Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA-and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatinremodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarkerdriven trials are currently underway.

Current biologics for treatment of biliary tract cancers

“…Targeting single pathways either as monotherapy or in combination with chemotherapy has shown varying degrees of improvements in response rates, but these have not translated to clinically significant increases in PFS or OS. Currently, some clinical trials are using a multi-target approach by using multikinase inhibitors or a combinatorial approach with multiple agents aimed at different pathways (12,72). Results from studies using multikinase inhibitors regorafenib and pazopanib are anxiously awaited.…”

FBXW7 Pathway Functions as a Promising Therapeutic Target of Cholangiocarcinoma

“…In addition, the clinical data of CCAs are usually collected over many years with a limited number of patients for the rarity of this disease, which inevitably lead to bias for the variability of diagnosis and treatment strategy. All these factors contribute to the difficulty of making comparisons between series and preclude clinical practice guidelines in establishing a "standard of care" for patients with advanced CCAs [15]. More confirmed evidences and treatment strategies are eagerly awaited for CCA patients.…”

Cholangiocarcinoma – current classification and challenges towards personalised medicine

“…Notably, no mutations were found in IDH1/2 or FGFR2 gene fusions, which has been described as important potential targets in iCCA. [20,21] A limited number of studies have investigated differences within the extrahepatic group and the conclusions that currently can be drawn are limited. One example is the differential expression of cell cycle related proteins between pCCA and dCCA, where some studies has shown that dCCA expressed a pattern more closely resembling pancreatic ductal adenocarcinoma (PDAC).…”

“…This development has been ongoing, primarily in iCCA, in which several studies have investigated the molecular pathogenesis and identified potential biomarkers, as well as goals for targeted therapy. [20] The number of studies characterising eCCA is significantly lower and there is a need of elucidating the molecular pathogenesis, as well as identifying unique biomarkers of pCCA and dCCA, respectively. This division will be necessary, not only because there are underlying differences in tumour biology, but also to deal with unique clinical problems in pCCA and dCCA.…”