Leading the Way to a Paradigm Shift in Cholangiocarcinoma: The International Cholangiocarcinoma Research Network

In the past decade, there has been a sea change in awareness about cholangiocarcinoma (CCA). However, the standard of care has remained unchanged for more than 10 years. This year, the FDA approved a new targeted therapy, pemigatinib, which became a treatment option for approximately 10% to 15% of patients with CCA. The process of drug discovery, as well as changes in the standard of care, are becoming increasingly reliant on collaborative approaches that leverage the expertise and resources of a wide range of partners to strengthen the tools and knowledge that advance the research objectives of all stakeholders.

In 2015, the Cholangiocarcinoma Foundation (CCF) launched the International Cholangiocarcinoma Research Network. This network is a global collaborative of clinicians, researchers, and scientists from leading academic medical centers and research institutions working together to improve prevention, early detection, treatment, and prognosis of CCA.

This global group is comprised of preeminent physicians and researchers from a spectrum of disciplines, including surgical oncology, radiation oncology, medical oncology, genomics, and immunology researchers working in close collaboration with CCF, which allows for its unique patient-centric research focus. The International Cholangiocarcinoma Research Network currently has 177 members, representing 85 institutions and 16 countries. The collaborative culture fosters interaction among industry, academia, regulatory, and patient-centered organizations to marry science with patient needs.

CCF launched the International Cholangiocarcinoma Research Network to provide a neutral body to coordinate the sharing of risks, costs, resources, data, and expertise related to CCA, while acknowledging and addressing the differences in culture and expectations that each participant brings to the partnership. The network’s goal is to convene participating clinicians, researchers, and institutions to support the identification, design, and implementation of multicenter clinical and translational research initiatives focused on CCA.

This collaborative body initially focused its work within discipline-specific working groups. Today, the approach has shifted to focus on project-based areas to facilitate cross-discipline and cross-institutional collaboration, as well as attracting and supporting the training of the next generation of CCA investigators and incentivizing senior researchers to focus on strategic initiatives.

Moving forward, the International Cholangiocarcinoma Research Network will focus on identifying critical research gaps and establishing priorities in CCA research, by building the clinical trials’ concepts and network required to facilitate collaborations between industry, regulators, academia, and other relevant stakeholders. In addition, the group is working to consolidate state-of-the-art information and share network resources (biobanks, databases, preclinical models, and repositories), and to build molecular databases with clinical annotation to define targetable disease subsets.

Finally, we believe that we can influence this disease by identifying possible solutions for the obstacles facing the diagnosis of CCA through discussions with FDA leaders, pharmaceutical companies, and companion diagnostics companies.

The network is using past successes, along with the changing landscape in CCA, to undertake major initiatives that advance this focus. The structure and unique expertise of its members serve to foster the ability to undertake paradigm-shifting, transformational research projects. Major initiatives being pursued by the International Cholangiocarcinoma Research Network include:

1. Genotype-phenotype focused on natural history of CCA, prognostic, risk and predictive biomarkers (leaders: Lipika Goyal, MD, Massachusetts General Hospital, Boston; Milind Javle, MD, M.D. Anderson Cancer Center, Houston, TX; and Lewis Roberts, MB ChB, PhD, Mayo Clinic, Rochester, MN).
2. Liquid biopsy focused on the use of liquid biopsy approaches for early detection, prognostication, disease monitoring, and resistance evolution (leaders: Sameek Roychowdhury, MD, PhD, Ohio State University, Columbus; Kabir Mody, MD, Mayo Clinic, Jacksonville, FL; and Flavio Rocha, MD, FACS, Virginia Mason Medical Center, Seattle, WA).
3. Precision therapeutics geared toward the development of targeted therapies and biomarkers and understanding the mechanisms of sensitivity and resistance (leaders: Laura Goff, MD, MSCI, Vanderbilt University Medical Center, Nashville, TN; John Bridgewater, PhD, FRCP, University College London Cancer Institute, England; Nilo Azad, MD, Johns Hopkins University School of Medicine, Baltimore, MD; and Mitesh J. Borad, MD, Mayo Clinic, Phoenix, AZ).
4. Big data, artificial intelligence, and real-world evidence tasked to derive knowledge from data (leaders: Eugene Koay, MD, PhD, M.D. Anderson Cancer Center); and Amit Mahipal, MBBS, MPH, Mayo Clinic, Rochester, MN).
5. Targeted neoadjuvant therapy—a collaborative endeavor among experts in genomics, surgery, and medical oncology, which aims to develop a platform to study presurgical targeted therapy (leaders: Shishir Maithel, MD, FACS, Emory University, Atlanta, GA; Rachna Shroff, MD, MS, University of Arizona, Tucson; and Ghassan Abou-Alfa, MD, MBA, Memorial Sloan Kettering Cancer Center, New York, NY).
6. Drug repurposing, natural products, and novel cytotoxics designed to leverage these platforms as sources for therapeutics (leader: Florin Selaru, MD, Johns Hopkins, Baltimore, MD).

Currently, several projects in these areas include:

• A genomic/immunologic heterogeneity of intrahepatic CCA. This is a multicenter project that will open 3 immuno-oncology clinical trials to explore genomic and immunological heterogeneity between Asian and US intrahepatic CCA as a part of the correlative work. This 4-year project has been funded by the Department of Defense.
• The development of CCA organoids. International Cholangiocarcinoma Research Network members are working collaboratively to develop 50 viable CCA organoids from biopsies or surgically resected fresh tissue samples.
• A pilot study for the development of FGFR mutation–positive CCA organoids undertaken in partnership with SEngine.
• The creation of a multi-institution retrospective database to explore the outcome of various radiation therapy approaches in the management of patients with CCA.
• A multi-institutional, international, translational project to validate US and Asian CCA immune-competent cell lines.

International Cholangiocarcinoma Research Network members are also working together to build a centralized global database for all biliary tract cancers. This database will be globally invaluable in characterizing the clinical history of different CCA molecular subtypes and assessing the frequency of CCA molecular subtypes by geography. It will also create a database of outcomes from standard therapies for patients with CCA with specific molecular alterations that serve as a resource for academia, biopharma, and regulatory agencies to understand disease biology, design clinical trials, and evaluate data for novel therapies.

By working collaboratively across institutions, we believe we can accelerate discovery and developments in CCA. To learn more about the International Cholangiocarcinoma Research Network, or to become a member, contact Reham Abdel-Wahab, MD, PhD, Director of Research for CCF, at This email address is being protected from spambots. You need JavaScript enabled to view it..