Final Report Summary - RESTART (Refined screening for novel targets in the tumor vasculature) 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 current project was aimed at using Next Generation Sequencing (NGS) to identify the population of genes specifically expressed in primary prostate carcinoma and its metastases. Subsequently, this population of genes was screened for markers that are re-used during angiogenesis, and consequently overexpressed in the tumor endothelium. Prioritization of targets was 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 was done through loss- and gain-of-function assays. The NGS screen of metastasis RNA and the entire adult pool of RNA was performed and compared with the transcriptome of tumor endothelial cells. Fourteen (14) genes were found to be specific marker of tumor endothelial cells. One of these genes was PR-1, the growth factor receptor, known for binding of PR-1 ligand. Although the project was terminated early, a large amount of findings on PR-1 was achieved. These results identified PR-1 as an attractive target for anti-angiogenic targeting of a broad array of solid tumors. Future directions are to produce monoclonal antibodies against the other identified target molecules and to test them in the preclinical murine models. The long-term goal of this research line is to develop a new effective treatment approach for cancer.In order the spread awareness of RESTART, a dedicated project website was built. The RESTART website, through which general information on RESTART is made available, plays a crucial role in the dissemination of the project activities.
