation may directly be associated with radiation resistance, given that this was the only adjuvant therapy administered to this subset of patients.


CONCLUSIONS
Activation of the PI3K pathway is significantly associated with increasing tumor grade, decreased levels of apoptosis, and with adverse clinical outcome in human gliomas. Molecular pathways regulating PI3K activation would appear to be promising targets in the clinical management of glioma patients.
Chakravarti
Arnab
A
Department of Radiation Oncology, Massachusetts General Hospital, Boston, 02114, USA. achakravarti@partners.org
Zhai
Gary
G
Suzuki
Yoshiyuki
Y
Sarkesh
Sormeh
S
Black
Peter M
PM
Muzikansky
Alona
A
Loeffler
Jay S
JS
D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008404:Massachusetts; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C494918:AKT1 protein, human