Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

Abstract

The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and-2 mutations which are each present in around 10-20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.

FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention

“…However, the results of clinical trials have clearly demonstrated that only tumors carrying genetic alterations of the FGFRs such as mutations or fusions might respond to treatment with FGFR inhibitors, at least when used as single agents. In this respect, targeted therapies for FGFR-aberrant tumors may offer an effective therapeutic strategy in some cancer types, such as cholangiocarcinoma, which is often diagnosed in advanced stages when only palliative treatment is available [67]. In the last years, the rapid improvement in the development of drugs targeting FGFR alterations, including fusions, combined with the availability of ever more efficient diagnostic tests, allowed the selection of patients who might benefit from FGFR inhibitors.…”

The Emerging Role of MicroRNAs in Regulating the Drug Response of Cholangiocarcinoma

“…However, it is still a challenge to implement miRNA-based therapeutics in patients. As several targeted therapies might change the treatment paradigm in at least a minority of patients with CCA [ 116 ], further studies will continue to shed light on potential miRNA targets involved in targeted drug resistance. To promote miRNA-based therapeutics that surmount drug resistance or enhance antitumor effects in CCA, future studies should focus on nanomedicine to facilitate the synergistic delivery of chemotherapy and miRNAs.…”

“…A number of emerging targeted drugs have been investigated to treat CCA, such as FGFR2 small molecule kinase inhibitors, mutant IDH inhibitors, Mcl-1 selective inhibitors, and MEK inhibitors [ 116 ]. Previously, several tyrosine kinase inhibitors in the treatment of CCA have been reported, but their efficacy is not promising.…”

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

“…Table 1. Prevalence of therapeutically relevant genetic alterations in patients with advanced biliary tract cancer and the corresponding targeted therapies [27]. In general, isocitrate dehydrogenase (IDH) and FGFR aberrations tend to cluster in iCCA, whereas HER2 (ERBB2) aberrations are more frequent in eCCA and GBC [28].…”