Cholangiocarcinoma: molecular pathways and therapeutic opportunities

Abstract

Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options.

Fig. 1

Molecular pathways in cholangiocarcinoma (CCA) and inhibitors. Several molecular pathways are dysregulated in CCA. Inhibitors targeting these pathways are entering human clinical trials. The prevalence of each genetic aberration and potential therapeutic strategies are listed.

Fig. 2

IL-6/STAT3 signaling and inhibitors. Binding of IL-6 to its receptor activates Janus kinase (JAK) with subsequent phosphorylation, activation, dimerization, and nuclear translocation of STAT3. STAT3 upregulates Mcl-1 transcription. Inhibitors of IL-6, JAK, STAT3, and Mcl-1 are currently in development.

Fig. 3

Notch signaling pathway and inhibitors. The Notch signaling pathway has been implicated in cholangiocarcinoma (CCA) carcino-genesis. Enhanced expression of NICD occurs in CCA. Several inhibitors of the Notch pathway are currently in development. These include inhibitors of γ-secretase, a key enzyme in the Notch pathway, as well as monoclonal antibodies (mABs) targeting the Notch receptors and ligands.

Fig. 4

Selective deletion of cancer-associated fibroblasts (CAFs) from cholangiocarcinoma (CCA) tumor microenvironment. Cancer-associated fibroblasts produce factors that promote survival of tumor cells. Cancer-associated fibroblasts are primed or sensitized for apoptosis and hence can be selectively targeted by BH3 mimetics such as navitoclax and ABT-199. Cholangiocarcinoma cells overexpress Mcl-1, which does not bind navitoclax, and hence are not a direct target of navitoclax. However, CAF deletion from the tumor microenvironment leads to secondary cancer cell death due to loss of CAF-mediated prosurvival signals.