Targeted Therapies in Cholangiocarcinoma: Emerging Evidence from Clinical Trials

Abstract

Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs and symptoms in the early stages. This fact, along with the poor results of the local and systemic therapies currently employed, is responsible for the poor outcome of CCA patients and strongly supports the need for novel therapeutic agents and strategies. In recent years, the introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the genetic pathophysiology of CCA and, consequently, for the identification and evaluation of new treatments tailored to the molecular features or alterations progressively elucidated. In this review article, we describe the potential targets under investigation and the current molecular therapies employed in biliary tract cancers. In addition, we summarize the main drugs against CCA under evaluation in ongoing trials and describe the preliminary data coming from these pioneering studies.

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

“…In cancer specimens of CCA, the expression of Hedgehog pathway components have been associated with disease stage and prognosis [85]. In pre-clinical models of CCA different HH inhibitors showed anti-tumor activity, especially in association with chemotherapy, by increasing intratumoral vascularization and drug delivery [86].…”

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

“…For patients presenting with unresectable or metastatic CCA, systemic chemotherapy remains the mainstay palliative treatment modality, and only gemcitabine plus cisplatin combination has offered limited advantages [15,16], usually followed by a fluoropyrimidine-based regimen when gemcitabine-based treatment fails [69]. The identification of genetic and epigenetic alterations and the increased knowledge about the molecular pathophysiological mechanisms governing cholangiocarcinogenesis and tumor recurrence, resistance and metastasis have allowed the development of more specific therapies, although clinical results evaluating specific molecular agents demonstrate no or only very modest survival benefits of the agents tested [4,5,70].…”

Genomics and Interventional Oncology in Primary Liver Cancer

“…35,37 Fusions of FGFR2 have been documented in 3 to 50% of ICC and overexpression of MET in 12 to 58%. 38 Other mutations that have been found at an increased rate in ICC include PTEN, IDH1, IDH2, ARID1A, and PBRM1. [38][39][40] Radiomic investigations have delineated some distinguishing image features of ICC.…”

“…38 Other mutations that have been found at an increased rate in ICC include PTEN, IDH1, IDH2, ARID1A, and PBRM1. [38][39][40] Radiomic investigations have delineated some distinguishing image features of ICC. A 32 patient study was used to show that the degree of enhancement on delayed phase CT could be a useful prognosticator for ICC.…”