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MTOR inhibitors synergistically induce regression, reversal of gene expression and autophagy in hepatocellular carcinoma

ABSTRACT: The mTOR-allosteric inhibitor, RAD001, in combination with a PI3K/mTOR ATP-site competitive inhibitor, BEZ235, causes gene reprogramming, autophagy and tumor regression, in a mouse model approximating human HCC with poor prognosis, leading to an investigator Phase 1B-2 clinical trial. Comparative study of total RNA obtained from normal and tumor liver tissue under RAD001, BEZ235, or RAD001 + BEZ235.

ORGANISM(S): Mus musculus

SUBMITTER: Manway Liu

PROVIDER: E-GEOD-37129 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma.

Thomas Hala Elnakat HE Mercer Carol A CA Carnevalli Larissa S LS Park Jongsun J Andersen Jesper B JB Conner Elizabeth A EA Tanaka Kazuhiro K Matsutani Tomoo T Iwanami Akio A Aronow Bruce J BJ Manway Liu L Maira S Michel SM Thorgeirsson Snorri S SS Mischel Paul S PS Thomas George G Kozma Sara C SC

Science translational medicine 20120425 139

Hepatocellular carcinoma (HCC) affects more than half a million people worldwide and is the third most common cause of cancer deaths. Because mammalian target of rapamycin (mTOR) signaling is up-regulated in 50% of HCCs, we compared the effects of the U.S. Food and Drug Administration-approved mTOR-allosteric inhibitor, RAD001, with a new-generation phosphatidylinositol 3-kinase/mTOR adenosine triphosphate-site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in i ...[more]

PMID: 22539746

Similar Datasets

mTOR inhibitors synergistically induce regression, reversal of gene expression and autophagy in hepatocellular carcinoma

Project description:The mTOR-allosteric inhibitor, RAD001, in combination with a PI3K/mTOR ATP-site competitive inhibitor, BEZ235, causes gene reprogramming, autophagy and tumor regression, in a mouse model approximating human HCC with poor prognosis, leading to an investigator Phase 1B-2 clinical trial.

2012-07-12 | GSE37129 | GEO

Transcription profiling of mouse ventral prostate treated with placebo or RAD001 for 12h, 48h, 6d,9d, and 15d

Project description:A mTOR depedent and a phenotype dependent sigature can be identified. Experiment Overall Design: This study aims to separate pharmacodynamic and response biomarkers in response to RAD001 treatment

2008-06-15 | E-GEOD-6610 | biostudies-arrayexpress

Targeting metabolic reprogramming by influenza infection for therapeutic intervention

Project description:Influenza infection is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry we found metabolic changes occurring after influenza infection in primary human respiratory cells, and validated infection associate increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen and high throughput titering that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in glucose and glutamine metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on viral entry or the early stages of viral replication. In a lethal infection model, BEZ235 significantly increased survival while reducing viral titer and respiratory distress. Here we show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.

2017-05-24 | PXD006263 | Pride

Effect of a dual specificity PI3K/mTOR inhibitor, NVP-BEZ235, on human ovarian cancer cell lines grown in 3D culture

Project description:Analysis of the effects of a dual specificity PI3K/mTOR inhibitor on two human ovarian cell lines, OV2008 and MCAS. Results provide insight into the adaptive response to PI3K/mTOR inhibition in matrix attached ovarian cancer cells. The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and thus represents an important target for cancer therapeutics. Here we show that dual inhibition of PI3K/mTOR in ovarian cancer 3D-spheroids leads to death of the inner matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance is associated with up-regulation of a cellular survival program that involves both FOXO-regulated transcription and a novel translational resistance mechanism resulting in specific up-regulation of IRES-mediated, cap-independent translation. Inhibition of any of several up-regulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to dual PI3K/mTOR inhibition. These results demonstrate that acute adaptive response to PI3K/mTOR inhibition resembles well-conserved adaptive response to nutrient and growth factor deprivation and how development of rational drug combinations can bypass resistance mechanisms. Total RNA was isolated 6h and 24h after treatment with 1 M-NM-<M NVP-BEZ235 or DMSO vehicle control from 3D grown structures

2012-03-13 | E-GEOD-28992 | biostudies-arrayexpress

Comparison of gene expression pattern of THP-1 cell treated with ATRA and RAD001

Project description:To explore the mechanism related to the induction of monocytic differentiation in AML combination of ATRA and RAD001, gene expression patterns of THP-1 cells were analyzed using the Agilent Whole Human Genome Expression Array. Gene expression patterns of THP-1 cell cultured under four different conditions were analyzed. The conditions were as follows; 1, untreated. 2, treated with ATRA (1mM) and RAD001 (2.5nM). Total RNA was extracted at 5 days after starting treatment.

