Cholangiocarcinoma Research

Cholangiocarcinoma is a prime example of what makes a rare cancer so challenging: an absence of basic research tools, published information, and funding that results in a lack of treatment options. Since 2011, TargetCancer Foundation has addressed these challenges by investing over $1.1 million in cholangiocarcinoma research.

MGH-Research-Lab_Nabeel-Bardeesy_Portrait-by-Mitch-Weiss-small

Nabeel Bardeesy, PhD
, Gallagher Endowed Chair in Gastrointestinal Cancer Research, Massachusetts General Hospital Cancer Center;
 Associate Professor, Harvard Medical School

A founding goal of TargetCancer Foundation was to change the research landscape for this disease through a long-term commitment to the Bardeesy Lab at the Massachusetts General Hospital Cancer Center. Through strategic seed funding to Dr. Nabeel Bardeesy’s lab, research has progressed faster than ever expected by focusing on key research elements necessary to build a comprehensive research program:

Cell lines and patient-derived xenografts. The TargetCancer Foundation Cholangiocarcinoma Cell Line Bank was established in 2012 in response to the need for a collection of well-characterized cholangiocarcinoma cell lines and associated xenografts. In 2019, the development of this comprehensive collection was completed, and work to move the collection fully into the public domain was initiated.

Understanding driver mutations. Among other studies, TargetCancer Foundation has supported research into the functions of the IDH1 and 2 genes, which are mutated in about 30% of intrahepatic cholangiocarcinoma cases. The Bardeesy lab published a groundbreaking paper in Nature (July 2014) on the effects of mutant IDH1/2 in causing cholangiocarcinoma. This research informs the design and interpretation of clinical trials using mutant IDH inhibiting drugs, and holds great promise for future therapies.

As published in Nature in July 2014.

Funding has also been extended to also support research into the role of FGFR2 gene alteration, which appears in about 10% of intrahepatic cholangiocarcinoma cases and has emerged as a significant therapeutic target.

Community building. No single lab can take on the tremendous task of studying a rare cancer. Through programs like the TargetCancer Foundation Think Tank on Cholangiocarcinoma, we have helped build a collaborative community of researchers across disease areas. In addition, TargetCancer Foundation has funded cholangiocarcinoma research outside of the Bardeesy Lab in an effort to foster a greater research community.

Animal models. With our help, the Bardeesy Lab has successfully engineered a series of mouse models representing several different genetic mutations, allowing for a deeper study of the events driving the development of cholangiocarcinoma in humans.

These areas of focus have led to tremendous progress in a relatively short time, and the impact for patients is real. The first clinical trial informed by TargetCancer Foundation-funded research opened in 2014, and several subsequent trials have followed, offering patients new opportunities for more effective treatments. The potential for the Bardeesy Lab to continue driving research forward remains strong, as does TargetCancer Foundation’s support for these initiatives.

Published Research (click/tap to view)

The below papers were published with support from TargetCancer Foundation.

SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers
Nature Cancer, March 2023

EGFR inhibition potentiates FGFR inhibitor therapy and overcomes resistance in FGFR2 fusion-positive cholangiocarcinoma
Cancer Discovery, April 2022

Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma
Cancer Discovery, March 2022

Biology of IDH mutant cholangiocarcinoma
Hepatology, February 2022

FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma
Cancer Discovery, October 2021

TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma
Cancer Discovery, May 2019

Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma
Cancer Research, August 2018

New Horizons for Precision Medicine in Biliary Tract Cancers
Cancer Discovery, September 2017

Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma
Cancer Discovery, December 2016

The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets
Oncotarget, April 2016

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma
Clinical Cancer Research, January 2016

Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma
Cancer Discovery, July 2016

Biliary Tract Cancers: Finding Better Ways to Lump and Split
Journal of Clinical Oncology, August 2015

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression
Cell Reports, March 2015

IDH mutations in liver cell plasticity and biliary cancer
Cell Cycle, November 2014

Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer
Nature, September 2014

D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice
Genes and Development, March 2014

KrasG12D and p53 Mutation Cause Primary Intrahepatic Cholangiocarcinoma
Cancer Research, January 2012

Total grants awarded

$1,123,000

Primary Grant Recipient

Nabeel Bardeesy, PhD
Massachusetts General Hospital Cancer Center

Additional Grant Recipients

Marina Baretti, MD
Johns Hopkins University

Liron Bar-Peled, PhD
Massachusetts General Hospital Cancer Center

James Cleary, MD and Srivatsan Raghavan, MD, PhD
Dana-Farber Cancer Institute

Andrew Zhu, MD, PhD
Massachusetts General Hospital Cancer Center