CpG-STAT3siRNA for Castration-Resistant Prostate Cancer Therapy
Abstract
Majority of human prostate cancers activate STAT3 signaling which is associated with progression to castration-resistant phenotype. STAT3 is also activated in diverse immune cell associated with prostate cancers. Therefore, STAT3 is a highly desirable target for prostate cancer therapy. Within the three years of funding, we have completed feasibility studies using CpG-siRNA strategy to target tumorigenic STAT3 and NF-B/RELA transcription factors in xenotransplanted models of TLR9+ CRPCs. We demonstrated that blocking TLR9/NF-B/STAT3 signaling axis reduces self-renewal and tumor-initiating potential of prostate cancer cells in vivo. Next, we characterizedTLR9+/phosphoSTAT3+ immune cell populations in CRPC patients. The comparison of blood samples from healthy, localized- and metastatic-stage patients found accumulation of granulocytic myeloid-derived suppressor cells (G-MDSCs; LinHLA-DRCD14CD15+CD33low) with progression of the disease. The G-MDSCs in prostate cancer patients expressed TLR9 and showed high levels ofSTAT3 activation which correlated with their ability to suppress T cell proliferation in vitro. We found that STAT3 induced expression of arginase which was mainly responsible for tolerogenic functions of MDSCs and we demonstrated that targeting STAT3 signaling in TLR9+MDSCs using CpG-siRNA restores T cell proliferation. Finally, we completed feasibility studies demonstrating that local intratumoral injections of CpG-STAT3siRNA result in systemic antitumor immune responses and inhibit growth of distant tumor lesions.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2015
- Accession Number
- AD1007321
Entities
People
- Marcin Kortylewski