Angiogenesis in biliary tract cancer: targeting and therapeutic potential

ABSTRACT

Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.

Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.

Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.

KEYWORDS:

• Biliary tract cancer
• anti-angiogenic drugs
• tyrosine-kinase inhibitors
• bevacizumab
• immune checkpoint inhibitors
• cholangiocarcinoma
• vegf

ARTICLE HIGHLIGHTS

• Biliary tract cancer is a multifaceted disease with a poor prognosis in the more advanced stages. Alas, this is coupled with limited availability of therapeutic options; hence, new treatment options in this setting are urgently needed.

• Evidence of overexpression of neo-angiogenic pathways in BTC, including the VEGF and MEK/ERK pathways, offer a robust biomolecular rationale for the testing of antiangiogenic drugs in preclinical and clinical settings.

• The monoclonal antibody Bevacizumab in combination with standard chemotherapy has yielded promising data in first- and second line therapies; however, this approach does not offer practice-changing results.

• There are no conclusive findings with the use of tyrosine kinase inhibitors, but encouraging results have been achieved with several TKIs, including Cediranib, Apatinib, Regorafenib, and Pazopanib plus Trametinib in combination. Conversely, Sorafenib in monotherapy and combination and Vandetanib and Sunitinib failed to confer survival benefits for BTC patients.

• The promising combination of antiangiogenic therapies and checkpoint inhibitors, which exploit the synergic effect of these two classes of drugs, are being investigated.

• In the so-called multi-OMICS era, the ambition is to dig deeper into the biomolecular and genomic profile of this complex disease to identify and validate some predictive biomarkers that may enable selection of patients more likely to respond to antiangiogenic drugs

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.