Project description:Affymetrix SNP6.0 array data used to reveal predictive biomarkers of tumour sensitivity to MI-773 . MI-773 is a recently developed small-molecule inhibitor of the Mouse Double Minute 2 (MDM2) proto-oncogene. Here we report an integrative pharmacogenomic study to gain further insights into the therapeutic potential of the compound

2021-10-27 | GSE178763 | GEO

Expression data from neuroblastoma cells treated with MI-773

Project description:Neuroblastoma (NB) is a common pediatric malignancy tumor with poor outcome. Recent studies show that MDM2 protein inhibitors are promising anti-cancer agents. MI-773 is a novel and specific antagonist of MDM2 and the molecular mechanisms of MI-773 in neuroblastoma are still unclear. In this study, we used microarrays to analyze the global change in gene expression as a result of MI-773 treatment in the human neuroblastoma cell line SH-SY5Y.

2021-08-06 | GSE174450 | GEO

Pharmacogenomic characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

Project description:MI-773 is a recently developed small-molecule inhibitor of the Mouse Double Minute 2 (MDM2) proto-oncogene. Here we report an integrative pharmacogenomic study to gain further insights into the therapeutic potential of the compound.

2021-10-27 | GSE152529 | GEO

MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models

Project description:Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 23 differentially abundant metabolites across both panels (FDR < 0.05, log2 FC < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome.

2020-05-22 | ST001405 | MetabolomicsWorkbench

Copy number profiling of 92 human lung tumors on Affymetrix 100K SNP arrays

Project description:Copy number profiling of 92 human lung tumors on Affymetrix 100K SNP arrays was conducted in order to assess the interaction of common genomic alterations with response to targeted anti-cancer therapeutics. Class 1 phosphatidylinositol 3' kinase (PI3K) plays a major role in cell proliferation and survival in a wide variety of human cancers. Here we investigate biomarker strategies for PI3K pathway inhibitors in non-small-cell lung cancer (NSCLC). Molecular profiling of NSCLC tumor samples showed that copy number gains in PIK3CA and total loss of PTEN protein were common in squamous cell carcinoma samples, whereas LKB1 loss and mutations in KRAS and EGFR were common in adenocarcinomas. A panel of NSCLC cell lines characterized for alterations in the PI3K pathway was screened with PI3K and dual PI3K/mTOR inhibitors to assess the preclinical predictive value of candidate biomarkers. Cell lines harboring pathway alterations (RTK activation, PI3K mutation or amplification, PTEN loss) were exquisitely sensitive to the PI3K inhibitor GDC-0941. A dual PI3K/mTOR inhibitor had broader activity across the cell line panel and in tumor xenografts. The combination of GDC-0941 with paclitaxel, erlotinib, or a MEK inhibitor had greater effects on cell viability than PI3K inhibition alone. CONCLUSIONS: Candidate biomarkers for PI3K inhibitors have predictive value in preclinical models and show histology-specific alterations in primary tumors, suggesting that distinct biomarker strategies may be required in squamous compared with non-squamous NSCLC patient populations. Lung tumors were profiled on Affymetrix GeneChip Mapping 100K Set Arrays Tumor samples were profiled for copy number without any treatment of the tumor.

2013-01-10 | E-GEOD-39793 | biostudies-arrayexpress

Trametinib + HDM201 in CRC Patients With RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type

Project description:Recent preclinical studies suggest that combining MEK and MDM2 inhibition synergize to induce apoptosis in RAS/BRAF-mutant and TP53 wild-type CRC models. In vitro, in RKO cell lines (poorly differentiated colon carcinoma cell line resistant to single agent targeting MDM2 and MEK and BRAF inhibition), the MDM2 plus MEK inhibitor combination generated a synergistic increase in apoptotic index. In vivo, in mice harboring human RKO colon tumor xenografts the combination of MDM2 plus MEK inhibition elicited 93% decreases in tumor volume. This trial is to conduct a single-center, Phase 1 dose escalation study of trametinib combined with HDM201 (a HDM2 inhibitor) in patients with advanced/metastatic RAS/RAF mutant and TP53 wt CRC.

| 2287507 | ecrin-mdr-crc

Stage III serous ovarian adenocarcinomas

Project description:The clinical outcome for patients with ovarian cancer is difficult to predict. However, the use of biomarkers as additional prognostic factors may improve the outcome for these patients. In order to find novel candidate biomarkers, differences in gene expressions were analyzed in 54 stage III serous ovarian adenocarcinomas with oligonucleotide microarrays containing 27,000 unique probes. The microarray data was verified with quantitative real-time polymerase chain reaction for the genes TACC1, MUC5B and PRAME. With a hierarchical cluster analysis we detected a sub-group including 60% of the survivors. The gene expressions in tumours from patients in this sub-group of survivors were compared to the remaining tumours, and 204 genes were found to be differently expressed. We conclude that the sub-group of survivors might represent patients with favourable tumour biology and sensitivity to treatment. A selection of the 204 genes might be used as a predictive model to distinguish patients within and outside of this group. Alternative chemotherapy strategies could then be offered as first-line treatment, which could improve the clinical outcome for these patients. Keywords: Comparison between groups of samples 20 fresh frozen tumors from 5 year survivors were compared to 34 tumors from deceased patients in order to find genes where the expression differed between the two groups

2010-05-25 | E-GEOD-12418 | biostudies-arrayexpress

Expression data from neuroblastoma cells treated with MI-773

Project description:Expression data from neuroblastoma cells treated with MI-773

| PRJNA729997 | ENA