Past studies have linked two mutant proteins, inisocitrate dehydrogenase 1 (IDH1) and IDH2, as among the most common genetic differences in intrahepatic cholangiocarcinoma (iCCA), and new research has now identified why. In genetically engineered mouse models of adult livers, the expression of those IDH1 and IDH2 mutations impaired liver cell development and liver regeneration, and increased the number of cells, leading to tumor formation, according to the data, published in Nature (2014:513;110-114).
"iCCA is resistant to standard treatments like chemotherapy and radiation," said one of the coauthors, Josep Maria Llovet, MD, Director of the Liver Cancer Program at Icahn School of Medicine at Mount Sinai. "Understanding the molecular mechanism of the disease is key to finding a treatment that works."
Previous research has shown that mutant IDH proteins in ICCA and other malignancies acquire an abnormal enzymatic activity, resulting in alterations in cell differentiation, survival, and extracellular matrix maturation, according to the study. The data from this research showed that in the mouse models, IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2-hydroxyglutarate (2HG) and suppression of the master transcriptional regulator of hepatocyte differentiation, HNF-4[alpha].
The mouse models expressing mutant IDH in the adult liver also showed an abnormal response to hepatic injury, characterized by HNF-4[alpha] silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation, according to the study.
The results showed that mutant IDH worked with the KRAS gene to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic iCCA.
The findings provide new insights about the development of iCCA, which could inform novel treatment options, Llovet added. Phase I trials are currently ongoing for patients with iCCA with specific IDH1/2 mutations.
The study was conducted through partnerships with Massachusetts General Hospital Cancer Center; the Department of Medical Oncology at Dana-Farber Cancer Institute; the Department of Medicine at Harvard Medical School; HCC Translational Research Laboratory of Barcelona-Clinic Liver Cancer Group of the Liver Unit at Institut d'Investigacions Biomediques August Pi i Sunyer; Hospital Clinic at University of Barcelona; the Gastrointestinal Surgery and Liver Transplantation Unit of the National Cancer Institute; the Department of Experimental Oncology in Milan, Italy; the Department of Pharmacology, Toxicology and Therapeutics at the University of Kansas Medical Center; the University of Rochester Medical Center; Agios Pharmaceuticals; Institucio Catalana de Recerca i Estudis Avancats; and the University of Barcelona.