Abstract 3959: PRDM14 silencing by siRNA combined with an innovative nanoparticle reduced breast tumor formation and metastasis in vivo

Abstract

Abstract Triple negative breast cancer (hereafter TNBC) exhibits resistant to chemotherapy and radiotherapy, and develops distant metastases. Conventional treatments have had little impacts on TNBC. PRDI-BF1 and RIZ (PR) domain zinc finger protein 14 (PRDM14) is specifically expressed in embryonic stem cells (ESC) and primordial germ cells (PgC), and is required for the maintenance of ESC pluripotency and early differentiation in PgC. There is no expression of PRDM14 in the non-cancerous tissues, however PRDM14 is expressed in ~50% of TNBC, approximately. PRDM14 conferred the ability of resistance to chemotherapy, tumorigenicity and metastasis, in other words ‘cancer stemness', on cancer cells (Taniguchi H, et al. Oncotarget 2017). PRDM14 was localized in nucleus, then we planned to develop an oligonucleotide therapeutics against PRDM14. Our therapeutic methods are built on clinical application of basic science and technologies. #1. Methods of design the siRNA sequences with higher selectivity to its target and elimination off-target effects. #2. RNA-DNA chimera modification of small interfering RNA (chimera siRNA) exhibited stability in the bloodstream and low immunogenicity. #3. A polyion complex (PIC) nanocarrier exhibited high retention in blood, and accumulated siRNA in targeted cancer tissues, not in liver and spleen, due to the enhanced permeability and retention effect compared with typical nanocarriers, such as Lipid Nanoparticle. Mice were orthotopically grafted with PRDM14+ HCC1937 (TNBC) cells. We also injected PRDM14+ MDA-MB-231 (TNBC) cells into mice via the tail vein for lung metastasis. PRDM14-specific chimera siRNA (1mg/kg) mixed with a PIC nanocarrier (N/P ratio = 5) was injected into mice tail vain 3 times a week for a month, after the HCC1937 tumor reached over 100mm3. This treatment caused 50.3% reduction of mean relative tumor volume, 98% reduction by synergistic effect with docetaxel (3.0mg/kg), and almost no lung metastatic lesions of MDA-MB-231 cells without any adverse effects. GLP toxicology studies of PRDM14-specific chimera siRNA mixed with a PIC nanocarrier in female rats and monkeys showed no severe toxicity at 0.2, 1, or 2 mg/kg/day, twice a week for 4 weeks. Concomitant PK/TK studies revealed much higher exposure for PIC formulated siRNA than that for naked siRNA. Cmax was14900 ± 3200ng/ml, and AUC0-24h was 3730 ± 790 ng·h/mL for PIC formulated siRNA at 1mg/kg at day25.Naked siRNA was only detectable in plasma of animals for 2 h after administration of 1 mg/kg. We plan to submit an academic IND for First time in a human Phase I clinical trial for TNBC after finishing further extensive formulation works in 2019. Citation Format: Hiroaki Taniguchi, Chiharu Moriya, Shiro Akinaga, Kozo Imai, Kazunori Kataoka. PRDM14 silencing by siRNA combined with an innovative nanoparticle reduced breast tumor formation and metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3959.