Enhancing Anti-Breast Cancer Immunity by Blocking Death Receptor DR5
Abstract
As described in the 2008 progress report, the revised hypothesis is that agonist DR5 Ab induced by DNA vaccination will trigger tumor cell apoptosis without compromising T cell activity. The specific aims are to (1)Construct and test DR5 vaccines to induce anti-DR5 Ab, (2) Test the agonist activity of vaccine-induced anti-DR5 Ab, and (3) Amplify anti-tumor activity of DR5 vaccination with novel chemotherapeutics. Using three DNA constructs, phDR5 encoding full length human DR5, phDR5(delta) encoding human DR5 with a premature termination signal in the death domain (aa.1-338) and phDR5ECTM encoding the extracellular and transmembrane domains of DR5 (aa. 1-223), we demonstrated the induction of agonist polyclonal antibodies that inhibited the growth of triple negative breast cancer (TNBC) in vitro and in vivo. Anti-tumor activity of DR5 agonist mAb was amplified when tumor cells were treated simultaneously with MS-275, an inhibitor of histone deacetylase (HDAC), indicating potential therapeutic advantage by combining HDAC inhibitor with DR5 vaccination. Because Her-2 positive and ER positive breast cancers are more resistant to DR5 agonists, the mechanism of resistance was tested. Activation of Akt survival pathway by TRAIL was shown in T47D and OVCA 432 cells. Strategies that block survival pathway may be exploited to amplify DR5 vaccination efficacy in Her-2 or ER positive breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2009
- Accession Number
- ADA514610
Entities
People
- Wei-Zen Wei
Organizations
- Wayne State University