Page 168 - ebook HCC

166 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 167
FEBRUARY 13 - 16, 2014

BETA-CATENIN IN HEPATOCELLULAR CANCER: NOTES
BASIS OF PERSONALIZED MEDICINE

Satdarshan P. Monga 1
1 Department of Pathology, University of Pittsburgh, Pittsburgh, United States
Corresponding author’s e-mail: rohallta@upmc.edu

Activation of Wnt signaling due to various reasons has been observed in a significant
subset of hepatocellular cancer (HCC) patients. In fact around 60% of HCC patients
display aberrant beta-catenin localization in the form of nuclear and/or cytoplasmic
staining. Around 1/3 of these patients, exhibit point mutations in exon-3 of CTNNB1,
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while others are more heterogeneous displaying mutations in AXIN1/2, silencing of Wnt
inhibitors or enhanced Wnt/Frizzled expression. Since b-catenin activation is associated
with enhanced expression of target genes that encode for proteins critical in tumor cell
proliferation, survival, metabolism, angiogenesis and cancer stem cell maintenance and
expansion, its therapeutic inhibition in a select group of patients is expected to be of high
translational value. Since b-catenin is also important in maintaining adherens junctions
(AJ) in the epithelial cells, we have shown its knockdown by various modalities to not
adversely impact AJ integrity due to compensation by gamma-catenin that maintains
contact with E-cadherin. However, b-catenin cannot be unequivocally targeted in every
CLINICAL SPEAKERS ABSTRACTS exposure. Hence the treatment will need to be personalized with identification of a correct CLINICAL SPEAKERS ABSTRACTS
HCC since enhanced liver injury and paradoxical increase in HCC was observed in
hepatocyte-specific b-catenin conditional knockout mice following chemical carcinogen-
subset of patients. Immunohistochemistry, when feasible, may identify such patients
with concomitant nuclear b-catenin and tumor-wide staining of its target Glutamine
Synthetase. Once identified, b-catenin inhibition is predicted to have significant therapeutic
consequences based on several proof-of-concept in vitro studies using HCC cell lines.
Using previously characterized mouse model that induces HCC via CTNNB1 mutations,
we now show that b-catenin knockdown after tumor development has a dramatic impact
on tumor growth such that majority of mice showed no evidence of HCC. Additional small
molecule has also been identified that affects beta-catenin signaling in several HCC cell
lines as well as in vivo in a Wnt reporter zebrafish. Thus, we demonstrate in vivo efficacy
of b-catenin therapeutic inhibition as a treatment option in HCC.