Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence

Table 1

Clinical evaluation of PTEN/PI3K/AKT/mTOR pathway activation in GBM patients.

No. of samples	Methods	Main findings	Reference
45	Immunohistochemistry	Correlation between PTEN loss and AKT activation, correlation between AKT phosphorylation and FOXO and S6 activation, and correlation between EGFRvIII expression and PI3K pathway activation	43
92	Western blot	No difference in PI3K AKT and S6K total expression between GBM and non-GBM tumors; increased PI3K, AKT, and S6K phosphorylation in GBM compared with non-GBM tumors; correlation between PI3K, AKT, and S6K phosphorylation and adverse outcome	44
259	Microarray and immunohistochemistry	AKT and NF-κB activation in tumor samples and not in normal brain and positive correlation between AKT and NF-κB activation and tumor grade	45
29	Immunohistochemistry	Correlation between AKT activation and TSC2, S6K, and S6 phosphorylation	46
65	Western blot and immunohistochemistry	No correlation between AKT activation and EGFR or PTEN status	47
89	Immunohistochemistry	No difference of AKT phosphorylation between low- and high-grade glioma	48
87	Immunohistochemistry	Higher levels of AKT, mTOR, and S6K in high-grade glioma compared with low-grade glioma	49
111 + 3 primary GBM cell cultures	Immunohistochemistry and western blot	Absence of mTOR, S6K, and 4EBP1 positivity in normal brain tissues; increase of mTOR and 4EBP1 phosphorylation with histological grade; correlation between 4EBP1 expression and adverse prognosis; correlation between mTOR phosphorylation and disease-free survival	50
225	Immunohistochemistry	Higher mTOR expression in WT IDH1 GBM compared with healthy tissues and R132H IDH1-mutant GBM and increased mTOR and S6 phosphorylation in WT IDH1 GBM compared with R132H IDH1-mutant GBM	51
36 + 5 GBM cell cultures	Immunohistochemistry, western blot, real-time PCR, and cell proliferation and migration assays	Undetectable mTORC2 activation in normal cells and high expression in GBM cell cultures and correlation between RICTOR expression and mTORC2 activation	52
196	Immunohistochemistry and western blot	Increased AKT phosphorylation in GBM compared with normal brain tissues and correlation between increased AKT activation and reduced overall survival	53