Woodchuck hepatocellular cancer (HCC): a translational model for developing anti-angiogenic therapies for human hepatocellular cancer

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HCC is a lethal, vascular endothelial growth factor (VEGF) driven cancer that frequently occurs in patients with chronic hepatitis B virus (HBV) infection. The woodchuck model of HCC is appealing since it shares many of the characteristics of human HCC. At birth, woodchucks were innoculated with standardized quantities of woodchuck hepatitis virus (WHV) derived from infectious pools of serum from chronic WHV carrier woodchucks. By 12 months, the chronic WHV infection rate was 60% or higher. WHV carriers develop HCC at a median age of 24 months. We characterized the extracellular matrix (ECM), basement membrane (BM) and angiogenic pathway changes during HCC progression in woodchucks and have developed imaging methods to screen anti-angiogenic therapies such as sunitinib. Liver specimens were stained with antibodies specific for VEGF-activated endothelial cells, VEGFR2, PECAM1, collagen IV, laminin, and fibronectin. Tumor blood flow and size was assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). After a single oral dose of sunitinib at 4 dose levels (2, 6, 12 and 20mg/kg), plasma samples were collected for pharmacokinetic (PK) assessment of the drug and its active metabolite SU 12662 (n=3 per group). Histologically, human and woodchuck HCC were similar. DCE-MRI protocols used in humans were standardized for assessment of HCC size and vascularity in woodchucks. HCC development was associated with an increase in the number of laminin and PECAM1 expressing vessels, increased VEGFR2 expression, increased ligation of VEGF to VEGFR, and a decrease in the number of collagen IV-positive blood vessels. In contrast, fibronectin expression was abundant throughout the livers of each group during HCC progression. Sunitinib C_max and AUC increased proportionally with dose; T_1/2 was 14-200Hr. Total sunitinib concentrations were >IC₅₀ for VEGF inhibition at doses > or = 6mg/kg; simulations showed that 12mg/kg daily appear optimal to achieve steady state concentrations between 50- 100ng/ml in woodchucks. The woodchuck is a useful model for assessing angiogenesis and developing new therapies in human HCC. (Supported by the Roswell Park Alliance Foundation)