Angiogenic Switch in Patients With Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colon Cancer,Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2161751 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:The primary objective of the two phase PERMAD trial is the evaluation of the impact of a personalized marker-driven treatment approach with early detection of progression and modification of treatment on cytokines and angiogenic factors (CAF) and efficacy.
In regard of the two parts, the primary objective of the run-in phase (n=50 patients) with conventional switch of chemotherapy together with the anti-angiogenic agent is the determination of a distinct cytokines and angiogenic factor (CAF) profile during treatment with FOLFOX and bevacizumab, which allows early detection/prediction of progressive disease. The primary objective of the marker-driven randomized part (n=150 patients) with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy is the evaluation of the efficacy of an early marker-driven switch of anti-angiogenic treatment (bevacizumab to aflibercept)
This is a multicentre, multinational, open labeled, prospective, randomized, controlled phase II study designed to assess the clinical utility of an early marker driven change of anti-angiogenic treatment (bevacizumab to aflibercept) maintaining the chemotherapy backbone until definite radiological progression in first line treatment of patients with metastatic colorectal cancer. After completing the run in phase of the study, with at least 30 patients completing their first line treatment (due to progression, secondary resection or toxicity) and being evaluable for CAF analyses, the results will be reviewed by an Independent Data Monitoring Committee (IDMC). Based on that review the decision to continue with, modify or cancel the randomized part will be made.
The primary endpoint of the run-in phase with conventional switch of chemotherapy together with the anti-angiogenic agent is:
• Progression free survival (PFS1) of first line treatment
The primary endpoint of the randomized part with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy is:
• Progression free survival rate at 6 months (PFSR@6) after first cycle after randomization.
| 2181422 | ecrin-mdr-crc
Project description:Naba A, Clauser KR, Mani DR, Carr SA, Hynes RO. The angiogenic switch, the time at which a tumor becomes vascularized, is a critical step in tumor progression. Indeed, it has been demonstrated that without blood supply, tumors will fail to grow beyond 1mm3 and are unlikely to disseminate. The extracellular matrix (ECM), a major component of the tumor microenvironment, is known to undergo significant changes during tumor progression and, in particular, during angiogenesis. However the extent of these changes remains unknown. In this study, we used quantitative proteomics to characterize the composition of the ECM of pancreatic islets in a transgenic mouse model of insulinoma characterized by a precisely timed angiogenic switch. Out of the 120 ECM proteins quantified, 35 were detected in significantly different abundance as pancreatic islets progressed from being hyperplastic to angiogenic to insulinomas. Among these, the core ECM proteins, EFEMP1, Fibrillin 1 and periostin were found in higher abundance, and decorin, Dmbt1, hemicentin and Vwa5 in lower abundance during tumor progression. The angiogenic switch being a common feature of solid tumors, we propose that some of the proteins identified represent potential novel anti-angiogenic targets. In addition, we report here the characterization of the ECM composition of normal pancreatic islets and propose that this could be of interest for the design of tissue engineering and regenerative strategies for treatment of diabetes.
| MSV000080124 | MassIVE
Project description:Angiogenesis represents a rate-limiting step during tumor progression. Molecular mechanisms driving tumor angiogenesis (e.g. implicating signaling by VEGFs and their receptors) have been elucidated and allowed to design targeted therapies. However, limits of such anti-angiogenic therapies have emerged, notably because tumor cells adapt and tumors recur in more aggressive fashions. There is therefore a need to identify novel mechanisms implicated in tumor angiogenesis that have a potential towards translational applications. Using a transgenic murine model of pancreatic neuroendocrine cancer (Hanahan, Nature 315, 1985) where angiogenesis represents an early and discrete step of multi-stage tumor progression (Folkman et al. , Nature 339, 1989), we compared non-angiogenic and angiogenic early tumors to obtain a comprehensive description of the tumor angiogenic switch at the level of gene expression.
