Gene expression changes during resistance toward vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) therapy in renal cell carcinoma (RCC)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE64052 | GEO | 2015/05/21
SECONDARY ACCESSION(S): PRJNA269968
REPOSITORIES: GEO
Similar Datasets
Project description:This study was performed to understand the gene expression changes that accompany treatment of renal cell carcinoma (RCC) with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) therapy. Human RCC cell lines were implanted into the flanks of nude beige mice, allowed to reach 12mm in long axis, and then treated with TKIs (sunitinib or sorafenib). Tumors were excised at 2 timepoints (prior to any therapy and at the 20mm endpoint of the study) and gene expression analysis was performed. Sunitinb or sorafenib were administered to mice bearing either 786-O or A498 xenografts. Mice were sacrificed and tumors excised for RNA extraction at pretreatment size of 12mm, or at 20mm, the mandated maximum tumor size allowed at our institution.
2015-05-21 | E-GEOD-64052 | biostudies-arrayexpress
Project description:The clinical response to sunitinib in advanced renal-cell carcinoma (RCC) is frequently limited in magnitude and duration due to drug resistance, but the underlying mechanisms remain elusive. To discover mechanisms of resistance, we developed drug-resistant cell lines and have their gene expressions profiled and compared. Results provide insight into the molecular mechanisms underlying sunitinib-resistance.
2016-09-30 | GSE69535 | GEO
Project description:Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O6-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O6-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors.
2012-09-11 | GSE40776 | GEO
Project description:Renal cell carcinoma (RCC) represents about 2-3% of all cancers with over 400,000 new cases per year. Sunitinib, a vascular endothelial growth factor tyrosine kinase receptor inhibitor, has been used mainly for first-line treatment of metastatic clear-cell RCC with good or intermediate prognosis. However, about one third of metastatic RCC patients do not respond to sunitinib, leading to disease progression. Here we aim to find and characterize proteins associated with poor sunitinib response in a pilot proteomics study. 16 RCC tumors from patients responding (8) vs. non-responding (8) to sunitinib in 3 months after treatment initiation, together with their adjacent non-cancerous tissues, were analyzed using data independent acquisition mass spectrometry. Proteomics analysis quantified 1996 protein groups (q<0.01) and revealed 27 proteins deregulated between tumors non-responding vs. responding to sunitinib, representing a pattern of deregulated proteins potentially contributing to sunitinib resistance. Gene set enrichment analysis showed up-regulation of epithelial-to-mesenchymal transition with transgelin as one of the most significantly abundant protein. Transgelin expression was silenced by CRISPR/Cas9 and RNA interference, and the cells with reduced transgelin level exhibited significantly slower proliferation. Our data indicate that transgelin is an essential protein supporting RCC cell proliferation which could contribute to intrinsic sunitinib resistance.
2021-11-03 | PXD027065 | Pride
Project description:Resistance to tyrosine kinase inhibitors is an essential issue concerning targeted therapy in renal cancer. This research focuses on molecular background of resistance to axitinib and sorafenib observed from the very beginning of a standard two-dimensional cell culture in monolayer as well as in three-dimensional models (soft agar and suspension cultures). Resistance was observed only in commercially available human kidney cancer stem cells. Mass spectrometry analysis revealed several proteins which may be functionally connected with the resistance to axitinib in normoxia and to sorafenib in hypoxia.
2018-01-02 | PXD002600 | Pride
Project description:Mathematical modeling of regulatory T cell effects on renal cell carcinoma treatment
Lisette dePillis 1, , Trevor Caldwell 2, , Elizabeth Sarapata 2, and Heather Williams 2,
1.
Department of Mathematics, Harvey Mudd College, Claremont, CA 91711
2.
