Targeting the Akt-pathway to Improve Radiosensitivity in Glioblastoma

Ravi      S. Narayan; Carlos      Alexandre Fedrigo; Lukas      J.A. Stalpers; Brigitta      G. Baumert; Peter      Sminia

Abstract

Glioblastoma multiforme (GMB) is the most malignant and common type of all astrocytic tumors. Current standard of care entails maximum surgical resection of the tumor, followed by radiotherapy and chemotherapy, usually by the alkylating agent Temozolomide (TMZ). Despite this aggressive combination therapy, the survival rate of GBM patients is still low. Deregulation of the phosphatidylinositol 3-kinase (PI3K) / Akt pathway is a frequent occurrence in GBM. Activation of the PI3K-Akt pathway results in disturbance of control of cell growth and cell survival, which contributes to a competitive growth advantage, metastatic competence as well as to therapy resistance. The PI3K-Akt pathway is therefore an attractive therapeutic target in GBM, because it serves as a convergence point for malignant processes and intervention might overcome resistance to chemotherapy and radiation. The present review shows the importance of Akt in GBM and its role in the DNA damage response. Furthermore, an overview is given of specific inhibitors of Akt which are currently being tested in preclinical and in early phase clinical studies.

Keywords: Glioblastoma multiforme, PI3K-Akt pathway, radiotherapy, DNA damage repair, targeted therapy, malignant, chemotherapy, cell growth, cell survival, clinical studies