The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets

Abstract

Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets.

Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

“…Since the prognosis of CCA remains poor with traditional chemotherapy, in the era of personalized medicine several research teams have been working on the molecular and genetic characterization of CCA to identify molecular targets (5)(6)(7)(8)14). Landscape of signalling pathways offers multiple therapeutic targets including growth factor receptors (GFRs) like epidermal (EGFR), vascular (VEGFR), human epidermal growth factor receptor 2 (HER2), the ligand of VEGFR (VEGF) and their downstreaming signal molecules of RAS-RAF-MEK-ERK and PI3K-ACT-mTOR (5)(6)(7)(8)14). Targetspecific monoclonal antibodies and tyrosine kinase inhibitors are able to block selectively the over-expressed or over-activated signal molecules potentiating the growth and invasion of CCA cells.…”

“…In CCA the frequency of BRAF V600E has been reported to range 0-12% in EH and 0-22% in IH subtypes (5)(6)(7)(8)14). Although BRAF V600 can serve as a potential molecular target in CCA, until now there was no evidence of benefit using BRAF inhibitor therapy.…”

“…Due to the dismal prognosis with conventional chemotherapy, attention has been shifting to the potential role of molecularly targeted agents in advanced CCA. Several clinical trials had been carried out, where targeted agents were applied alone or in combination with chemotherapy with only modest or no proven benefit at all (5)(6)(7)(8). One main limitation of most trial design was subject heterogeneity with regards to the anatomical and molecular characteristics of the cholangiocellular malignancies.…”

Emerging therapies for the treatment of cholangiocarcinoma

“…Genetic studies of biliary tumors have identified known growth factor gene mutations [100,101] and signaling pathways [102] that control tumor growth and survival. Target-specific monoclonal antibodies and small molecule inhibitors directed against the signaling pathways that promote the growth and spread of cholangiocarcinoma are being developed [103].…”

“…Other novel mutations include isocitrate dehydrogenase (IDH), BRCA1-associated protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1) [100].…”