GENE · Genomic screening of the Embryo for Novel targets in the tumor Endothelium
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2013-05-01 → 2015-04-30
- Финансиране от ЕС
- 175 975 €
- Участници
- 1
- Схема
- MC-IEF
Линиите свързват координатора с партньорите.
Накратко на български
Гените, които се активират при развитието на ембриона, се търсят в кръвоносните съдове на туморите. Това помага за откриването на нови мишени за лекарства, които да действат по-точно и да намалят страничните ефекти при пациентите.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Genomic screening of the Embryo for Novel targets in the tumor Endothelium
Angiogenesis is the formation of new blood vessels from pre-existing vasculature. In the healthy body angiogenesis takes place during wound healing or the growth of the endometrium. However, in diseases abnormal angiogenesis may occur. An example is the excess of angiogenesis in cancer, meaning that a tumor actively recruits blood vessels to supply itself with oxygen and nutrients. Currently, there are several angiogenesis inhibitors on the market for treatment of cancer. Most of these drugs target pro-angiogenesis signaling by tumor cells through neutralization of growth factors or by inhibiting kinase activity of growth factor receptors. Although these drugs experience (commercial) success, it is now becoming evident that these agents, in general, only have moderate effect on survival rates of patients. Furthermore, these angiogenesis inhibitors show severe side effects in patients. The aim of this project was to identify novel specific markers of angiogenic tumor endothelium, which we can target with specific drugs. Advantages are that this approach is independent of the growth factor production by tumor cells, which reduces the risk of tumor cell mutation into drug resistant variants. In addition, since the identified targets are specific to the tumor endothelial cells, toxic side effects will be minimized. Our hypothesis was that certain genes with an exclusive function in the embryo also are present in the tumor vasculature. Therefore we have isolated the full transcriptome of mouse embryos at early and late developmental stages, and compared it with adult mouse isolates to identify the embryo-specific genes. Next we screened the transcriptome of tumor endothelial cells for the expression of the found embryo-specific genes. For the genomic screen next generation sequencing was used to maximize the identification of specific genes or splice variants. In our analysis we found 24 candidate genes, which are 100-fold higher expressed in tumor endothelial cells and embryo compared to the adult mouse. We validated the expression of the 10 most promising (extracellular expressed) candidate genes in the source material and continued with three of these targets. Currently, we are testing the targets in in vitro angiogenesis assays and are making vaccines against these targets. Future directions are to test the developed vaccines in preclinical mouse models and to produces monoclonal antibodies against the identified target molecules.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Several angiogenesis inhibitors are in the market for treatment of cancer, but efficiency in terms of prolongation of survival is still very moderate. This can be explained by induction of resistance to therapy, since most agents neutralize tumor produced growth factors.An alternative and preferred strategy would be to directly target the tumor endothelial cells, which will not easily mutate to resist treatment due to genetic stability. It is hypothesized that by mining the pool of genes that have embryo-specific functions, new and fully specific markers of tumor endothelial cells can be found.The approach will be to isolate the full transcriptome of mouse embryos at early and late developmental stages, and compare it with adult mouse isolates. The pool of purely embryo-specific genes will be screened for expression in the transcriptome of FACS sorted tumor endothelial cells. Genomic screening will be performed, by next-generation sequencing, to maximize the identification of specific genes or splice variants. Gene function will be tested by genetic loss- and gain-of-function approaches in in vitro angiogenesis assays. Transmembrane and secreted tumor endothelial specific molecules will receive priority. Endogenous binding partners will be identified by yeast 2-hybrid technology and peptide design will yield specific drugs. Also, antibodies against target molecules will be generated. Initial preclinical testing will be part of this project. Translation of the technology for treatment of patients, i.e. finding the human orthologs, and extensive preclinical testing will be beyond the scope of this project and will be subject of a new grant application.""
Оригинален текст от CORDIS (на английски).
Участници
- STICHTING VU · AmsterdamКоординаторНидерландия
Връзки
Данни: CORDIS, © Европейски съюз