CpG-STAT3siRNA for Castration-Resistant Prostate Cancer Therapy
Technical Report,28 Sep 2012,27 Sep 2015
City of Hope Beckman Research Institute Duarte United States
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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-BRELA transcription factors in xenotransplanted models of TLR9 CRPCs. We demonstrated that blocking TLR9NF-BSTAT3 signaling axis reduces self-renewal and tumor-initiating potential of prostate cancer cells in vivo. Next, we characterizedTLR9phosphoSTAT3 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-DRCD14CD15CD33low 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 TLR9MDSCs 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.