Cholangiocarcinoma: novel therapeutic targets

ABSTRACT

Introduction: Cholangiocarcinoma (CCA) is a liver cancer derived from the biliary tree with a less than 30% five-year survival rate. Early diagnosis of CCA is challenging and treatment options are limited. Some CCA patients have genetic mutations and several therapeutic drugs or antibodies have been introduced to target abnormally expressed proteins. However, CCA is heterogeneous and patients often present with drug resistance which is attributed to multiple mutations or other factors. Novel approaches and methodologies for CCA treatments are in demand.

Area covered: This review summarizes current approaches for CCA treatments leading to the development of novel therapeutic drugs or tools for human CCA patients. A literature search was conducted in PubMed utilizing the combination of the searched term ‘cholangiocarcinoma’ with other keywords such as ‘miRNA’, ‘FGFR’, ‘immunotherapy’ or ‘microenvironment’. Papers published within 2015–2019 were obtained for reading.

Expert opinion: Preclinical studies have demonstrated promising therapeutic approaches that target various cells or pathways. Recent studies have revealed that hepatic cells coordinate to promote CCA tumor progression in the tumor microenvironment, which may be a new therapeutic target. Although further studies are required, novel therapeutic tools such as extracellular vesicles could be utilized to manage CCA and its microenvironment.

KEYWORDS:

• Cholangiocarcinoma
• immunotherapy
• tumor microenvironment
• microRNA
• long non-coding RNA
• extracellular vesicles

Article Highlights

• Cholangiocarcinoma is a cancer that may emerge in any part of the biliary tree or cholangiocytes with a < 30% five-year survival rate

• Treatments of cholangiocarcinoma are limited, hence novel therapeutic approaches are required

• Numerous signaling pathways are involved in CCA development or progression, and small molecules targeting these pathways, such as antagonists against serotonin receptors, may have the potential as a novel therapeutic drug for CCA.

• Various targets have been unearthed based on genetic aberrations or the microenvironment

• Non-coding RNAs are associated with tumor progression and invasion in cholangiocarcinoma

• Targeting the tumor microenvironment and immunotherapies had promising results in recent studies.

• Extracellular vesicles could be utilized to manage tumor progression by delivering non-coding RNAs

This box summarizes key points contained in the article.

Acknowledgments

We thank Elise Slevin (Indiana University School of Medicine, Indianapolis, IN) for her assistance in proofreading of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by: The Senior Research Career Scientist Award to Dr. Alpini and the VA Merit awards to Dr. Meng (1I01BX001724), Dr. Glaser (5I01BX002192), Dr. Francis (1I01BX003031), and Dr. Alpini (5I01BX000574) from the United States Department of Veteran’s Affairs Biomedical Laboratory Research and Development Service; U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grants DK108959, DK119421, DK115184, DK054811, DK076898, DK107310, DK110035, and DK062975 to Drs. Meng, Glaser, Francis, and Alpini and NIH National Institute on Alcohol Abuse and Alcoholism Grants AA025997 and AA025157 to Drs. Meng, Glaser, and Alpini; The Hickam Endowed Chair, Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine to Dr. Alpini; The project described was supported by the Indiana University Health – Indiana University School of Medicine Strategic Research Initiative. Dr. Alpini acknowledges the support from PSC Partners Seeking a Cure (460933-00001). This material is the result of work supported by resources at the Central Texas Veterans Health Care System, Temple, TX, Richard L. Roudebush VA Medical Center, Indianapolis, IN, and Medical Physiology, Medical Research Building, Temple, TX. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.