Dual Targeting of Vascular Endothelial Growth Factor-A Together With Angiopoietins in Chemotherapy-naïve Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2098728 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Despite rapid advances in treatment options, challenges still persist in advanced breast cancer. Bevacizumab is a VEGF-neutralizing antibody with proven efficacy in combination with chemotherapy for treatment of HER2 negative metastatic breast cancer (mBC). Vinorelbine, a semisynthetic vinca alkaloid, is a well-established and well tolerated chemotherapeutic in breast cancer. The combination of vinorelbine with platinum and addition of bevacizumab is relatively underreported in the literature. We propose this combination regimen as safe, well tolerated and efficacious in HER2 negative mBC patients.
2024-05-16 | GSE267621 | GEO
Project description:Objective: Insights about differences in tumor vasculature and how it reacts to VEGF inhibition is limited, but nevertheless of major relevance to anti-angiogenic therapy. In this study we therefore characterize the effect of bevacizumab combined with chemoradiotherapy (CRT), and explore molecular and genetic markers for response prediction to this combination treatment. Material and Methods: In an academic multicentric randomized phase II study, patients with advanced rectal cancer have been treated with bevacizumab (5mg/kg) in combination with capecitabine (1650mg/m2/day) and radiotherapy (45Gy; 1.8Gy/day) with (50mg/m2) or without oxaliplatin prior to surgery. Of 59 patients, tumor tissue and blood samples were collected before treatment and after the first loading dose of bevacizumab but before CRT (week 3). First, cDNA micro-arrays were performed on the biopsies to investigate differences in gene expression of tumors from patients with and without a pathological complete response (pCR) before start of treatment and to identify biological processes affected by bevacizumab delivery. The paraffin embedded tissue was stained for blood vessels (CD31/CD34) combined with α-SMA (pericytes) and CA-IX (hypoxia). To explore candidate blood-based biomarkers ELISA’s were performed for PDGF-AA, PDGF-BB, THBS-1, IL-8, CYR61 and Ang-2. The expression of all markers was correlated with the pathological response of the patients. Results: Differences in tumoral gene expression are observed between patients with and without a pCR, with the first response group presenting a more angiogenic phenotype before start of treatment and changes in angiogenic processes after bevacizumab delivery. One dose of bevacizumab leads to a decrease in the number of pericyte covered blood vessels, a decrease in circulating PDGF-AA, PDGF-BB and Thrombospondin-1. Patients showing a pCR having less pericyte covered blood vessels, more hypoxia, and less circulating PDGF-BB compared to patients who did not have a pCR after bevacizumab treatment with chemoradiation and bevacizumab. Conclusions: The translational data demonstrate that tumors with an angiogenic expression profile respond better to bevacizumab combined with CRT and points towards a possible role for PDGF, CA-IX and pericyte covered blood vessels for the early response prediction to this treatment. Our findings suggest a role for mural cell recruitment and vessel maturation for the susceptibility of the tumor vasculature to bevacizumab treatment. Further validation of our biological observations and hypothesis generating data in randomized trials is needed.
2016-08-02 | GSE60331 | GEO
Project description:The combination of bevacizumab with temozolomide and radiotherapy was shown to prolong progression-free survival in newly diagnosed glioblastoma patients, and this emphasizes the potential of bevacizumab as a glioma treatment. However, while bevacizumab effectively inhibits angiogenesis, it has also been reported to induce invasive proliferation. This study examined gene expression in glioma cells to investigate the mechanisms of bevacizumab-induced invasion. We made a human glioma U87ΔEGFR cell xenograft model by stereotactically injecting glioma cells into the brain of animals. We administered bevacizumab intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology and mRNA was extracted. In vivo, bevacizumab treatment increased glioma cell invasion. qRT-PCR array analysis were perfomed.