Harvey Mudd College, Claremont, CA 91711, United States, United States, United States
Abstract
We present a mathematical model to study the effects of the regulatory T cells (Treg) on Renal Cell Carcinoma (RCC) treatment with sunitinib. The drug sunitinib inhibits the natural self-regulation of the immune system, allowing the effector components of the immune system to function for longer periods of time. This mathematical model builds upon our non-linear ODE model by de Pillis et al. (2009) [13] to incorporate sunitinib treatment, regulatory T cell dynamics, and RCC-specific parameters. The model also elucidates the roles of certain RCC-specific parameters in determining key differences between in silico patients whose immune profiles allowed them to respond well to sunitinib treatment, and those whose profiles did not.
Simulations from our model are able to produce results that reflect clinical outcomes to sunitinib treatment such as: (1) sunitinib treatments following standard protocols led to improved tumor control (over no treatment) in about 40% of patients; (2) sunitinib treatments at double the standard dose led to a greater response rate in about 15% the patient population; (3) simulations of patient response indicated improved responses to sunitinib treatment when the patient's immune strength scaling and the immune system strength coefficients parameters were low, allowing for a slightly stronger natural immune response.
Keywords: Renal cell carcinoma, mathematical modeling., sunitinib, immune system, regulatory T cells.
2024-09-02 | BIOMD0000000908 | BioModels
Project description:Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O6-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O6-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors. RNA was isolated from parental U87 (U87_EV) and MGMT-transfected U87 (U87_MGMT) triplicate. Pairwise gene expression differences were compared between the two cell lines. Features selected had more than 2-fold up-or down-regulated (P values of >05, unpaired Studentâs t-test with Bonferroni multiple testing correction) were identified. Database for annotation, visualization, and integrated discovery23 was used to identify enriched gene ontology (GO) biological themes.24 The GO data mining was conducted at a term specificity level 3.25 The EASE score was set at 0.05 and the minimum number of genes in a category was 5.
2012-09-11 | E-GEOD-40776 | biostudies-arrayexpress
Project description:Interventions: Group of VEGFR-TKI maintenance therapy:None;Group of standard maintenance treatment group:None
Primary outcome(s): 6-Months Progression-free survival
Study Design: Cohort study
| 83521 | ecrin-mdr-crc
Project description:Sunitinib is a TKI inhibitor used for managing metastatic renal cell carcinoma (RCC). However, chronic sunitinib treatment in RCC usually results in the development of drug resistance via alternating phosphorylation dynamics. On the other hand, 17-beta-estradiol, or estrogen, has been demonstrated to repress RCC growth partly through regulating cell signallings. To investigate how estrogen can repress sunibitinib-resistant RCC growth and its the possible mechanism of action related protein phosphorylation, a label-free quantitative phosphoproteomics study is performed.
2020-08-07 | PXD011020 | Pride
Project description:We have used a chimeric VEGFR-2 in which the extracellular domain of mouse VEGFR-2 was replaced with the extracellular domain of human CSF-1 receptor. VEGFR-2 was immunoprecipitated with anti-VEGFR-2 antibody from PAE cells ectopically expressing VEGFR-2. The immunoprecipitated proteins were eluted and separated on SDS-PAGE, followed by in-gel chymotrypsin or trypsin digestion. The digested samples were analyzed by nano LC/MS/MS on a Thermo Fisher LTQ Orbitrap XL. The LC-MS/MS data were analyzed using Proteome Discoverer (Thermo Fisher Scientific; Version 1.3.0.339). MS/MS search was carried out using Sequest search algorithm against the sequence of target mouse protein from the UniProtKB database. Search parameters included chymotrypsin as the enzyme with four missed cleavage allowed; methylation at lysine and arginine, phosphorylation of serine, threonine, and tyrosine, alkylation at cysteine, and oxidation of methionine were set as dynamic modifications. Precursor and fragment mass tolerance were set to 5 ppm and 0.8 Da, respectively. The false discovery rate was calculated by enabling the peptide sequence analysis using a decoy database. High confidence peptide identifications were obtained by setting a target false discovery rate threshold of 1% at the peptide level.
2019-11-22 | PXD000520 | Pride