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.

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

“…This data correlates with human iCCA cell lines mutated in KRAS and with p53 deficiency, which show elevated autophagy compared with normal iCCA cells, and CQ also inhibited the growth of these cells [86], similar to the situation described for pancreatic and lung cancers [56,[87][88][89][90][91]. No specific RAS inhibitors have been developed so far, and targeted therapies aiming to modulate KRAS downstream pathways such as MEK1/2 inhibitor selumetinib are in development for CCA, pointing to the potential combination with autophagy inhibitors to improve their therapeutic potential [4,92].…”

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

“…Finally, an unconventional target in CCA is represented by cancer-associated fibroblasts (CAF). CAFs often outnumber tumor cells, contribute to CCA development by the production of tumor stroma, and the secretion of soluble factors, involved in the neoplastic process [90]. Inhibition of CAFs activity has already shown anti-tumor activity in pre-clinical models [91].…”

Immune Therapy for Liver Cancers

“…The complex landscape of BTC genetic alterations has been deciphered, including some druggable mutations or rearrangements, paving the way for personalized targeted therapies [66][67][68]. Interestingly, some alterations were enriched in specific primary tumor locations [69] ( Figure 2). Hence, isocitrate dehydrogenase 1/2 (IDH1/2) mutations and fibroblast growth factor receptor 2 (FGFR2) gene fusions were each described in 10-20% of iCCA [70].…”

“…Moreover, a growing interest has developed regarding tumor stroma as well as its role in supporting and promoting tumor growth and its involvement in resistance to treatment. By analogy with pancreatic ductal adenocarcinoma, which is also characterized by an abundant desmoplastic stroma, strategies targeting tumor microenvironment (e.g., CAFs and other components the microenvironment) are emerging in BTCs [68,69,105].…”