November 8, 2023

Refining treatment of cholangiocarcinoma

Two researchers working in a laboratory
Dr. Jeremy Kratz (left) and Dr. Md Shahadat Hossan work together in the Kratz Lab.

A new $1 million research grant will help Dr. Jeremy Kratz and his collaborators investigate a new targeted therapy for patients with a rare form of cancer.

Cholangiocarcinoma, also called bile duct cancer, forms in the bile ducts that connect the liver to the gallbladder and small intestine. Only about 8,000 patients per year are diagnosed with the disease, and it typically impacts older adults. The Veteran Health Administration has been interested in rare disease specific to U.S. military veterans due to their large integrated network to connect researchers across the country.

Kratz, a physician-scientist for UW Carbone Cancer Center and UW Center for Human Genomics, is investigating a more targeted approach to increase effectiveness of current treatments.

“We know that chemotherapy has been the backbone of treating this cancer, it’s been the standard of care and continues to be the standard of care,” Kratz said. “We’re pursuing how we can further augment the response of DNA damage (from chemotherapy) by preventing the adaptive response in cancer cells.”

Cancer cells often adapt in response to stress such as with use of chemotherapy. Kratz, who specializes in hepatobiliary and pancreatic cancers, and his team are interested in tracking that response based on that production of RNA, which is the effector signal on the path to resistance. They are investigating at a cellular level which mechanisms help these cancer cells repair themselves and how to disrupt processes in the cell cycle to improve treatment efficacy.

“We believe as a lab that those mechanisms of resistance start with the production of RNA, including the development of protein molecules that help repair DNA,” Kratz said. “The goal of this project is to turn off the ability of the cancer to make that RNA strand that eventually becomes the repair mechanism for the cancer. Can we prevent the cancer from adapting in response to chemotherapy?”

This research grant comes from the U.S. Department of Veterans Affairs. Kratz is also part of a related $3.4 million award to understand the mutational processes that cause this rare cancer in veterans, map the genetic variations that can occur, and further study new precision treatment methods.

“The goal of that project is to understand if there are differences in environmental exposures in the development of a veteran’s cancer using whole genome sequencing,” Kratz said.

Because cholangiocarcinoma is so uncommon, this is a nationwide collaborative effort among many research institutions to pool resources and insights from their own work.

Patient tumor samples are crucial for both projects, and Kratz is thankful to the generous patients who have consented to sharing tissue.

“We find that that tissue contribution to lab is one of the most fantastic gifts. This provides us the opportunity to generate the hallmark molecular subtypes of cholangiocarcinoma. Utilizing our living models of cancer, we have these avatars of cancer to expand the breadth of personalized therapeutic targets.”