Extensive genomic analysis led by MD Anderson researchers has opened new avenues to explore in the treatment of a rare and tenaciously lethal type of liver cancer.
Cholangiocarcinoma — cancer of the bile ducts — is treated with chemotherapy and surgery. It’s occurring more frequently in the United States, with incidence rising from .44 cases per 100,000 population in 1973 to 1.18 per 100,000 in 2012. Median survival of patients newly diagnosed with the disease is less than a year.
A team co-led by Lawrence Kwong, Ph.D., assistant professor of Translational Molecular Pathology, conducted an integrative genomic analysis of patient samples through The Cancer Genome Atlas, identifying two potential targets for treating tumors with mutations in IDH1 or IDH2 genes.
“Drugs that target IDH mutations are under clinical investigation. So far, they don’t seem to do that well by themselves, so our idea is that insights from these findings will allow us to design combination therapies to more effectively treat cholangiocarcinoma,” Kwong said.
Potential targets identified by the researchers involve a crucial metabolic pathway and another involved in methylation – the chemical silencing of genes.
“Our lab is looking to model IDH-mutant tumors and test some of these ideas preclinically,” Kwong says.
Such translational research, taking information from human tumors back to lab experiments where researchers will gain the understanding necessary to develop new treatments for testing in clinical trials, is a vital aspect of a new, multidisciplinary effort targeting cholangiocarcinoma at MD Anderson.
A $500,000 gift from the Janet M. and George J. Ehni III estate and an initial gift of $100,000 by the Linda A. Blum Fund for Cholangiocarcinoma Research will fund major infrastructure investment to better study the disease, including an integrated molecular and pathology biorepository that will include frozen tumor samples, blood and tissue arrays and clinical information associated with the samples.
“This will provide new capacity to perform additional experiments, improve profiling of tumors and develop new cholangiocarcinoma cell lines,” Kwong says. “There are very few cell lines of this cancer anywhere.”
This important biliary cancer laboratory is being developed
by Ignacio Wistuba, M.D., chair of Translational Molecular Pathology, says Milind Javle, M.D., professor of Gastrointestinal Medical Oncology.
Javle leads the Biliary Cancer team, which includes surgeons, GI oncologists, pathologists, radiation oncologists, and diagnostic radiologists. MD Anderson treats more than 400 cholangiocarcinoma patients per year, one of the largest clinical programs in the world.
Kwong and colleagues analyzed 38 cholangiocarcinoma samples from patients who had not been treated with radiation or chemotherapy, and who did not have hepatitis B or C or liver flukes, known risk factors for the disease. By minimizing known and potential sources of molecular heterogeneity in the tumors, the researcher hoped to get a clear picture of other diverse factors that drive the disease.
They conducted whole-exome sequencing, RNA sequencing, and analyzed gene copy number, DNA methylation and protein expression, reporting their results in Cell Reports.
About 20% of samples had either IDH1 or IDH2 mutations in the original set and in an additional set of 15 samples. The IDH mutants had distinct mRNA, copy number and DNA methylation features.
“All the IDH mutants had increased mitochondrial gene expression,” Kwong says, “and they had hypermethylation of DNA. We found the tumor-suppressing gene ARID1A was hypermethlyated and silenced by IDH mutants.”
IDH-mutant tumors also had low expression of genes that modify chromatin, the packaging of genes and histone proteins that make up chromosomes and affect methylation.
“We think there’s a link through ARID1A between mitochondrial and chromatin gene expression,” Kwong says.
The team will be looking at inhibitors of EZH2, which regulates methylation, and drugs that block oxidative phosphorylation, the main metabolic function of the mitochondria, in its preclinical studies.
Additionally, the researchers compared the characteristics of cholangiocarcinoma, hepatocellular carcinoma (the most common form of liver cancer) and pancreatic tumors. They found striking similarities in a subgroup of the hepatocellular carcinoma tumors with the cholangiocarcinoma tumors, which is consistent with an emerging view that liver tumors comprise a continuous spectrum of molecular types.
“Although larger studies are needed to validate and identify further molecular subclasses, our results provide a proof of principle that subclasses of cholangiocarcinomas have distinct, multi-level molecular characteristics that suggest potential therapeutic approaches,” Kwong and colleagues wrote.