In vivo Therapeutic Inhibition of the Tp53-Induced Glycolysis and Apoptosis Regulator (TIGAR) by Intravenous Administration of an Anti-Oncological siRNA-Biopolymer, TI6752 (Tituxistatin), in a Preclinical Xenograft Model of Colorectal Cancer.

INTRODUCTION: The TP53-induced glycolysis and apoptosis regulator (TIGAR) is upregulated in many cancers and often correlates with poor clinical prognoses and serves as a key determinant of therapy-responsiveness. The TIGAR protein is structurally nearly identical to the phosphatase subunit of the bifunctional, fructose-6-phosphokinase/fructose-2,6-bisphosphatase, which has likely hindered efforts to date to develop small-molecule pharmacological inhibitors of TIGAR.

PURPOSE: The objective of this study was to investigate the efficacy of a siRNA-tigar-biopolymer, TI6752 (Tituxistatin), to therapeutically inhibit tumorigenesis in an in vivo xenograft model of colorectal cancer.

MATERIALS AND METHODS: The overexpression of TIGAR within K-Ras+ tumor cells and the infiltration of PECAM-1+ endothelial progenitors in primary colorectal carcinoma clinical samples were detected by immunoconfocal microscopy. Immunodeficient NIH III-nude mice were subcutaneously engrafted with HCT116 colon cancer cells and then treated with three doses of TI6752 (1 mg/kg bw) or a Vehicle control, administered intravenously at weekly intervals. The animals were humanely sacrificed and HCT116 cells within the tumor tissues were visualized using an Anti-human Ki67 primary antibody. The accumulation of biotin-labeled TI6752 within preexisting HCT116 tumor tissues, compared to other secondary organs (heart, liver, kidneys), was visualized using an AlexaFluor488-conjugated Anti-Biotin primary antibody.

RESULTS: We have shown that TIGAR is highly expressed in K-Ras+ colorectal carcinoma clinical samples and correlates with robust angiogenesis. Using a preclinical HCT116 xenograft model of colorectal carcinoma, we have demonstrated that therapeutic IV-administration of a pegylated siRNA-biopolymer, TI6752, inhibited tumor growth and reduced the infiltration of PECAM-1+ endothelial progenitors into xenograft tumor tissues without causing any adverse secondary effects.

CONCLUSION: This study has demonstrated that IV-delivery of a pegylated siRNA-biopolymer, TI6752, targeted against tigar mRNA transcripts, effectively inhibited tumor growth and angiogenesis in an HCT116 xenograft model of colorectal carcinoma. TI6752 could represent a effective therapeutic approach to target TIGAR's pro-oncogenic functions in human cancers.