Abstract 3252: Anti-tumor effect of the combination of a lipid nanoparticle suspension of an AKT-1 antisense oligonucleotide (WGI-0301) with tyrosine kinase inhibitors in an orthotopic murine tumor model

Abstract Background: Archexin is a fully phosphorothioated 20-mer antisense oligonucleotide, complementary to AKT-1 mRNA, which leads to the inhibition of translation and the downstream pathway activities of AKT-1 mRNA. WGI-0301 is a proprietary lipid nanoparticle formulation (QTsomeTM) of Archexin designed to enhance delivery. A phase I clinical study of WGI-0301 as monotherapy in patients with advanced solid tumors is currently ongoing in the U.S. Given the limited efficacy of TKIs compared to immunotherapy and growing incidence resistance, WGI-0301 combined with TKIs may augment the therapeutic response to TKIs by enhancing angiogenic blockade, inhibiting AKT-1, and overcome resistance. Methods: The anti-tumor effect of combining WGI-0301 with Lenvatinib/Sorafenib/Cabozantinib was assessed using a Hep3B-Luciferase orthotopic mouse tumor model. We divided sixty-four female Balb/c nude mice into groups (8 mice per group), including vehicle control, WGI-0301 (8 mg/kg), Lenvatinib (10 mg/kg), Sorafenib (20 mg/kg), Cabozantinib (20 mg/kg), WGI-0301+Lenvatinib (8+10 mg/kg), WGI-0301+Sorafenib (8+20 mg/kg), and WGI-0301+Cabozantinib (8+20 mg/kg). We administered treatments via tail vein injection (vehicle/WGI-0301, QW4 weeks) or oral administration (Lenvatinib/Sorafenib/Cabozantinib, QD28 days). We monitored body weight twice weekly and measured tumor burden using bioluminescence with an IVIS (Lumina III) imaging system twice weekly as well. Treatment was suspended between Day 29 and Day 70 for survival observation. Results: The tumor growth inhibition (TGI) rates of the combination of WGI-0301 with Lenvatinib/Sorafenib/Cabozantinib were 66.05%, 86.81%, and 75.89%, respectively. These values were higher than those of the Lenvatinib/Sorafenib/Cabozantinib single drug group with TGI rate of 50.84%, 55.68%, and 47.84%. The tumor bioluminescence signal intensities of the two drugs combination (56.74*108, 22.28*108, and 40.40*108 photon/s) were slightly lower than that of the Lenvatinib/Sorafenib/Cabozantinib single drug group (81.97*108, 73.95*108, and 86.96*108 photon/s). The median survival time was 35.0, 46.0, 55.5, and 51.5 days in the vehicle, WGI-0301+Lenvatinib, WGI-0301+Sorafenib and WGI-0301+Cabozantinib, respectively. The median survival time of Sorafenib, the two-drug combinations were 55.5, 55.5, 58.0, and 53.5 days, which was significantly prolonged compared to the vehicle in the mice bearing the Hep3B-luc orthotopic tumor model. No severe adverse effects were observed in the drug combination groups. Conclusion: The combination of WGI-0301 with TKIs demonstrated superior anti-tumor efficacy over TKI monotherapy in the absence of substantial increase in toxicity. This finding warrants further robust clinical investigation in patients with advanced HCC. Citation Format: Fengyang Xie, Tao Lin, Chao Wang, Jia Wei, Robert J. Lee, Ben Zhao, Yuxin Angela Men. Anti-tumor effect of the combination of a lipid nanoparticle suspension of an AKT-1 antisense oligonucleotide (WGI-0301) with tyrosine kinase inhibitors in an orthotopic murine tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3252.