2019-02-07 | GSE126168 | GEO
Project description:Objective: Insights about differences in tumor vasculature and how it reacts to VEGF inhibition is limited, but nevertheless of major relevance to anti-angiogenic therapy. In this study we therefore characterize the effect of bevacizumab combined with chemoradiotherapy (CRT), and explore molecular and genetic markers for response prediction to this combination treatment. Material and Methods: In an academic multicentric randomized phase II study, patients with advanced rectal cancer have been treated with bevacizumab (5mg/kg) in combination with capecitabine (1650mg/m2/day) and radiotherapy (45Gy; 1.8Gy/day) with (50mg/m2) or without oxaliplatin prior to surgery. Of 59 patients, tumor tissue and blood samples were collected before treatment and after the first loading dose of bevacizumab but before CRT (week 3). First, cDNA micro-arrays were performed on the biopsies to investigate differences in gene expression of tumors from patients with and without a pathological complete response (pCR) before start of treatment and to identify biological processes affected by bevacizumab delivery. The paraffin embedded tissue was stained for blood vessels (CD31/CD34) combined with α-SMA (pericytes) and CA-IX (hypoxia). To explore candidate blood-based biomarkers ELISAâs were performed for PDGF-AA, PDGF-BB, THBS-1, IL-8, CYR61 and Ang-2. The expression of all markers was correlated with the pathological response of the patients. Results: Differences in tumoral gene expression are observed between patients with and without a pCR, with the first response group presenting a more angiogenic phenotype before start of treatment and changes in angiogenic processes after bevacizumab delivery. One dose of bevacizumab leads to a decrease in the number of pericyte covered blood vessels, a decrease in circulating PDGF-AA, PDGF-BB and Thrombospondin-1. Patients showing a pCR having less pericyte covered blood vessels, more hypoxia, and less circulating PDGF-BB compared to patients who did not have a pCR after bevacizumab treatment with chemoradiation and bevacizumab. Conclusions: The translational data demonstrate that tumors with an angiogenic expression profile respond better to bevacizumab combined with CRT and points towards a possible role for PDGF, CA-IX and pericyte covered blood vessels for the early response prediction to this treatment. Our findings suggest a role for mural cell recruitment and vessel maturation for the susceptibility of the tumor vasculature to bevacizumab treatment. Further validation of our biological observations and hypothesis generating data in randomized trials is needed. This study involves samples of patients enrolled in the AXEbeam trail that were analysed by Primeview microarray (Affymetrix). Biopsies were taken at two different timepoints: before treatment (tumor and normal mucosa) and after the first loading dose of bevacizumab but before chemoradiation (only tumor, week 3). Patients were classified into two groups: with a complete pathological response at time of surgery (Responders=R) or non-responders (NR). For the responders, we collected 21 samples in total (7 tumor samples and 8 normal mucosa samples taken before treatment and 6 tumor samples collected at week 3). From the non-responders we had 26 samples in total (9 tumor and 10 mucosa samples before treatment and 7 tumor samples at week 3 after a single dose of bevacizumab). Microarrays were run in two batches (15xxx versus 16xxx CEL file samples; indicated in the description field). Three samples (NJ 04/003 T1, RVS 09/002 M and NJ 04/003 W3) were put twice on the array (15897+16789; 15893+16790; 15898+16791) to verify and exclude batch effects. Please note that, due to these three technical repeats the total number of microarray CEL files is 50 (21 Responders, 26 Non-responders and 3 repeats).
2016-08-02 | E-GEOD-60331 | biostudies-arrayexpress
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Project description:Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Studies in human MS and its animal model experimental autoimmune encephalomyelitis (EAE) have shown that new abnormal vessels develop in demyelinating plaques through pathological neo-angiogenesis, which exacerbates MS/EAE pathology by contributing to the leakage of serum components and infiltration of immune cells into the CNS. However, the cellular origin and the signaling pathways underlying this pathology remain poorly understood. Here, using single-cell RNA sequencing and validation with in situ hybridization and immunofluorescence, we discovered that neo-angiogenesis is initiated specifically by venous endothelial cells during EAE. Moreover, we identified VEGF-A signaling as the primary driver of neo-angiogenesis in EAE, as treatment with the VEGF-A blocking antibody, bevacizumab, ameliorated the EAE pathology by reducing neo-angiogenesis in vivo. Our findings may lead to the development of novel therapeutics designed to reduce neo-angiogenesis and improve long-term neurological deficits in MS.
2023-03-14 | GSE210776 | GEO
Project description:The mechanisms by which tumors develop resistance to angiogenesis inhibitors, and the relative contributions of tumor cells and stroma to resistance, are not completely understood. We developed three human lung adenocarcinoma murine models of resistance to the VEGF inhibitor bevacizumab and, using species-specific profiling, separately investigated tumor cell and stromal molecules associated with resistance. Gene expression changes associated with acquired resistance occurred predominantly in stromal (mouse) and not tumor (human) cells. Components of the EGFR and FGFR2 pathways were significantly upregulated in stroma, but not in tumor cells. Increased activated EGFR was detected on pericytes of xenografts that acquired resistance and on endothelium of tumors with relative primary resistance. Acquired resistance was associated with a pattern of pericyte-covered, normalized revascularization, whereas tortuous, uncovered vessels were observed in relative primary resistance. Dual targeting of VEGF and EGFR pathways with bevacizumab and erlotinib, or the VEGFR/EGFR inhibitor vandetanib, reduced pericyte coverage and increased progression-free survival. These findings demonstrate that alterations in tumor stromal pathways, including EGFR and FGFR2, are associated with, and may contribute to VEGF inhibitor resistance and that targeting these pathways may improve therapeutic efficacy. Understanding stromal signaling may be critical for developing biomarkers for angiogenesis inhibitors and improving combination regimens.
2011-04-22 | GSE26644 | GEO
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2013-06-01 | E-GEOD-37543 | biostudies-arrayexpress
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