Cholangiocarcinoma (CCA) is a devastating disease with a 5-year survival rate of 2%. The incidence of CCA has increased almost two-fold over the last three decades in the United States, and as such, there is an urgent need to find effective therapies for this lethal disease. Understanding the molecular pathogenesis of CCA development may lead to strategies for intervention and treatment. Recently, IDH1 and IDH2 mutations have been identified in about 20% of CCA patients. IDH1 and IDH2 mutations, which generate an oncometabolite--2-hydroxyglutarate (2-HG) rather than 2-oxoglutarate (2-OG), have been suggested to be the possible cause for CCA development and progression by altering epigenetic modifications. Several small molecule inhibitors (SMIs) developed aiming to target IDH1 and IDH2 mutations for suppressing 2-HG production have undergone clinical trials in treating CCA and other cancers with these mutations. Nevertheless, there is still no potential therapy for those 80% of CCA patients with wild-type (WT) IDH1/2. Additionally, it has been shown that CCA patients with IDH1/2 mutations have a better prognosis than those with WT IDH1/2, suggesting that the 2-OG-mediated pathway may be required for the CCA malignant progression in the 80% of CCA patients. Our exciting preliminary data show that TET1 is heavily involved in CCA malignant progression by targeting cell growth, apoptosis, and DNA damage in CCA cells in vitro and in vivo. With these strong preliminary data, we highly speculate the involvement of TET1 in the phenotype that CCA patients with IDH1/2 mutations have a better prognosis than those with WT IDH1/2. Thus, our central hypothesis is that the 2-HG produced by IDH1/2 mutation suppresses CCA progression by targeting TET1 enzymatic activity. We propose two aims to validate or refute our hypothesis. We propose two aims to validate or refute our hypothesis. In aim 1, we will investigate the molecular mechanisms by which TET1 modulates CCA malignant progression by using RNA sequencing and ChIP sequencing. In aim 2, we will determine how TET1 is involved in IDH1/2 mutation mediated CCA progression by using the service of Computational Biology core at the Brown University for analyzing RNA sequencing and TCGA data.
Cholangiocarcinoma (CCA) is a devastating disease with a 2% 5-year survival rate if the disease spread outside the liver, suggesting there is an urgent need to develop effective therapies. The IDH1 mutation has been identified in about 20% of CCA patients but those patients have a better prognosis than ones with wild-type IDH1. Investigating how TET1 is involved in the observed phenotype may clarify the how this occurs and identify a potential therapy for CCA patients.