Dr. Gradilone receives $1.7 million for cutting-edge study on bile duct cancer

A major federal grant has been awarded to The Hormel Institute, University of Minnesota to research better ways to treat cholangiocarcinoma, a malignancy also known as bile duct cancer that has limited treatment options.Researchers also are hopeful the project’s discoveries potentially could be applied to other liver diseases and other forms of cancer, such as breast, kidney, pancreatic and prostate cancers.

Dr. Sergio Gradilone, leader of the Cancer Cell Biology & Translational Research section at The Hormel Institute, has received a five-year, $1.7 million grant from the National Cancer Institute, part of the federal National Institutes of Health, to fund research on cholangiocarcinoma or CCA. The grant starts today and runs through 2020.

CCA – often labeled a “silent disease” due to symptoms many times going unnoticed until it is in the advanced stage –starts in the bile duct, a thin tube that reaches from the liver to the small intestine. The bile duct’s main function is to move fluid called bile from the liver and gallbladder to the small intestine, where it helps digest food.

This is a significant project, Gradilone said, because there is a vital need to find new targets of CCA leading to better therapeutic strategies for this lethal form of cancer. His team is focusing on the role played during tumor formation by primary cilia, which are multisensory organelles that act similar to a cell antenna in that they sense and receive signals from the environment surrounding the cells.

“We believe our study will provide a link between primary cilia loss and tumor progression in CCA,” Gradilone said. “We also hope it lays the foundation for potentially developing anti-cancer therapeutics based on rescuing cilia’s architecture and function.”

Gradilone has found that primary cilia are lost in tumor cells, and, given that, is trying to understand the mechanisms of ciliary loss and determine the related consequences. Malformation or loss of primary cilia also has been described in other solid tumors, including breast, kidney, pancreatic and prostate cancers. Cilia only recently have become the subject of intense scientific investigation, Gradilone said, but it’s an important area to study because cilia formation is potentially reversible.

Recent findings by Gradilone’s team have shown reduced expression of cilia in CCA, indicating that ciliary dysfunction might be associated with cancer development and/or progression. The newly funded study aims to identify potential targets for treating CCA by examining and utilizing the intracellular signaling mediated by primary cilia that have the potential of acting as a tumor-suppressor mechanism.

“Our preliminary studies suggest that restoring primary cilia and their complex, multisensory signals by HDAC6 gene targeting could act as a tumor-suppressor mechanism,” Gradilone said. “Studies also suggest that HDAC6 specific targeting might have minimal adverse health effects for the patient.”
Malignancies involving the liver, bile ducts and gallbladder account for 13 percent of annual cancer-related deaths worldwide and 3 percent of those in the United States. It is estimated more than 2,500 U.S. cases are diagnosed each year.

Gradilone joined The Hormel Institute in fall 2014 after doing research at Mayo Clinic in Rochester. His lab focuses on understanding the basic biological processes involved with a normal cell transforming into a cancerous one. Better understanding these mechanisms then could lead to improved cancer treatment options.

The Hormel Institute is in the midst of a 2014-16 expansion to double its current facility footprint and add up to 15 new cancer research sections and 125 scientists and staff in the coming years. For the past year, construction has been ongoing on the Institute’s east side to add another 20 state-of-the-art laboratories. This spring, work started on the west side to create a new Live Learning Center that will include a 250-seat lecture hall with theater-style seating and advanced technology to facilitate global medical research collaborations and presentations. Both projects are expected to be completed by early 2016. Two international cancer research symposiums already are planned for 2016 in The Hormel Institute’s Live Learning Center.