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Expression profiling of ccRCC samples treated with anti-VEGF therapies reveals distinct markers

ABSTRACT: Metastatic renal cell carcinoma (mRCC) patients treated with anti-vascular endothelial growth factor (VEGF) therapies demonstrate promising outcomes but not all patients benefit. Factors that predict response remain to be elucidated. Nephrectomy material from 37 patients with mRCC receiving bevacizumab 6 erlotinib was used for protein and gene expression assessment. Protein lysates were subjected to reverse-phase protein array profiling. RNA extracts were used to carry out gene expression microarray-based profiling. Normalized protein and gene expression data were correlated with overall survival (OS) and progression-free survival (PFS) using univariate Cox hazard model and linear regression. Immunoblotting was carried out to validate the results. High protein levels of AMP-activated protein kinase and low levels of cyclin B1 (CCNB1) were associated with longer OS and PFS. Further validation revealed reduced expression and activation of phosphoinositide 3-kinase (PI3K) pathway components and cell cycle factors in patients with prolonged survival after therapy. Gene expression analysis revealed up-regulation of PI3K- and cell cycle-related pathways in patients with shorter PFS. The OS and PFS of bevacizumab 6 erlotinib-treated patients with renal cell carcinoma were associated with changes in expression of protein and gene expression markers related to PI3K pathway and cell cycle signaling. Expression profiling of ccRCC samples post-treatment (bevacizumab plus erlotinib, or bevacizumab alone). Note: sample 'Jonasch_R06_Tumor_3-27-08_CMM' was not used in the publication (PMID: 20089566).

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PROVIDER: S-DIXA-D-1076 | biostudies-other |

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Expression profiling of ccRCC samples treated with anti-VEGF therapies reveals distinct markers

Project description:Metastatic renal cell carcinoma (mRCC) patients treated with anti-vascular endothelial growth factor (VEGF) therapies demonstrate promising outcomes but not all patients benefit. Factors that predict response remain to be elucidated. Nephrectomy material from 37 patients with mRCC receiving bevacizumab 6 erlotinib was used for protein and gene expression assessment. Protein lysates were subjected to reverse-phase protein array profiling. RNA extracts were used to carry out gene expression microarray-based profiling. Normalized protein and gene expression data were correlated with overall survival (OS) and progression-free survival (PFS) using univariate Cox hazard model and linear regression. Immunoblotting was carried out to validate the results. High protein levels of AMP-activated protein kinase and low levels of cyclin B1 (CCNB1) were associated with longer OS and PFS. Further validation revealed reduced expression and activation of phosphoinositide 3-kinase (PI3K) pathway components and cell cycle factors in patients with prolonged survival after therapy. Gene expression analysis revealed up-regulation of PI3K- and cell cycle-related pathways in patients with shorter PFS. The OS and PFS of bevacizumab 6 erlotinib-treated patients with renal cell carcinoma were associated with changes in expression of protein and gene expression markers related to PI3K pathway and cell cycle signaling.

2011-01-07 | GSE25698 | GEO

Expression profiling of ccRCC samples treated with anti-VEGF therapies reveals distinct markers

2011-01-07 | E-GEOD-25698 | biostudies-arrayexpress

Anti-VEGF therapies in the clinic.

Project description:The development and use of antiangiogenesis agents, particularly those targeting vascular endothelial growth factor (VEGF), has become an integral component of anticancer regimens for many tumor types. This review is intended to highlight some of the most important clinical successes and failures of anti-VEGF therapies, and where possible, to suggest important lessons that have been learned. This review emphasizes data from agents that have been FDA approved and/or have completed phase III studies.

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Leukostasis retinopathy treated with Anti-VEGF therapy.

Project description: Not available

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Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches.

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Whole-brain microscopy reveals distinct temporal and spatial efficacy of anti-Aβ therapies.

Project description:Many efforts targeting amyloid-β (Aβ) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-Aβ treatments through high-resolution light-sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to β-secretase inhibitors, polythiophenes, or anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance, with polythiophenes emerging as a potent anti-Aβ compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each Aβ therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of Aβ plaques. This may also contribute to the clinical trial failures of Aβ-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.

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Moving Past Anti-VEGF: Novel Therapies for Treating Diabetic Retinopathy.

Project description:Diabetic retinopathy is the leading cause of blindness in working age adults, and is projected to be a significant future health concern due to the rising incidence of diabetes. The recent advent of anti-vascular endothelial growth factor (VEGF) antibodies has revolutionized the treatment of diabetic retinopathy but a significant subset of patients fail to respond to treatment. Accumulating evidence indicates that inflammatory cytokines and chemokines other than VEGF may contribute to the disease process. The current review examines the presence of non-VEGF cytokines in the eyes of patients with diabetic retinopathy and highlights mechanistic pathways in relevant animal models. Finally, novel drug targets including components of the kinin-kallikrein system and emerging treatments such as anti-HPTP (human protein tyrosine phosphatase) β antibodies are discussed. Recognition of non-VEGF contributions to disease pathogenesis may lead to novel therapeutics to enhance existing treatments for patients who do not respond to anti-VEGF therapies.

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Comparative single-cell RNA-sequencing profiling of BMP4-treated primary glioma cultures reveals therapeutic markers.

Project description:BackgroundGlioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4.MethodsCell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly-sensitive to BMP4 (high therapeutic efficacy) and one with low-sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures.ResultsHigh variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was up-regulated within one day in cultures that were very sensitive to BMP4.ConclusionThe changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.

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2023-07-21 | GSE219148 | GEO

Gene expression profiling reveals distinct features of various porcine adipose tissues.

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