Project Summary
The long-term goal is to develop novel drug therapy for liver cancer, the 2rd leading cause of cancer death
worldwide. Phosphatase and tensin homolog (PTEN), a key tumor suppressor and metabolic regulator, is
frequently mutated/silenced in human liver cancers. Mice with liver-specific knockout (LKO) of Pten develop
progressive steatohepatitis, cirrhosis, and liver carcinoma. The molecular mechanisms and histological
feature in Pten-null mice closely resemble the pathogenesis of non-alcoholic steatohepatitis (NASH) and liver
cancer in humans. Glucocorticoid receptor (GR) critically regulates liver pathophysiology. Literature shows
that GR signaling is largely impaired in human hepatocellular carcinoma (HCC), and our preliminary data
showed that hepatic GR-target genes were markedly down-regulated in liver tumors developed in Pten LKO
mice. However, the roles of hepatic GR in the pathogenesis and treatment of PTEN-deficiency-induced
NASH and liver cancer remain unclear; such knowledge gaps will be bridged by this study. Literature reports
and our preliminary data strongly suggest that activation of GR can not only treat liver cancer, but also protect
against liver injury and liver fibrosis. However, activation of GR in extrahepatic tissues can cause many side
effects that negate the benefits of glucocorticoid (GC) therapy in liver cancer. Bile acid (BA)-drug conjugates
have been successfully developed for liver-specific drug targeting via the liver-specific BA transporter Na+-
taurocholate cotransporting polypeptide (NTCP). We have successfully synthesized two first-in-class cholic
acid (CA) conjugates of dexamethasone (DEX-CA) and verified their NTCP-dependent transport and cellular
activity. The objective of this R03 proposal is to develop DEX-CAs as new prodrug candidates for liver
cancer, and uncover how liver-specific deficiency and activation of GR regulate hepatic gene expression and
the progression from NASH to liver cancer. The central hypothesis is that GR in hepatocytes is essential to
protect against NASH and liver cancer. By decreasing the adverse effects of GCs in extrahepatic tissues and
exerting cytoprotection, anti-inflammation, anti-fibrotic, and anti-cancer effects in the liver, NTCP-mediated
liver-specific GR activators will be a highly novel therapy for NASH-induced liver cancer. Aim 1 will delineate
how gene-dosage-dependent liver-specific deficiency of GR in mice affects the progression from steatosis to
liver cancer induced by Pten deficiency. Aim 2 will delineate how liver-specific activation of GR by DEX-CAs
affects NASH and liver cancer in Pten LKO mice. This R03 proposal is highly innovative because of its
conceptual advances and up-to-date approaches. This study will develop novel DEX-CA conjugates as new
prodrug candidates and the first pharmacological tool for liver-specific activation of GR. It will uncover novel
roles of liver-specific gene-dosage-dependent GR deficiency and activation of GR in the pathogenesis and
treatment of PTEN-deficiency-induced NASH and liver cancer. This will help develop innovative therapy of
NASH and liver cancer via NTCP-mediated delivery of DEX-CA conjugates for liver-specific activation of GR.