Pharmacogenomic profiling of PI3K/PTEN-AKT-mTOR pathway in tumors elucidated.

2004 JUL 1 - (NewsRx.com & NewsRx.net) -- Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common tumors has been elucidated.

"The protein synthetic machinery is activated by a variety of genetic alterations during tumor progression and represents an attractive target for cancer therapy. The mammalian target of rapamycin (mTOR) plays an important role in regulating protein translation through phosphorylation of p70 S6 kinase 1 (S6K1), a protein involved in ribosome biogenesis, and 4E-BP1 (eIF-4E binding protein), a translation repressor," investigators in the United States wrote.

"It has been shown that mTOR has a direct linkage to the phosphatidylinositol-3'-kinase (PI3K)/PTEN-AKT survival pathway. Recent studies have demonstrated that mTOR inhibition by rapamycin or its analogues have remarkable activity against a wide range of human cancers in vitro and in human tumor xenograft models. Phase I clinical evaluations also suggested an anti-tumor effect of rapamycin analogue such as CCI-779," G.U. Xu and colleagues indicated.

"The clinical challenge for the application of this class of anticancer drug is the ability to prospectively identify which tumors will be sensitive to mTOR inhibition," said Xu. "Recent studies have identified cellular markers that are associated with the in vitro activity of rapamycin or CCI-779. However, there have been no reports on how these cellular markers are expressed together in human tumor specimen."

"In this study, multiple components of the P13K/PTEN-AKT-mTOR pathway were evaluated by immunohistochemistry in tissue arrays containing 124 tumors from 8 common tumor types. The results show variable expression of all the signaling proteins. For example, mTOR expression was low in brain tumors, but high in ...