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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE37129 | GEO | 2012/07/12

SECONDARY ACCESSION(S): PRJNA158305

REPOSITORIES: GEO

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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. Comparative study of total RNA obtained from normal and tumor liver tissue under RAD001, BEZ235, or RAD001 + BEZ235.

2012-07-11 | E-GEOD-37129 | biostudies-arrayexpress

Human basal-like breast cancer cell line HCC1143 treated with BET inhibitor JQ1 in combination with MEK inhibitor Trametinib or PI3K/mTOR inhibitor BEZ235

Project description:The goal of this experiment was to understand the changes in gene expression in the human basal-like breast cancer cell line HCC1143 following treatment with the MEK inhibitor Trametinib (T), PI3K/mTOR inhibitor BEZ235 (B), the BET inhibition JQ1 (JQ), Trametinib + JQ1 (TJ), or BEZ235 + JQ1(BJ), compared to a DMSO control (D). Samples were treated for 72hr and run in triplicate.

2017-05-30 | GSE82032 | GEO

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

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

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

RNA seq NVP-BEZ235 treatment of U87MG cells

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2021-12-01 | GSE179667 | GEO

Integrated molecular characterization of patient-derived models reveals therapeutic strategies for treating CIC-DUX4 sarcoma.

Project description:Capicua–double homeobox 4 (CIC-DUX4) rearranged sarcomas (CDSs) are extremely rare, highly aggressive primary sarcomas that represent a major therapeutic challenge. To identify selective therapeutic targets of CDS, we performed RNA sequencing of primary tumor samples from patients, patient-derived xenografts (PDXs) and PDX-derived cell lines and we highlighted an HMGA2/IGF2BPs/IGF2/IGF1R/AKT-mTOR axis that characterizes CDS. This highly active axis confers to CDSs sensitivity to both trabectedin, which prevents HMGA proteins from binding to IGF2BP2/3 promoters, and PI3K/mTOR inhibitor NVP-BEZ235 (dactolisib). Combined treatments with trabectedin and NVP-BEZ235 completely abolish the activation of the IGF2/IGF1R/AKT/mTOR axis and the in vivo growth of CDS tumors. The development of representative PDXs and PDX-derived cell lines models has helped to identify the unique sensitivities of CDS towards AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer.

2022-01-12 | GSE165032 | GEO

Phase I/Randomized Phase II Study of Second Line Therapy With Irinotecan + Cetuximab +/- RAD001 for Colorectal Cancer

Project description:The addition of RAD001, an mTOR inhibitor, to irinotecan and anti-EGFR antibody cetuximab may increase efficacy for patients with metastatic colorectal cancer who progressed on prior chemotherapy. This approach is biologically directed to overall target the cancer cell at multiple levels, and potentially preventing chemotherapy and EGFR-therapy resistance.

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Cytoplasmic MTDH associates with mRNAs

Project description:To examine whether MTDH is a novel RNA binding protein and regulates either metabolism or translation of various mRNAs, we performed a RNA-binding protein immunoprecipitation (RIP) with MTDH and IgG antibodies, and the resulting immunoprecipitated RNA was subjected to a microarray to identify transcripts associating with MTDH. In addition we tested the effect of PI3K inhibition using BEZ235 (a dual PI3K/mTOR inhibitor) on the association of MTDH with target mRNAs. The microarray was performed on three biological triplicates as well as three experimental triplicates of immunoprecipitated MTDH and IgG in Hec50co endometrial cancer cells. Magna RIP (RNA-binding protein immunoprecipitation, Millipore) Kit and microarray were used to immunoprecipitate MTDH associated RNAs and to identify mRNAs that associate with MTDH in the absence or presence of 100nM BEZ235 (LC Labs). Fold changes represent immunoprecipitated MTDH RNA compared to IgG immunoprecipitated RNA. Representative mRNAs associated with MTDH and the effect of BEZ235 on the association of MTDH with mRNAs are shown.

2011-07-12 | E-GEOD-30588 | biostudies-arrayexpress

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

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