COMBATING β-CATENIN DRIVEN HEPATOCELLULAR CARCINOMA

Hepatocellular Carcinoma (HCC) is the most common primary liver tumor and is a major cause of cancer related death worldwide with few avenues of treatment that benefit patients. There are many causes of HCC making the cancer difficult to treat as a homogenous disease. Many molecular pathways are deregulated during the onset of hepatocarcinogenesis, and one commonly activated signaling cascade in HCC is the Wnt/β-catenin pathway. β-Catenin plays multiple roles in cellular processes from maintenance of cellular adhesions to regulating regenerative signals required for the liver to grow. In cancer, β-catenin signaling is aberrantly regulated and has now been shown to play roles in tumor cell proliferation, survival and metabolism contributing to disease progression. Knowing the prevalence and importance of β-catenin in HCC, it is critical to develop targeted, personalized therapeutics which may impact multiple aspects of tumor biology. Here, we have identified several different avenues that target active Wnt signaling. We demonstrate the importance of computational biology to identify novel small molecules (SMs) to target β-catenin signaling. SM treatment results in decreased β-catenin signaling leading to decreases in downstream targets affecting HCC growth and survival. We also utilized antisense treatments which target β-catenin at the genetic level decreasing β-catenin protein expression and leading to subsequent cell death and decrease in tumor burden. Additionally, we identified angiogenesis as a notable event regulated by Wnt/β-catenin signaling. In fact, inhibiting Wnt signaling in HCC cells led to reduced production of pro-angiogenic secreted factors which in turn inhibited angiogenic characteristics in tumor associated endothelial cells. Our studies validate the significance of targeting β-catenin in HCC that should lead to notable effects on tumor growth and development. With the current studies providing the final proof-of-concept, we now believe that β-catenin directed therapies may in fact be plausible, and have potential clinical implications