Cholangiocarcinoma: bridging the translational gap from preclinical to clinical development and implications for future therapy

ABSTRACT

Introduction: Cholangiocarcinoma (CCA) is a devastating liver tumor with a poor prognosis. While less than 50% of the patients with CCA may benefit from surgical resection, the rest undergoes chemotherapy with disappointing results (mean survival <2 years). Alternative pharmacological treatments are needed to improve the outcomes in patients with CCA.

Areas covered: In this review, we discuss CCA-related (1) experimental systems used in preclinical studies; (2) pharmacological targets identified by genetic analysis; (3) results obtained in preliminary trials in human with their pros and cons; and (4) possible targeting of endocrinal modulation. A PubMed bibliographic search matching the term ‘cholangiocarcinoma’ with ‘experimental model’, ‘preclinical model’, ‘genetic target’, ‘targeted therapy’, ‘clinical trial’, or ‘translational research’ was conducted and manuscripts published between 2010 and 2020 were retrieved for reading and reviewing.

Expert opinion: Several factors contribute to the translational gap between bench research and clinical practice in CCA. The tumor heterogeneity, lack of a preclinical model recapitulating the different features of CCA, and difficult patient enrollment in clinical trials are elements to consider for basic and clinical research in CCA. Establishment of international networks formed by experts in the field of CCA may improve future research and its translational findings on patients.

KEYWORDS:

• Cholangiocarcinoma
• cholangiocyte
• endocrine regulation
• preclinical model
• targeted therapy
• translational gap

Article highlights

• Cholangiocarcinoma is a devastating tumor with a poor survival (mean survival <2 years).

• Available chemotherapy for cholangiocarcinoma achieves suboptimal results; thus, new pharmacological treatments are needed.

• Preclinical experimental models of cholangiocarcinoma do not adequately reproduce all the heterogeneous features of this tumor and need implementation in order to achieve consistent results for therapy.

• Identification of genetic aberrations in cholangiocarcinoma has stimulated the development of molecules targeting the corresponding deranged pathways. Some of these drugs are currently under evaluation in ongoing clinical trials.

• Other targets for cholangiocarcinoma treatment might be represented by hormones, neurotransmitters, and the corresponding cellular receptors, that have been shown to regulate tumor growth and invasiveness in preclinical studies.

• International networks, stimulating collaborative projects on cholangiocarcinoma, are a possible tool to accelerate our knowledge and improve therapy for this disease.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

Portions of this work were supported by The Senior Research Career Scientist Award to Dr Alpini (1IK6BX004601), Research Career Scientist Award to Dr Francis (1IK6BX005226) and the U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grants DK108959 and DK119421 to Dr Francis and DK110035, DK115184, DK054811 and DK076898 to Drs 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 to Drs Alpini and Francis. 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.