Two genetic mutations in liver cells may drive tumor formation in intrahepatic cholangiocarcinoma (iCCA), the second most common form of liver cancer, according to a research published in the July issue of the journal Nature.
A team led by the Icahn School of Medicine at Mount Sinai and Harvard Medical School has discovered a link between the presence of two mutant proteins IDH1 and IDH2 and cancer. Past studies have found IDH mutations to be among the most common genetic differences seen in patients with iCCA, but how they contribute to cancer development was unknown going into the current effort.
iCCA strikes bile ducts, tube-like structures in the liver that carry bile, which is required for the digestion of food. With so much still unknown about the disease, there is no first-line, standard of care and no successful therapies.
"iCCA is resistant to standard treatments like chemotherapy and radiation," said Josep Maria Llovet, MD, Director of the Liver Cancer Program, Division of Medicine, Icahn School of Medicine at Mount Sinai, and contributing author. "Understanding the molecular mechanism of the disease is the key to finding a treatment that works."
Dr. Llovet and colleagues demonstrated that the expression of mutant IDH in the adult liver of genetically engineered mice impairs liver cell development and liver regeneration – a process in which the liver responds to injury – and increases the number of cells to form a tumor. Moreover, mutant IDH were found to work with activated KRAS, a gene essential in cancer development, causing the development of premalignant lesions and a progression to metastatic iCCA.
"Our findings provide novel insights into the development iCCA and offers a possible treatment option for patients suffering from this fatal disease," said Dr. Llovet.
By pinpointing one pathway of iCCA, this study opens up a new line of investigation to identify biomarkers of the disease. Already, Phase 1 clinical trials are being conducted with specific IDH1/2 mutations. The hope is that results of these and future studies can help doctors make life-saving decisions for their patients.
This study was conducted through partnerships with Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA; HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia, Spain; Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, and Department of Experimental Oncology, Milan, Italy; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS; University of Rochester Medical Center, Rochester, NY; Agios Pharmaceuticals, Cambridge, MA; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain; and the University of Barcelona, Catalonia, Spain.
About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.
The System includes approximately 6,600 primary and specialty care physicians, 12-minority-owned free-standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.
For more information, visit http://www.mountsinai.org, or find Mount Sinai on Facebook, Twitter and YouTube.
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