Project description:The mouse Ikaros-deficient thymic lymphoma cell line T29 was treated with a gamma-secretase inhibitor or vehicle (DMSO) for 36h and subjected to transcriptome analysis.
Project description:The mouse Ikaros-deficient thymic lymphoma cell line T29 was treated with a gamma-secretase inhibitor or vehicle (DMSO) for 36h and subjected to transcriptome analysis. 4 samples
Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
Project description:We have investigated the role of the Notch pathway in the generation and maintenance of KrasG12V-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and Rbpj activities are both essential in the formation of NSCLCs. Interestingly, pharmacologic treatment of mice carrying endogenous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth and induces partial regression. Treated cancers show a reduction in Hes1 levels, reduced phosphorylated Erk, decreased proliferation and higher apoptosis. We demonstrate that HES1 directly binds and represses the promoter of DUSP1, a dual phosphatase with activity against phospho-ERK, and this repression is relieved by GSI treatment both in mouse and human NSCLCs. Our data provide proof for the in vivo therapeutic potential of γ-secretase inhibitors in primary NSCLCs and provide a mechanistic explanation for its therapeutical effect. We have included 6 samples. 3 with vehicle and 3 with the gamma-secretase inhibitor DAPT and we compare both groups.
Project description:Analysis of five Notch signaling-dependent human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) treated with gamma-secretase inhibitor (GSI) to block Notch signaling. Samples include parental cells, cells rescued by retroviral transduction with ICN (a GSI-independent form of activated Notch1), and cells retrovirally transduced with c-Myc (an important downstream target of Notch1). Results allow segregation of bona fide Notch targets from other genes affected by gamma-secretase inhibition as well as from targets downstream of c-Myc. Thirty samples were analyzed. Five human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) were treated with gamma-secretase inhibitor (1.0 micromolar compound E) vs. DMSO vehicle control for 12 hours. Each cell line was also retrovirally transduced with ICN or c-Myc, FACS sorted, and then treated with GSI vs. DMSO.
Project description:Notch signalling regulates various cancer cell beahviors. Influence of notch signaling inhibitor, a gamma secretase inhibitor (DAPT) on human oral squamous cell carcinoma is not yet widely investigated. Here, the differential mRNA expression of DAPT treated HSC4 cell line was examined using RNA sequencing technique. Results demonstraetd that DAPT regulated various pathways in HSC4, including cell cycle and DNA replication pathways.