2011-04-25 | E-GEOD-28818 | biostudies-arrayexpress

MYC drives resistance to PI3K/mTOR targeted inhibition (gene expression)

Project description:Gene expression signatures were measured after treatment of cells with 50nM BEZ235. Affymetrix HG-U133AV2 expression arrays were performed according to the manufacturer's directions using RNA extracted by Qiagen RNeasy from engineered human cell-lines grown for 72h in the presence of 50nM BEZ235 Resulting expression signatures where derived based on phenotypic properties(resistance to BEZ235) of the cells (enriched vs GFP/HR).

2011-08-30 | E-GEOD-25172 | biostudies-arrayexpress

AKT_Prostate_RAD001_v_PLACEBO

Project description:Transgenic (Probasin driven Myr-AKT)or wild-type littermates were treated with RAD001 or placebo and sacrificed at 12 and 48 hours following the beginning of treatment Keywords = AKT Prostate RAD001 mTOR PIN Keywords: time-course

2004-05-17 | GSE1413 | GEO

Influence of BEZ235 and MYC on gene expression in SW620 cells

Project description:SW620 were transfected with siMYC or siCTR at time point 0h. 24h later cells were splitter 1:2, additional 24 h later (48h after transfection) cells were treated with BEZ235 (200nM) or DMSO. Cells were harvested after additional 24h (72h after siRNA transfection; 24h BEZ235 treatment.

2015-08-27 | E-MTAB-2882 | biostudies-arrayexpress

mTORC1 and -2 Coordinate Transcriptional and Translational Reprogramming in Resistance to DNA Damage and Replicative Stress in Breast Cancer Cells

Project description:mTOR coordinates growth signals with metabolic pathways and protein synthesis and is hyperactivated in many human cancers. We have characterized the coordinated mTORC1 and -2 transcription and translation response using genome-wide translatome and transcriptome profiling on cells inhibited in mTORC1/2 with PP242 or only mTORC1 with RAD001, with or without concurrent IR. In this dataset, we include the expression data obtained from SUM149 cells treated with RAD001 + IR, RAD001, PP242+IR, PP242, IR, DMSO. We include both total (transcriptional) data as well as polysome arrays. These data are used to obtain differentially expressed genes in all treatments compared to DMSO in both polysome and transcriptional data.

2016-12-20 | GSE92598 | GEO

Targeting PI3K/mTOR signaling exerts potent antitumor activity in pheochromocytoma in vivo

Project description:Pheochromocytomas (PCC) are mostly benign tumors, amenable to complete surgical resection. However, 10–17% of cases can become malignant, and once metastasized, there is no curative treatment for this disease. Given the need to identify effective therapeutic approaches for PCC, we evaluated the antitumor potential of the dual PI3K/mTOR inhibitor BEZ235 against these tumors. We employed an in vivo model of endogenous PCCs (MENX mutant rats), which closely recapitulate the human tumors. Mutant rats with PCCs were treated with 2 doses of BEZ235 (20 and 30 mg/kg), or with placebo, for 2 weeks. Treatment with BEZ235 induced cytostatic and cytotoxic effects on rat PCCs, which could be appreciated by both staining the tumors ex vivo with appropriate markers, and non-invasively by functional imaging (diffusion weighted-DW-MRI) in vivo. Transcriptomic analyses of tumors from rats treated with BEZ235 or placebo identified potential mediators of therapy response. Slc6a2, encoding the norepinephrine transporter (NET), was downregulated in a dose-dependent manner by BEZ235 in rat PCCs. Moreover, BEZ235 reduced Slc6a2/NET expression also in PCC cell lines (PC12, MPC, MTT). Studies of a BEZ235-resistant derivative of the MPC cell line (MPCR) confirmed that the reduction of NET expression associates with the response to the drug. Reduction of NET expression following BEZ235 treatment in vivo could be monitored by Positron Emission Tomography (PET) using a tracer targeting NET. Altogether, we demonstrate the efficacy of BEZ235 against PCC in vivo, and show that functional imaging can be employed to monitor the response of PCC to PI3K/mTOR inhibition therapy.

2016-11-03 | GSE83401 | GEO

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