Study Suggests Treatment Approaches for Cholangiocarcinomas

Genomic analysis of cholangiocarcinomas, aggressive bile duct malignancies, indicates that some of them may respond to drugs that curb cells' energy production or target chromatin remodeling defects.

Previous genomic studies have identified some driver mutations for the disease, and researchers are starting to test targeted therapies. Last year, for example, researchers began a phase III trial of AG-120 (ivosidenib; Agios Pharmaceuticals) following the discovery that cholangiocarcinomas often have IDH1 or IDH2 mutations; AG-120 targets mutant IDH1.

However, “the real problem is that less than half of patients have mutations in druggable genes such as IDH1, KRAS, and FGFR2, so we need more targets,” says Lawrence Kwong, PhD, of The University of Texas MD Anderson Cancer Center in Houston. Discovering them might also allow combination therapies, he adds.

To obtain a more complete picture of genomic changes in cholangiocarcinoma, Kwong and researchers with The Cancer Genome Atlas (TCGA) profiled tumors from 38 patients using seven different approaches, including whole-genome sequencing, DNA methylation analysis, RNA sequencing, and copy-number analysis. They found that the cancers fell into four groups, including one that exhibited mutations in IDH1 or IDH2. These findings show that tumors with IDH1/2 mutations not only are molecularly distinct, but also often show hypermethylation and reduced expression of ARID1A, which encodes a chromatin remodeling protein.

This genomic analysis also suggests that therapies other than IDH1 inhibitors might be effective in tumors with IDH1/2 mutations. For instance, the researchers found increased expression of mitochondrial genes that help drive the citric acid cycle and electron transport. Thus, patients with these tumors could benefit from drugs that disrupt oxidative phosphorylation, such as IACS-10759, which has just entered a phase I trial for acute myeloid leukemia. The finding that these tumors also often exhibit ARID1A hypermethylation suggests that they may respond to EZH2 inhibitors, several which of are under development or have reached early-stage clinical trials.

Some cholangiocarcinomas occur in bile ducts within the liver, but others grow in ducts that are outside the liver, including the section of the common bile duct that traverses the pancreas. To determine how cholangiocarcinomas differ from tumors in these organs, Kwong and colleagues compared their findings to TGCA data for liver and pancreatic cancers. They discovered that 4% of liver tumors are molecularly closer to cholangiocarcinomas, including in their DNA methylation patterns and their tendency to carry IDH1/2 mutations. If targeted therapies for cholangiocarcinomas receive approval, they might also benefit patients with these tumors.

“It's a well done, comprehensive study,” says Maeve Lowery, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who wasn't connected to the research. “This paper helps us better understand the complexity of cholangiocarcinoma.”

Bin Tean Teh, MD, PhD, of the Cancer Science Institute of Singapore, agrees. "This paper provides a data resource for further functional and cellular analysis and translational studies,” he says.

Emmanuel Thomas, MD, PhD, of the University of Miami Miller School of Medicine, FL, notes that one obstacle to using genomic analysis for treatment decisions in cholangiocarcinoma is the difficulty of obtaining tissue samples. “We need to see if it [the genomic approach] could provide useful information from nucleic acids obtained in liquid biopsies.” –Mitch Leslie