2015-01-01 | GSE51637 | GEO
Project description:Wnt/beta-catenin activated Ewing sarcoma cells promote the angiogenic switch
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Project description:The combination of FOLFOX and bevacizumab (FOLFOX-Bev) is a promising treatment for advanced colorectal cancer (CRC). To gain insights into the cellular changes associated with FOLFOX-Bev treatment, we conducted single-cell transcriptomic analysis of CRC samples derived from a patient before and after treatment. Our results show that cancer cells with high proliferative, metastatic, and pro-angiogenic properties respond better to FOLFOX-Bev treatment. Moreover, FOLFOX-Bev enhances CD8+ T cell cytotoxicity, thereby boosting the anti-tumor immune response. Conversely, FOLFOX-Bev impairs the functionality of tumor-associated macrophages, plasma cells, and cancer-associated fibroblasts, leading to a decrease in VEGFB-mediated angiogenesis. Furthermore, FOLFOX-Bev treatment reset intercellular communication, which could potentially affect the function of non-cancer cells. Our findings provide valuable insights into the molecular mechanisms underlying the response of advanced CRC to FOLFOX-Bev treatment and highlight potential targets for improving the efficacy of this treatment strategy.
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Project description:Wnt/beta-catenin signaling is active in small subpopulations of Ewing sarcoma cells and these cells display a more metastatic phenotype, in part due to antagonism of EWS-FLI1-dependent transcriptional activity. Importantly, these beta-catenin-activated Ewing cells also alter secretion of extracellular matrix (ECM) proteins. We thus hypothesized that, in addition to cell autonomous mechanisms, Wnt/beta-catenin-active tumor cells might contribute to disease progression by altering the tumor microenvironment (TME). Activation of canonical Wnt signaling leads Ewing sarcoma cells to upregulate expression and secretion of pro-angiogenic ECM proteins, collectively termed the angiomatrix. Here we tested the role of Wnt-related TGF-beta signaling in angiomatrix induction by obtaining mRNA from Wnt3a-treated TC32 cells in the presence and absence of SB505124, a chemical inhibitor of TGF-beta receptor 1 (TGFBR1) and subjecting it to short read RNA-sequencing.
2020-06-23 | GSE124523 | GEO
Project description:The gene expression profiles of two groups of triplicate human glioblastoma (GBM) xenografts grown in immunodeficient rats were compared. The first group of xenografts was derived from a patient biopsy with Epidermal Growth Factor Receptor (EGFR) amplification which grows highly invasive and is independent of angiogenesis. The second group was obtained by introducing a dominant-negative EGFR mutant into the tumor cells, leading to a progression of the tumors to an angiogenic phenotype associated with a transition from a proneural to a mesenchymal GBM molecular subtype.
2017-07-05 | E-MTAB-4898 | biostudies-arrayexpress
Project description:The Goal of this study is to explore the transcriptional differences between angiogenic and non-angiogenic tumors generated in Dr. Folkman's Lab, Harvard Medical School.<br>Referneces:<br>Almog N, Henke V, Flores L, Hlatky L, Kung AL, Wright RD, Berger R, Hutchinson L, Naumov GN, Bender E, Akslen LA, Achilles EG, Folkman J.<br>Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis.<br>FASEB J. 2006 May;20(7):947-9.<br><br>Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E, Watnick RS, Straume O, Akslen LA, Folkman J, Almog N.<br>A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype.<br>J Natl Cancer Inst. 2006 Mar 1;98(5):316-25.<br>
2009-02-03 | E-TABM-390 | biostudies-arrayexpress
Project description:In response to vascular injury, early EPC or Circulating angiogenic cells (CAC) are thought to be recruited to the damaged areas, participating mainly in a paracrine fashion, by releasing pro-angiogenic factors, promoting the mobilization of other cell populations such as the late EPC, or endothelial colony-forming cells (ECFC). ECFC will help by replacing the damaged endothelium and promoting neovascularization. Unfortunately, however, despite the regenerative role, the number and function of EPC are severely affected under pathological conditions, making compulsory to better understand how these cells react under those environments in order to implement their use in regenerative cell therapies. Herein we evaluated, for the first time to our knowledge, the effect of atherosclerotic factors over the paracrine role of CAC, by direct incubation ex vivo of healthy CAC with the secretome of atherosclerotic arteries. The application of a label free proteomics approach allowed the identification of 194 altered proteins in the secretome of pre-conditioned CAC, many of them related, among others, with inhibition of angiogenesis and cell migration. Functional assays corroborated that, after atherosclerotic pre-conditioning, the pro-angiogenic effect of CAC over ECFC was impaired, affecting ECFC migration as well as their ability to form tubules on a basement membrane matrix assay. Up-regulation of several anti-angiogenic proteins in the CAC secretome could help to explain such angiogenic switch which, in turns, could reflect a protective and beneficial effect against the atherosclerotic process.
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