Insulin-Like Growth Factor Receptor 1 and Mammalian Target Of Rapamycin Blockade: Novel Mechanisms of Resistance and Synergistic Drug Combinations for Ewing Sarcoma
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PROVIDER: PRJNA312656 | ENA |
REPOSITORIES: ENA
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Project description:Ewing sarcoma is a highly aggressive solid tumor malignancy and the second most common bone cancer in children. Ewing sarcoma is driven primarily by EWS-FLI, a fusion oncoprotein that has been notoriously difficult to target with traditional pharmacological agents. Compared to adult cancers, pediatric malignancies are rarely driven by readily druggable oncogenic targets and there are few incentives for developing drugs for challenging targets restricted to relatively uncommon cancer types. In addition, the effectiveness of single-agent therapies for cancer treatment is often limited. Furthermore, there are numerous examples of promising combinations of preclinical small molecules that are never tested in pediatric clinical trials because agents fail to reach the market due to limited efficacy for common adult cancers. Therefore, the identification of novel effective candidate treatment combinations comprised of anti-cancer drugs already commercially available would likely expedite the development of clinical trials for patients with pediatric cancers. To identify candidate treatment combinations for Ewing sarcoma, we performed a high-throughput drug screening with 180 combinations of tyrosine kinase inhibitors, cell cycle inhibitors, and chemotherapies, that were largely FDA approved or in late stages of clinical development. The results of the screen revealed that a CDK4/6 inhibitor ribociclib combined with a PI3K inhibitor copanlisib exhibited strong synergistic anti-Ewing sarcoma activity. We showed that this combination induced apoptosis and cell cycle arrest more effectively than either agent alone in vitro and impaired tumor proliferation and prolonged survival in vivo compared to mice treated with vehicle or single-agent therapy. Our findings identified a new candidate therapeutic option for Ewing sarcoma patients using FDA-approved drugs and provide a resource of additional potential synergistic combinations for future validation.
2026-05-31 | GSE279738 | GEO
Project description:Ewing Sarcoma is caused by a pathognomonic genomic translocation that places an N-terminal EWSR1 gene in approximation with one of several ETS genes (typically FLI1). This aberration, in turn, alters the transcriptional regulation of more than five hundred genes and perturbs a number of critical pathways that promote oncogenesis, cell growth, invasion, and metastasis. Among them, translocation-mediated up-regulation of the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) are of particular importance since they work in concert to facilitate IGF-1R expression and ligand-induced activation, respectively, of proven importance in ES transformation. When used as a single agent in Ewing sarcoma therapy, IGF-1R or mTOR inhibition leads to rapid counter-regulatory effects that blunt the intended therapeutic purpose. Therefore, identify new mechanisms of resistance that are used by Ewing sarcoma to evade cell death to single-agent mTOR inhibition might suggest a number of therapeutic combinations that could improve its clinical activity.
2016-06-01 | GSE78122 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-01 | E-GEOD-78124 | biostudies-arrayexpress
Project description:Ewing Sarcoma is caused by a pathognomonic genomic translocation that places an N-terminal EWSR1 gene in approximation with one of several ETS genes (typically FLI1). This aberration, in turn, alters the transcriptional regulation of more than five hundred genes and perturbs a number of critical pathways that promote oncogenesis, cell growth, invasion, and metastasis. Among them, translocation-mediated up-regulation of the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) are of particular importance since they work in concert to facilitate IGF-1R expression and ligand-induced activation, respectively, of proven importance in ES transformation. When used as a single agent in Ewing sarcoma therapy, IGF-1R or mTOR inhibition leads to rapid counter-regulatory effects that blunt the intended therapeutic purpose. Therefore, identify new mechanisms of resistance that are used by Ewing sarcoma to evade cell death to single-agent IGF-1R or mTOR inhibition might suggest a number of therapeutic combinations that could improve their clinical activity.
2015-04-02 | GSE67529 | GEO
Project description:Ewing Sarcoma is caused by a pathognomonic genomic translocation that places an N-terminal EWSR1 gene in approximation with one of several ETS genes (typically FLI1). This aberration, in turn, alters the transcriptional regulation of more than five hundred genes and perturbs a number of critical pathways that promote oncogenesis, cell growth, invasion, and metastasis. Among them, translocation-mediated up-regulation of the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) are of particular importance since they work in concert to facilitate IGF-1R expression and ligand-induced activation, respectively, of proven importance in ES transformation. When used as a single agent in Ewing sarcoma therapy, IGF-1R or mTOR inhibition leads to rapid counter-regulatory effects that blunt the intended therapeutic purpose. Therefore, identify new mechanisms of resistance that are used by Ewing sarcoma to evade cell death to single-agent IGF-1R or mTOR inhibition might suggest a number of therapeutic combinations that could improve their clinical activity.
2016-06-01 | GSE78123 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-06-01 | GSE78124 | GEO
Project description:Ewing Sarcoma is caused by a pathognomonic genomic translocation that places an N-terminal EWSR1 gene in approximation with one of several ETS genes (typically FLI1). This aberration, in turn, alters the transcriptional regulation of more than five hundred genes and perturbs a number of critical pathways that promote oncogenesis, cell growth, invasion, and metastasis. Among them, translocation-mediated up-regulation of the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) are of particular importance since they work in concert to facilitate IGF-1R expression and ligand-induced activation, respectively, of proven importance in ES transformation. When used as a single agent in Ewing sarcoma therapy, IGF-1R or mTOR inhibition leads to rapid counter-regulatory effects that blunt the intended therapeutic purpose. Therefore, identify new mechanisms of resistance that are used by Ewing sarcoma to evade cell death to single-agent IGF-1R inhibition might suggest a number of therapeutic combinations that could improve its clinical activity.
2016-06-01 | GSE78121 | GEO
Project description:We examined the mode-of-action of synergistic drug combinations by microarray analysis. We focused on the drug combination of capsaicin and mitoxantrone, which were the top predicted drug pair identified by SyndrumNET. Combination therapy can offer greater efficacy on medical treatments. However, the discovery of synergistic drug combinations is challenging. We propose a novel computational method, SyndrumNET, to predict synergistic drug combinations by network propagation with trans-omics analyses. The prediction is based on the topological relationship, network-based proximity, and transcriptional correlation between diseases and drugs. SyndrumNET was applied to analyzing six diseases including asthma, diabetes, hypertension, colorectal cancer, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML), and it outperformed the previous methods in terms of high accuracy. We performed in vitro cell survival assays to validate our prediction for CML. Of the top 17 predicted drug pairs, 14 drug pairs successfully exhibited synergistic anticancer effects. Our mode-of-action analysis also revealed that the drug synergy of the top predicted combination of capsaicin and mitoxantrone was due to the complementary regulation of 12 pathways, including the Rap1 signaling pathway. The proposed method is expected to be useful for various complex diseases.
2024-05-06 | GSE254052 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE36857: Goldengate Methylation analysis: Ewing Sarcoma GSE36858: 5- AZA treatment of EWS cell lines Refer to individual Series
2012-09-01 | E-GEOD-36859 | biostudies-arrayexpress
Project description:Transcriptional response to standard AML drugs identifies synergistic combinations
| PRJNA944361 | ENA