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.

Figure 1:

Top-row: the formation of 3D spheroids with CCA cells only, HSC cells only, or CCA+HSC to show the importance of the tumor microenvironment with hepatic support cells, such as HSC. Bottom row: the formation of 3D microenvironment with CCA and HSC cell lines at 1h, 16h, 50h, and 96h in 3D culture demonstrating how cells migrate in the 3D tumor microenvironment. CCA= cholangiocarcinoma, HSC= hepatic stellate cells.

Figure 2:

The effect of secretin, somatostatin and melatonin on cholangiocarcinoma cell growth are reported with the corresponding receptors and pathways. Abbreviations: cAMP = adenosine 3’,5’-cyclic monophosphate; ERK=extracellular receptor kinase; Gαi= G protein alpha i; MEK=Mitogen-activated protein kinase; MT1= melatonin receptor-1; PKA=Protein Kinase A; SR=secretin receptor; SSRT2= somatostatin receptor-2. Symbols: ↓= decrease.