Abstract No. 2 - Inhibition of the PI3K/AKT/mTOR pathway prevents thermal ablation induced accelerated intrahepatic tumor growth in an orthotopic model of hepatocellular carcinoma

Abstract

Preliminary studies have shown that thermal ablation of liver accelerates local intrahepatic hepatocellular carcinoma (HCC) growth. Additionally, the PI3K/AKT/mTOR pathway has been shown to play a critical role in HCC cell survival, proliferation and resistance to heat stress in vitro. The aim of the present study was to test the hypothesis that inhibition of PI3K/AKT/mTOR pathway prevents thermal ablation induced accelerated local intrahepatic HCC progression. In an IACUC-approved study, Sprague-Dawley rats were randomized to receive the oral PI3K/mTOR inhibitor NVP-BEZ235 (25mg/kg; N = 13) or vehicle control (NMP/PEG; N = 13) on a 2-dose schedule: 1 hour prior to ablation and 24 hours post-ablation. 3x10^6 N1S1 HCC cells were inoculated into the median hepatic lobe of each rat. Rats were then randomized to receive immediate laser thermal ablation at 3W for 90s (N = 14) or sham ablation (N = 12) of normal liver in the same hepatic lobe. Tumor growth was monitored by T2-weighted magnetic resonance imaging (MRI) 18 days post-ablation. Tumor volumes calculated from MR images and compared between treatment groups (vehicle + sham, vehicle + ablation, BEZ235 + sham, BEZ235 + ablation) There was no significant difference in tumor volume among sham treated rats that received vehicle (vehicle + sham) or BEZ235 (BEZ235 + sham) (p>0.05). Thermal liver ablation induced accelerated HCC tumor growth in the vehicle + ablation compared to the vehicle + sham group by day 18 post-ablation (3843 ± 565 mm3 v. 2066 ± 611 mm3, respectively; p = 0.04). However, treatment with the dual PI3K/mTOR inhibitor prevented accelerated HCC tumor growth in the ablation group (BEZ235 + ablation) compared with the sham group (BEZ235 + sham) (1730 ± 565 mm3 v.1737 ± 611 mm3; p >.05). These data suggest that PI3K/AKT/mTOR signaling may mediate accelerated local HCC progression caused by thermal ablation of liver and that inhibition of this pathway may prevent thermal ablation induced accelerated tumor growth. Further pre-clinical studies in this model are needed to optimize the drug dosing and schedule for clinical translation.