Recombinant Fusion Proteins that Convert VEGF into a Cell Death Factor
Abstract
Two current strategies for targeted cancer drug development are inhibition of vascular endothelial growth factor (VEGF) and activation of pro-apoptotic death receptors such as Fas or TRAILR. The VEGF inhibitor bevacizumab has been shown to prolong progression-free survival in cancer patients, including ovarian cancer patients, but it yields little or no improvement in overall survival. Agent such as soluble TRAIL that target cell death receptors are in early clinical trials but to date have limited efficacy, in part because they do not efficiently aggregate and activate death receptors. We have investigated a novel approach to targeted cancer therapy that combines VEGF inhibition and cell death receptor activation. We generated two recombinant fusion proteins, designated R1FasL and R1TRAIL, that combine the VEGF-binding domain of VEGF receptor-1 with the receptor-binding domain of Fas ligand or TRAIL. The homotrimeric fusion proteins bind VEGF and form oligomeric complexes that efficiently bind to, aggregate and activate Fas or TRAIL cell death receptors. We developed reagents and methods to purify the fusion proteins and demonstrated that they induce cell death only in the presence of VEGF, effectively converting VEGF to act as a cell death factor. When tested on human ovarian cancer cell lines in vitro, R1TRAIL induced cell death when VEGF was present. Chemotherapy agents increased the activity of R1TRAIL. Our results indicate that R1TRAIL may provide a new strategy for combined VEGF inhibition and death receptor activation to more effectively kill cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2010
- Accession Number
- ADA549342
Entities
People
- Timothy Quinn
Organizations
- University of California, San Francisco