PI3K pathway activation provides a novel therapeutic target for pediatric ependymoma and is an independent marker of progression-free survival.
OBJECTIVE
Currently, there are few effective adjuvant therapies for pediatric ependymoma outside confocal radiation, and prognosis remains poor. The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in cancer. PI3Ks transduce signals from growth factors and cytokines, resulting in the phosphorylation and activation of AKT, which in turn induces changes in cell growth, proliferation, and apoptosis.


METHODS
PI3K pathway status was analyzed in ependymoma using gene expression data and immunohistochemical analysis of phosphorylated AKT (P-AKT). The effect of the PI3K pathway on cell proliferation was investigated by immunohistochemical analysis of cyclin D1 and Ki67, plus in vitro functional analysis. To identify a potential mechanism of PI3K pathway activation, PTEN protein expression and the mutation status of PI3K catalytic subunit α-isoform gene (PIK3CA) was investigated.


RESULTS
Genes in the pathway displayed significantly higher expression in supratentorial than in posterior fossa and spinal ependymomas. P-AKT protein expression, indicating pathway activation, was seen in 72% of tumors (n = 169) and P-AKT expression was found to be an independent marker of a poorer progression-free survival. A significant association between PI3K pathway activation and cell proliferation was identified, suggesting that pathway activation was influencing this process. PTEN protein loss was not associated with P-AKT staining and no mutations were identified in PIK3CA.


CONCLUSIONS
Our results suggest that the PI3K pathway could act as a biomarker, not only identifying patients with a worse prognosis but also those that could be treated with therapies targeted against the pathway, a strategy potentially effective in a high percentage of ependymoma patients.
Authors' Affiliation: Children's Brain Tumour Research Centre, D Floor Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
Hazel A
HA
Rogers
Cerys
C
Mayne
Rebecca J
RJ
Chapman
John-Paul
JP
Kilday
Beth
B
Coyle
Richard G
RG
Grundy
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D019938:Cyclin D1 / Q000378:metabolism; D018572:Disease-Free Survival; D004806:Ependymoma / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human