Dataset Information

Adherent and Spheroid Glioblastoma Proteomics

ABSTRACT: Dendritic cell (DC)-based immunotherapy against glioblastoma multiforme is a novel treatment hope. Glioblastoma stem-like cells are, however, potentially causing immunoresistance. Glioblastoma cells cultured as gliomaspheres show a stem-like phenotype as opposed to classical adherent culture. They are thus a promising antigen source to specifically target glioblastoma stem-like cells via DC therapy and so overcome immunoresistance. Here we study the importance of gliomasphere-specific. Methodologically, we used 7 gliomaspheres, 3 of them patient-derived, as model system. Gliomasphere-specific protein expression was explored via quantitative proteomics.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Glioblastoma

SUBMITTER: Fernando J. Sialana

LAB HEAD: Gert Lubec

PROVIDER: PXD008244 | Pride | 2019-04-15

REPOSITORIES: Pride

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Publications

Spheroid glioblastoma culture conditions as antigen source for dendritic cell-based immunotherapy: spheroid proteins are survival-relevant targets but can impair immunogenic interferon γ production.

Erhart Friedrich F Weiss Tamara T Klingenbrunner Simone S Fischhuber Katrin K Reitermaier René R Halfmann Angela A Blauensteiner Bernadette B Lötsch Daniela D Spiegl-Kreinecker Sabine S Berger Walter W Sialana Fernando J FJ Lubec Gert G Felzmann Thomas T Dohnal Alexander A Visus Carmen C

Cytotherapy 20190408 6

<h4>Background</h4>Glioblastoma is the most aggressive type of brain cancer. Dendritic cell (DC)-based immunotherapy against glioblastoma depends on the effectiveness of loaded antigens. Sphere-inducing culture conditions are being studied by many as a potential antigen source. Here, we investigated two different in vitro conditions (spheroid culture versus adherent culture) in relation to DC immunotherapy: (1) We studied the specific spheroid-culture proteome and assessed the clinical importanc ...[more]

PMID: 30975602

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Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).

Dataset Information

Adherent and Spheroid Glioblastoma Proteomics

Publications

Spheroid glioblastoma culture conditions as antigen source for dendritic cell-based immunotherapy: spheroid proteins are survival-relevant targets but can impair immunogenic interferon γ production.

Similar Datasets

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