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DSCR1, anti-angiogenesis drug target against solid tumors with focus on colorectal cancer

Investigators: Heinz-Josef Lenz; Fariborz Nasertorabi

Colorectal cancer is the second leading cause of cancer-related deaths in developed countries and the fourth worldwide. A 60% increase of diagnosed colon cancer is predicted by 2030. Recent statistics has revealed individuals with Down Syndrome have a considerably decreased rate of solid tumor cancers, while they are more prone to leukemia. This observation has drawn scientists’ attention to Chromosome 21, since Down Syndrome individuals carry a full or partial trisomy of this chromosome. The decreased solid cancer tumors in these individuals have been associated with over expression of genes that can be linked to the angiogenesis pathways. The Down Syndrome Candidate Region 1 (dscr1) gene is located on the chromosome 21, and the gene product, calcipressin 1, is demonstrated to play a crucial role in reducing cancer risk by suppressing angiogenesis. DSCR1 modulates the transcription of vascular endothelial growth factor receptor 1 (VEGFR1) through the calcineurin-Nuclear Factor of Activated T cells (NFAT) signaling pathway, thereby controlling VEGF-dependent angiogenesis. Increased expression levels of DSCR1 are linked to and correlate with decreased tumor growth. We have successfully expressed and purified the full-length human DSCR1 gene product and have confirmed its binding to calcineurin in vitro. We are now planning to dissect the calcipressin 1 protein, to identify the shortest druggable peptide of this protein with affinity to calcineurin and with the potential of having a downstream angiogenesis suppression effect on solid tumors. The identified promising peptide/s will be analyzed for efficacy and toxicity, when tested in situ using colorectal cancer cell lines for NFAT phosphorylation level and will be further validated in patient derived xenograft (PDX) animal models, which later can be potentially translated into early clinical trials.