Targeting cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA. Clinical trials targeting these specific driver mutations are in progress. However, The Tumor Genome Atlas (TCGA) marker analysis of CCA also highlights the tremendous molecular heterogeneity of this cancer rendering comprehensive employment of targeted therapies challenging. CCA also display a rich tumor microenvironment which may be easier to target. For example, targeting cancer associated fibroblasts for apoptosis with BH3-mimetics and/or and reversing T-cell exhaustion with immune check point inhibitors may help aid in the treatment of this otherwise devastating malignancy. Combinatorial therapy attacking the tumor microenvironment plus targeted therapy may help advance treatment for CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Keywords: Biliary tract cancer; Cholangiocarcinoma; Driver mutations; Microenvironment; Molecular targets.

Fig. 1

Summary of some of the most promising tumor cell targeted therapeutic approaches in CCA. Besides the important FGFR2 mutations, mutations in cMET, Her2, IDH and PRKACA/B are promising new targets. Numbers in parenthesis indicate current clinical trials.

Fig. 2

The tumor ‘ecosystem’ contains abundant activated cancer associated stromal fibroblasts beside the actual tumor cells. These activated fibroblast support tumor development and are sensitive to apoptosis induction by BH3 mimetics such as Navitoclax. Depletion of CAF reduces tumor growth in a murine model of CCA. PD-L1 inhibition reconstitutes T-cell response and anti-tumor immunity. Such inhibitors are established in other tumor entities and are currently under investigation for CCA.