Angiostatic compounds have made their way into the daily clinical management of cancer, but their impact on patient survival is rather limited. This is likely due to the fact that most current drugs are antagonists of tumor produced growth factors, a strategy expected to induce drug resistance. A better strategy would be to target the tumor vasculature directly. Several markers of tumor endothelial cells have been described but most of them lack sufficient specificity.
The applicant proposes to use Next Generation Sequencing (NGS) to identify the population of genes specifically expressed in primary prostate carcinoma and its metastases. Subsequently, this population of genes is screened for genes that are re-used during angiogenesis, and consequently overexpressed in the tumor endothelium. Prioritization of targets will be done by (i) level of (over)expression, (ii) membrane expression or secretion and (iii) existence of human ortho/homologs. After initial validation by qPCR in the source transcriptomes used for NGS, further validation of the targets will be done through loss- and gain-of-function assays. For 2-3 targets monoclonal antibodies will be generated. These antibodies will be tested in in vitro angiogenesis bioassays, and applicability will be preliminary tested in a preclinical mouse tumor model. Finally, the human ortho/homologs of the gene will be identified and validated for overexpression in human tumors.
The novelty of the proposed work is the NGS approach for selection of tumor endothelial markers, through screening for high expression in the full tumor transcriptome and absence in healthy full body RNA.
The prior experience of the applicant and the host laboratory will help the current project to succeed in reaching its goals.
In our view, it is feasible to develop a new vascular targeting strategy, ready for translation to clinical testing. The proposed work will strongly reinforce the collaboration between two European institutes.
Field of science
- /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance
- /medical and health sciences/clinical medicine/oncology/cancer
Call for proposal
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