Reference Detail

Ref Type

Journal Article

PMID

(19208828)

Authors

Gallia GL, Tyler BM, Hann CL, Siu IM, Giranda VL, Vescovi AL, Brem H, Riggins GJ

Title

Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	8	2	2009 Feb	386-93	Mol Cancer Ther

URL

Abstract Text

A commonly activated signaling cascade in many human malignancies, including glioblastoma multiforme, is the Akt pathway. This pathway can be activated via numerous upstream alterations including genomic amplification of epidermal growth factor receptor, PTEN deletion, or PIK3CA mutations. In this study, we screened phosphatidylinositol 3-kinase/Akt small-molecule inhibitors in an isogenic cell culture system with an activated Akt pathway secondary to a PIK3CA mutation. One small molecule, A-443654, showed the greatest selective inhibition of cells with the mutant phenotype. Based on these findings, this inhibitor was screened in vitro against a panel of glioblastoma multiforme cell lines. All cell lines tested were sensitive to A-443654 with a mean IC(50) of approximately 150 nmol/L. An analogue of A-443654, methylated at a region that blocks Akt binding, was on average 36-fold less active. Caspase assays and dual flow cytometric analysis showed an apoptotic mechanism of cell death. A-443654 was further tested in a rat intracranial model of glioblastoma multiforme. Animals treated intracranially with polymers containing A-443654 had significantly extended survival compared with control animals; animals survived 79% and 43% longer than controls when A-443654-containing polymers were implanted simultaneously or in a delayed fashion, respectively. This small molecule also inhibited glioblastoma multiforme stem-like cells with similar efficacy compared with traditionally cultured glioblastoma multiforme cell lines. These results suggest that local delivery of an Akt small-molecule inhibitor is effective against experimental intracranial glioma, with no observed resistance to glioblastoma multiforme cells grown in stem cell conditions.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
A-443654	A-443654	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
A-443654			Akt Inhibitor (Pan) 21	A-443654 is a pan-AKT inhibitor, which may inhibit proliferation and promote apoptosis in cancer cells (PMID: 19208828, PMID: 28476032).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA mutant	Advanced Solid Tumor	sensitive	A-443654	Preclinical	Actionable	In a preclinical study, cells expressing mutant PIK3CA demonstrated increased sensitivity to A-443654 compared to cells expressing wild-type PIK3CA (PMID: 19208828).	19208828