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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2016; 22(4): 1335-1347
Published online Jan 28, 2016. doi: 10.3748/wjg.v22.i4.1335
Molecular genetics and targeted therapeutics in biliary tract carcinoma
Eric I Marks, Nelson S Yee
Eric I Marks, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, United States
Nelson S Yee, Division of Hematology-Oncology, Department of Medicine, Penn State Hershey Medical Center, Hershey, PA 17033, United States
Nelson S Yee, Program of Experimental Therapeutics, Penn State Hershey Cancer Institute, Hershey, PA 17033, United States
Author contributions: Marks EI and Yee NS conceived and designed the study, reviewed the literature, collected and analyzed the data, and wrote the paper.
Conflict-of-interest statement: The authors Marks EI and Yee NS declare no conflicting interests that are related to this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nelson S Yee, MD, PhD, Program of Experimental Therapeutics, Penn State Hershey Cancer Institute, 500 University Drive, Hershey, PA 17033-0850, United State. nyee@hmc.psu.edu
Telephone: +1-717-5310003 Fax: +1-717-5315076
Received: May 22, 2015
Peer-review started: May 23, 2015
First decision: September 29, 2015
Revised: October 29, 2015
Accepted: November 19, 2015
Article in press: November 19, 2015
Published online: January 28, 2016
Abstract

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

Keywords: Biliary tract carcinoma, Cholangiocarcinoma, Gallbladder carcinoma, Molecular genetics, Personalized treatment, Precision therapy, Targeted therapy

Core tip: For patients with cholangiocarcinoma and gallbladder carcinoma, targeted therapeutics provide new opportunity of treatment that is potentially less toxic and more effective. These target-specific monoclonal antibodies and small molecule inhibitors are directed against the signaling pathways that drive the progression of biliary tract cancers. This article provides an updated review of the molecular pathogenesis of these malignant neoplasms as the framework for describing the mechanisms by which targeted agents work. The preclinical and clinical data from investigation of targeted therapeutics in biliary tract cancer are discussed.