PREDICT
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001000094 | EGA |
REPOSITORIES: EGA
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Project description:PREDICT/Predicting individual response and resistance to VEGFR/mTOR pathway therapeutic intervention using biomarkers discovered through tumour functional genomics.
2015-09-04 | E-ERAD-16 | biostudies-arrayexpress
Project description:PREDICT/Predicting individual response and resistance to VEGFR/mTOR pathway therapeutic intervention using biomarkers discovered through tumour functional genomics.
| EGAS00001000934 | EGA
Project description:The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibition has been shown to have clinical activity in patients with DLBCL, although overall response rates remain low. We therefore evaluated differences in the transcriptome between DLBCL cell lines with differential sensitivity to the mTOR inhibitor Rapamycin, to (A) identify gene-expression patterns(GEP) capable of identifying sensitivity to Rapamycin, (B) understand the underlying mechanisms of resistance to Rapamycin in DLBCL and (C) identify bioactive molecules likely to synergize with mTOR inhibitors. Using Affymetrix HuGene ST 1.0 microarrays, we were able to identify a gene expression signature capable of accurately predicting sensitivity and resistance to Rapamycin in DLBCL cell lines. Pathway analysis identified the serine/threonine kinase Akt as central to the differentially-expressed gene network. Connectivity mapping of our datasets identified compounds targeting the AKT pathway with a high likelihood of reversing the GEP associated with resistance to Rapamycin. Specifically, we evaluated the HIV protease inhibitor (PI) Nelfinavir, which is known to have anti-cancer and Akt-inhibitory properties, as well as the small molecule Akt inhibitor MK-2206, for their potential to synergize with to Rapamycin in DLBCL. Nelfinavir and MK-2206 caused profound inhibition of cell viability in combination with Rapamycin in DLBCL cell lines. Low nanomolar concentrations of Rapamycin inhibited phosphorylation of Akt and also downstream targets of activated mTOR when used in combination with these Akt inhibitors. These findings have the potential to significantly improve patient selection for mTOR inhibitor therapy, and to improve rates and depths of response. More broadly, they support the use of global RNA expression and connectivity mapping to improve patient selection and identify synergistic drug combinations for cancer therapy. DLBCL cell lines were tested for Rapamycin sensitivity and classified as "sensitive" or "resistant." Genome-wide analysis of all cell lines were performed using the Affymetrix HuGene ST 1.0 Array Platform. Genes with differential expression between sensitive and resistant cell lines were analyzed using Statistical Analysis of Microarrays (SAM) software, and a signature of genes determnined. This signature was found to accurately predict sensitivity or resistance of other DLBCL cell lines, and to identify the protein kinase Akt as central to resistance.
2012-04-29 | E-GEOD-27255 | biostudies-arrayexpress
Project description:Although biomarker candidates associated with psoriasis have been suggested, those for predicting the risk of cardiovascular disease (CVD) early in patients with psoriasis are lacking. We aimed to identify candidate biomarkers that can predict the occurrence of CVD in psoriasis patients. We pursued quantitative proteomic analysis of serum samples composed of three groups: psoriasis patients with and those without CVD risk factors, and healthy controls. Age/Sex-matched serum samples were selected and labeled with 16-plex tandem mass tag (TMT) and analyzed using liquid chromatography-mass spectrometry and subsequent verification with ELISA. Of the 184 proteins that showed statistical significance (P-value <0.05) among the three groups according to TMT-based quantitative analysis, 98 proteins showed significant differences (>2.0-fold) between the psoriasis groups with and without CVD risk factors. Verification by ELISA revealed that caldesmon (CALD1), myeloid cell nuclear differentiation antigen (MNDA), and zyxin (ZYX) levels were significantly increased in the psoriasis group with CVD risk factors. Further network analysis identified pathways including integrin signaling, which could be related to platelet aggregation, and actin cytoskeleton signaling. Three novel candidates (MNDA, ZYX, and CALD1) could be potential biomarkers for predicting CVD risks in psoriasis patients. We expect these biomarker candidates can be used to predict CVD risk in psoriasis patients in clinical settings although further studies including large validation are needed.
