A mutation in progenitor cells identified as origin and therapeutic target for cholangiocarcinoma

In recent years, cancer research has been focused on the identification of mutations in genes involved in tumor development. Nevertheless, the molecular pathways that contribute to the progression of the disease remain quite unknown. The journal Nature publishes a paper in which an international team of scientists, led by Nabeel Bardesy, PhD, from the Harvard Medical School, suggests that a mutation in the IDH enzyme (isocitrate dehydrogenase), that occurs in liver progenitor cells, promotes the progression of cholangiocarcinoma, a type of liver cancer. Josep M. Llovet, MD, PhD, ICREA Research Professor at the HCC Translational Research Lab of the Liver Unit at IDIBAPS and Director of Mount Sinai Liver Cancer Program at the Icahn School of Medicine at Mount Sinai (New York) has collaborated in the study together with Daniela Sia, PhD, and Helena Cornellà, members of the same research group.

Intrahepatic cholangiocarcinoma (IHCC) is the second most frequent hepatic neoplasia and represents 10% of liver cancers (around 70,000 new cases per year worlwide). This tumor is difficult to detect in early stages, which means that only 30% of patients are eligible for surgery and for which there is no molecular therapy. In this work researchers have identified that the mutation in IDH, detected in 25% of IHCC cases, induces proliferation of primary liver progenitor cells into cholangiocytes, the epithelial cells of the bile duct where this type of cancer occurs, instead of differentiation into hepatocytes. Moreover, they have discovered that it is an oncogenic mutation, promoting the tumor by itself and, in combination with mutations in the Kras gene, makes the disease much more aggressive. In this investigation has also participated Agios Pharmaceuticals, a biotech company, who has developed a molecular drug that selectively blocks the mutated form of IDH and stops the progression of the disease.

Thus, the study defines the mutated progenitor cells as the origin of this type of cancer and offers a new therapeutic target for the treatment of patients with cholangiocarcinoma, who currently have a very poor prognosis and are resistant to existing therapies.

Article reference:

Mutant IDH inhibits HNF-4a to block hepatocyte differentiation and promote biliary cancer. Supriya K. Saha et al. Nature (2014).