CpG-STAT3siRNA for Castration-Resistant Prostate Cancer Therapy
Abstract
Majority of human prostate cancers show STAT3 activation, which promotes more aggressive castration-resistant phenotype. In addition, STAT3 is activated in diverse immune cell associated with prostate tumors. Therefore, STAT3 is a highly desirable target for prostate cancer therapy. Within the first year, we made significant progress developing CpG-siRNA for STAT3 targeting in human prostate cancer cells and in the tumor microenvironment. Our studies using xenotransplanted models of TLR9+ CRPCs validated CpG-STAT3 siRNA as therapeutic approach to induce tumor cell death. In addition, we identified another molecular target, NF- B/RELA, a transcription factor activated downstream from TLR9, which contributes to STAT3 activation. We have also undertaken immunohistochemical studies to compare TLR9 expression and STAT3 activation in both tumor and lymph node specimen from. Our analyses indicated that increased TLR9 levels correlate with higher Gleason grade of prostate cancer specimens. TLR9 expression pattern indicates therapeutic opportunity for targeting not only primary but also disseminated prostate cancer cells in lymph nodes or bones. Finally, all tested prostate cancer patients samples indicated increased infiltration of CD68+ macrophages with increased levels of TLR9 levels and STAT3 phosphorylation. These results underscore the feasibility of using CpG-siRNA strategy to simultaneously target prostate cancer cells and tumor-associated immune cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA590648
Entities
People
- Marcin Kortylewski