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UK-Förderung (344.331 £): Ersatz von murinen Transplantationsassays durch 3-dimensionale in vitro Ersatzstoffe zur Beurteilung des therapeutischen Ansprechens von Krebsstammzellen. Ukri20.01.2014 Forschung und Innovation im Vereinigten Königreich, Großbritannien
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Ersatz von murinen Transplantationsassays durch 3-dimensionale in vitro Ersatzstoffe zur Beurteilung des therapeutischen Ansprechens von Krebsstammzellen.
| Zusammenfassung | The main objective of the proposed work is establishment of validated in vitro systems that allow replacement of murine transplantation for assessment of cancer therapeutics. Many millions of mice continue to be used worldwide for assessment of the therapeutic responses of cancers; in the UK alone, nearly half a million mice were used in 2010 for non-toxicological cancer research. Several developments in cancer research are now predicted to increase further the use of murine transplantation. These include new emphasis on the heterogeneity of tumour cell responses to therapeutics and on the roles of cancer stem cells and of epithelial to mesenchymal transition (EMT) in therapeutic resistance and tumour recurrence. A new development is the increasing clinical interest in "personalized tumour grafts" for prediction of the therapeutic responses of individual patient tumours. This approach is likely to be employed with increasing frequency despite problems of initially establishing tumorgrafts from the patient material and then of the 6-7 months needed to expand the size of the mouse population bearing a tumour up to the 150 or so mice required for the therapeutic testing. In principle, however, personalized tumour therapies could have major therapeutic benefits and development of suitable surrogate in vitro systems would, in addition to replacement of mouse tumorgrafts, provide the advantages of greater rapidity, economy, and patient benefit. Development of an appropriate in vitro environment. The trend towards increasing use of murine assays for therapeutic analyses is due in large part to the increasing importance being placed on the need for testing therapeutic responses in what is considered a physiologically appropriate microenvironment. This is interpreted as one that takes account of both the 3-dimensional nature of in vivo tissues and the important roles of tumour interactions with stromal fibroblasts and other cells. The work contained in this proposal is based on a wide body of evidence indicating that it is now possible to use in vitro technologies to replicate a physiologically appropriate 3-dimensional microenvironment that closely mimics the microenvironment human of tumours in situ and can therefore be effectively and beneficially used to replace in vivo models for early and later stages of drug testing. Analysis of effects of cellular heterogeneity. To fulfil the key objective of reversing current trends towards increasing use of in vivo mouse models, the proposed research will focus on analysis of effects of the in vitro environment on the differing therapeutic responses occurring within sub-sets of cancer cells. Evidence indicates that heterogeneity within carcinomas is related to the existence of at least 3 cellular phenotypes and that each phenotype may respond differently to a given therapeutic agent. The sequential stages of the study will be: (a) to confirm that patterns of cellular heterogeneity present in 3-D organotypic models correspond to those present in tumours in situ, (b) to analyse of the roles of heterogeneity in driving invasion through the 3-D matrix, and assessment of the degree to which mechanisms and signalling pathways in vitro are similar to those controlling EMT processes in tumours in situ, (c) to design, test, and validate a heterotypic 3-D organotypic system providing reproducible measurements of experimentally-induced changes in heterogeneity, (e) to provide a system that is responsive to hypoxia and cytokines, (f) to simplify the geometry of the culture system such that it is amenable to high-throughput analysis, and (g) to provide "proof of principle" that the model is responsive to therapeutic drugs, is relatively inexpensive and rapid, and is therefore commercially viable, both for new drug discovery and for dissection of the actions of existing therapeutics on sub-populations of tumour cells. |
| Kategorie | Research Grant |
| Referenz | NC/L00061X/1 |
| Status | Closed |
| Laufzeit von | 20.01.2014 |
| Laufzeit bis | 19.01.2017 |
| Fördersumme | 344.331,00 £ |
| Quelle | https://gtr.ukri.org/projects?ref=NC%2FL00061X%2F1 |
Beteiligte Organisationen
| Queen Mary University of London |
Die Bekanntmachung bezieht sich auf einen vergangenen Zeitpunkt, und spiegelt nicht notwendigerweise den heutigen Stand wider. Der aktuelle Stand wird auf folgender Seite wiedergegeben: Queen Mary University of London, London, Großbritannien.
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