BETA-CATENIN AS A THERAPEUTIC TARGET IN HEPATOCELLULAR CANCER

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DESCRIPTION (provided by applicant): Aberrant activation of ¿-Catenin occurs in many cancers including HCC. Although the activation of ¿-catenin in HCC has been shown to be multifactorial, all events converge at ¿-catenin, making it an attractive therapeutic target in HCC. We have shown pro-proliferative effect of ¿-catenin in liver in transgenic mice, liver regeneration, liver development & in hepatocyte cultures. To more efficiently elucidate its role in hepatic biology, we have generated conditional ¿-catenin knockout mice using the cre- lox system. ¿-Catenin floxed mice (Ex2-6) were bred to Albumin-Cre or a-fetoprotein-albumin-Cre mice to generate ¿-catenin conditional null mice: Ctnnb1 loxP/loxp:Alb-Cre OR Ctnnb1 loxP/loxp:aFP-Alb-Cre respectively. Both these mice are born normally & show about 95% loss of ¿-catenin by 2 weeks that persists throughout their normal life span in the former, while 100% loss of ¿-catenin occurs in the latter by 4-5 months and succumb due to diminished liver size & function. In addition, we have recently characterized the normal ¿-catenin over-expressing transgenic (TG) mice under albumin promoter/enhancer. These mice have a higher basal hepatocyte proliferation, with ensuing hepatomegaly. More recently we have generated TG mice that over expresses stable form of ¿-catenin (Ser45 mutated). These mice are being characterized, and demonstrate a more robust phenotype than normal ¿-catenin TG mice. These models give us a unique opportunity to conclusively address the role of ¿-catenin in HCC induction and progression. We propose to employ the DEN/phenobarbital model to investigate hepatocarcinogenesis in absence of ¿-catenin or presence of stable ¿-catenin. In addition, we propose to investigate oval cell activation, a preneoplastic event in liver, in knockout and transgenic mice to assertively address role of ¿-catenin in this event. Lastly, we would explore the role of therapeutic inhibition of ¿-catenin in transgenic models. We have identified role of R-Etodolac (enantiomer of NSAID Etolodolac, lacking cox-2 inhibition) in inhibiting ¿-catenin in hepatoma cells. This drug is in phase-ll clinical trials in refractory CLL. We propose to examine the effect of R-Etodolac in our transgenic mice and in tumor xenograft models in a series of both in vitro and in vivo studies to ascertain its role as an anti- ¿-catenin for treatment or chemoprophylaxis in HCC. Thus this proposal will lay the ground work for initiating clinical studies directed against ¿-catenin in HCC.