Final Report Summary - GENE (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.
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.
