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| Ref Type | Journal Article | ||||||||||||
| PMID | (20028853) | ||||||||||||
| Authors | Baryawno N, Sveinbjornsson B, Eksborg S, Chen CS, Kogner P, Johnsen JI | ||||||||||||
| Title | Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. | ||||||||||||
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| Abstract Text | Activation of the beta-catenin and receptor kinase pathways occurs often in medulloblastoma, the most common pediatric malignant brain tumor. In this study, we show that molecular cross-talk between the beta-catenin and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways is crucial to sustain medulloblastoma pathophysiology. Constitutive activation of phosphoinositide-dependent protein kinase 1 (PDK1), Akt, and phosphorylation of [corrected] glycogen synthase kinase 3beta (GSK-3beta) was detected by immunohistochemistry in all primary medulloblastomas examined (n = 41). Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected beta-catenin signaling by activation [corrected] of GSK-3beta, [corrected] resulting in cytoplasmic retention of beta-catenin and reduced expression of its target genes cyclin D1 and c-Myc. The PDK1 inhibitor OSU03012 induced mitochondrial-dependent apoptosis of medulloblastoma cells and enhanced the cytotoxic effects of chemotherapeutic drugs in a synergistic or additive manner. In vivo, OSU03012 inhibited the growth of established medulloblastoma xenograft tumors in a dose-dependent manner and augmented the antitumor effects of mammalian target of rapamycin inhibitor CCI-779. These findings demonstrate the importance of cross-talk between the PI3K/Akt and beta-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease. | ||||||||||||
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| OSU03012 | AR-12|OSU-03012 | PAK1 Inhibitor 11 PDPK1 Inhibitor 10 | OSU03012 is an inhibitor of PDPK1 and PAK1, which can indirectly inhibit beta-catenin by blocking Akt signaling resulting in apoptosis and anti-tumor activity (PMID: 20028853, PMID: 32863957). |
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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