2023-02-20 | PXD039645 | Pride
Project description:<p>We have used a "chemistry first" approach to discover druggable acquired vulnerabilities that arised in the pathogenesis of non-small cell lung cancer (NSCLC). We screened chemical libraries (~200,000 compounds) for chemical toxins that killed subsets of NSCLC but not normal human lung epithelial cells (HBECs). We first screened a panel of 12 NSCLC lines that represented a variety of known oncogenotypes and identified chemicals with large Z scores and appropriate properties including re-supply, chemistry, and reproducible drug response phenotypes. This was then narrowed down to a list of 202 chemicals and 18 drugs with known targeting (henceforth called "Precision Oncology Probe Set", or POPS). These, and a panel of 30 clinically available drugs, targeted therapies, and drug combinations, already in use or in trials for NSCLC treatment, were then tested on a panel of 96 NSCLC lines for their drug response phenotypes in 12-point dose response curves. This information was analyzed using scanning ranked KS (Kolmogorov-Smirnov) and elastic net biostatistics approaches to identify molecular biomarkers (mutations, mRNA expression, copy number variation, protein expression, and metabolomics) which could predict for sensitivity or resistance to a particular chemical toxin or treatment regimen. From this we have discovered that: our approach identifies already known molecular biomarker of drug sensitivities (e.g. EGFR mutations and EGFR TK inhibitors); many clinically available chemotherapy agents have molecular biomarkers predicting preclinical model drug responses; the POP set of chemical toxins provides novel drug response phenotype patterns in the large NSCLC panel different from those found with clinically available agents including a therapeutic window; many of the POP toxins only hit a small percentage (~5%) of the NSCLC panel but the POP set as a whole provides "coverage" of the entire NSCLC panel; there are simple, one or 2 component molecular biomarkers (mutations, mRNA expression) that predict responses to the different chemical toxins in the NSCLC panel; and that the molecular biomarkers provide some information on the targets and pathways involved in response to the chemical toxins. Thus, we have identified a group of chemical toxins with selectivity for subsets of NSCLC and associated tumor molecular biomarkers to facilitate their development for precision medicine, and also, in some cases, information on the targets and pathways interdicted by these chemical compounds. In addition, we have discovered NSCLC predictive biomarkers for clinically available agents.</p>
| phs001823 | dbGaP
Project description:The aim of our study was to identify a microRNA signature to predict the recurrence in stage II & III CRC patients who were treated with FOLFOX-based adjuvant chemotherapy after curative resection of tumors. We performed small RNA sequencing in 71 FFPE surgical specimens, and discovered differentially expressed microRNAs in patients who developed recurrence. Thereafter, selected microRNA biomarkers were validated in independent cohort using qRT-PCR assay.
2022-11-16 | GSE217978 | GEO
Project description:Newly diagnosed chronic phase chronic myeloid leukemia (CML) patients with a major cytogenetic response (MCyR) after 12 months of imatinib therapy have an excellent long-term outcome, while patients without MCyR have a high progression risk. Since patients with primary cytogenetic resistance may benefit from more intensive therapy up-front, we sought to identify biomarkers to predict MCyR. Keywords: Two group comparison to identify trasncriptomic signature that predicts response to therapy
2010-01-01 | GSE14671 | GEO
Project description:Hemorrhagic transformation (HT), which occurs with or without reperfusion treatments (thrombolysis and/or thrombectomy), deteriorates the outcomes of ischemic stroke patients. It is essential to find clinically reliable biomarkers that can predict HT. In this study, we screened for potential serum biomarkers from an existing blood bank and database with 243 suspected acute ischemic stroke (AIS) patients. A total of 37 patients were enrolled, who were diagnosed as AIS but did not receive reperfusion treatment. They were divided into two groups based on whether they accompanied with HT or not (5 HT and 32 non-HT). Serum samples were labeled by isobaric tags for relative and absolute quantitation (iTRAQ) and analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and compared under NCBInr database. A total of 647 proteins in sera samples were captured and the levels of 17 proteins (12 up-regulated and 5 down-regulated) were significantly different. These differentially expressed proteins were further categorized with Gene Ontology functional classification annotation and Kyoto Encyclopedia of Genes and Genomes metabolic pathway analysis into biological processes. Further protein-protein interaction analysis using String database discovered that, among the differential expressed proteins, 10 pairs of proteins were found to have crosstalk connections, which may have direct (physical) and indirect (functional) interactions for the development of HT. Our findings suggest that these differentially expressed proteins could serve as potential biomarkers for predicting HT after ischemic stroke.
2021-10-12 | PXD026950 | Pride
Project description:Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GVHD (cGVHD) carrying persistent CD4+ T cell clonal expansion which harbored somatic mTOR, NFKB2, and TLR2 mutations. Functional analysis of the discovered mTOR mutation indicated a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements supported increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggested mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest that somatic mutations may contribute to aberrant T cell proliferations and participate in the persistent immune activation in cGVHD paving the way for novel targeted therapies.
2020-04-12 | E-MTAB-8911 | biostudies-arrayexpress