Missing content? – Request curation!
Request curation for specific Genes, variants, or PubMed publications.
Have questions, comments or suggestions? - Let us know!
Email us at : email@example.com
|Ref Type||Journal Article|
|Authors||Allen JE, Krigsfeld G, Mayes PA, Patel L, Dicker DT, Patel AS, Dolloff NG, Messaris E, Scata KA, Wang W, Zhou JY, Wu GS, El-Deiry WS|
|Title||Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.|
|Journal||Science translational medicine|
|Date||2013 Feb 6|
|Abstract Text||Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Nivolumab + ONC201||Nivolumab ONC201||0||1|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|ONC201||TIC-10|TIC10||Akt Inhibitor (Pan) 19 ERK Inhibitor (pan) 15||ONC201 (TIC-10) binds to the G-protein coupled receptor, DRD2, leading to inactivation of AKT and ERK, which relocates Foxo3a to the nucleus and then leads to tumor cell apoptosis mediated by (TNF)-related apoptosis-inducing ligand (TRAIL) signaling (PMID: 23390247) and targets the mitochondrial protease, ClpP (PMID: 31021596, PMID: 31702782, PMID: 31456142).|
|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|
|AKT1 amp||Advanced Solid Tumor||predicted - sensitive||ONC201||Preclinical - Cell line xenograft||Actionable||In a preclinical study, ONC201 (TIC-10) inhibited Akt activation and induced apoptosis and tumor regression in a variety of cell line xenograft models (PMID: 23390247).||23390247|
|Unknown unknown||Advanced Solid Tumor||not applicable||ONC201||Preclinical - Cell line xenograft||Actionable||In a preclinical study, ONC-201 (TIC-10) induced apoptosis and tumor regression in a variety of cell line xenograft models, including colon, breast, and brain cancer (PMID: 23390247).||23390247|