Cotargeting VEGF and Neuropilins With Bevacizumab and Secreted Wnt Inhibitors in Prostate Cancer
Abstract
The objectives of this proposal are to test hypotheses: 1) WIF1 IgG fusion protein has an additive or synergistic effect with anti-VEGF therapy to inhibit tumor growth and metastasis; and 2) NRP2 is a wnt target gene and predicts prostate cancer progression. The WIF1 IgG fusion protein expression construct was re-engineered with pFUSE-hIgG1-Fc vector, which was suggested to have good stability in plasma and good pharmacokinetic properties. However, the produced WIF1-Fc fusion protein was still cleaved into an about 35 kd fragment. Bioinformatics analysis suggested that the potential cleavage sites are Lys339 and Arg340. Mutagenesis assays are in progress to solve the problem of the WIF1-Fc fusion protein cleavage. In addition, our results showed that Bevacizumab increased Wnt signaling and expression of c-Met and NRP2 protein, leading to increased migration and invasion of PC3 cells. Ectopic expression of WIF1and stable knock-down of NRP2 expression in PC3/LN4 cells decreased cell migration, invasion and tumor growth at the prostate of SCID mice and lymph node metastasis. NRP2 protein levels were elevated in castration-resistant prostate cancer tissues and correlate to LEF1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2013
- Accession Number
- ADA592130
Entities
People
- Blair Christopher
- Noriko Yokoyama
- Xiaolin Zi
Organizations
- University of California, Irvine