Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic

ABSTRACT

Introduction: Until recently, cholangiocarcinoma (CCA) was a largely overlooked disease, and among CCAs, extrahepatic CCA (eCCA) was even more neglected. Despite the growing impact of molecularly targeted therapies and immunotherapy, prognosis of eCCA is dismal. Therefore, unraveling the complex molecular landscape of eCCA has become an urgent need. Deep phenotyping studies have revealed that eCCA is a heterogeneous tumor, harboring specific alterations categorizable into four classes, ‘Mesenchymal’, ‘Proliferation’, ‘Immune’, ‘Metabolic’. Molecular alterations convey the activation of several pro-oncogenic pathways, where either actionable drivers or outcome predictors can be identified.

Areas covered: We offer insights on perturbed pathways, molecular profiling, and actionable targets in eCCA and present a perspective on the potential stepping-stones to future progress. A systematic literature search in PubMed/ClinicalTrials.gov websites was performed by authors from different disciplines according to their specific topic knowledge to identify the newest and most relevant advances in precision medicine of eCCA.

Expert opinion: eCCA is a distinct entity with unique features in terms of molecular classes, oncogenic drivers, and tumor microenvironment. Since more prevalent mutations are currently undruggable, and immunotherapy can be offered only to a minority of patients, international collaborations are instrumental to improve the understanding of the molecular underpins of this disease.

KEYWORDS:

• Cholangiocyte
• cholangiocarcinoma
• extrahepatic cholangiocarcinoma
• epithelial-to-mesenchymal transition
• immunotherapy
• molecularly targeted therapies
• oncogenic drivers
• tumor microenvironment

Article highlights

• Extrahepatic cholangiocarcinoma (eCCA) is a biliary epithelial malignancy defined by well-established anatomical criteria with unique phenotypic traits.

• eCCA is characterized by marked aggressiveness and poor prognosis, with scarce therapeutic options.

• Within the wide eCCA heterogeneity, four molecular classes, ‘Mesenchymal’, ‘Proliferation’, ‘Immune’, and ‘Metabolic’, have been recently identified by whole-genome analysis-based studies.

• Molecular alterations converge into stimulation of four main pro-oncogenic signaling, RTK-RAS-PI3K, TGF-β, histone modification, and TP53-RB, collectively resulting in the presence of actionable drivers in about 25% of eCCA.

• Compared with the intrahepatic variant, FGFR and IDH mutant-enriched subtypes are less common in eCCA.

• Phenotypic features associated with immunotherapy response are present in only 2% of eCCA.

• Among 256 clinical trials ongoing, the only one actually approved for eCCA treatment involves the use of pembrolizumab, a PD-1 monoclonal antibody.

This box summarizes key points contained in the article.

Supplemental data

Supplemental data for this article can be accessed here.

Declaration of interest

• AL received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, Incyte and AAA; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche; she is a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen.

• MS is member of the advisory board of Engitix, outside the submitted work.

• JMB reports grants from INCYTE and ROCHE, personal fees for lecturer from BAYER and INTERCEPT, and consulting for QED and OWL METABOLOMICS, outside the submitted work.

The authors have no other 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.

Additional information

Funding

→ AL received funding from The Christie Charity and fromthe European Union’s Horizon 2020 Research and Innovation Programme [grant number 825510, ESCALON]; she is a member of the COST Action European Cholangiocarcinoma Network, supported by COST (European Cooperation in Science and Technology; www.cost.eu), a funding agency for research and innovation networks.→ LaFo received funding from ANR (ANR-17-CE14-0013-01), Les Entreprises contre le Cancer Paris – Ile-de-France (GEFLUC) (2019), Cancéropôle Ile-de-France (2019).→ MS received funding by the National Institutes of Health (RO1DK096096 and DK101528), by Silvio O. Conte Digestive Diseases Research Core Center (DK034989).→ JJGM received funding by the CIBERehd (EHD15PI05/2016) and ‘Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III’, Spain (PI16/00598 and PI19/00819, co-funded by European Regional Development Fund/European Social Fund); ‘Junta de Castilla y Leon’ (SA063P17); AECC Scientific Foundation (2017/2020), Spain; ‘Centro Internacional sobre el Envejecimiento’ (OLD-HEPAMARKER, 0348_CIE_6_E), Spain; Fundació Marato TV3 (Ref. 201916-31).→ JMB received funding from Spanish Carlos III Health Institute (ISCIII) [(FIS PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129 and CPII19/00008) cofinanced by ‘Fondo Europeo de Desarrollo Regional’ (FEDER); ‘Instituto de Salud Carlos III’ (CIBERehd); Department of Health of the Basque Country (2017111010); ‘Euskadi RIS3’ (2019222054, 2020333010); BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD); Department of Industry of the Basque Country (Elkartek: KK-2020/00008); La Caixa Scientific Foundation (HR17-00601); ‘Fundación Científica de la Asociación Española Contra el Cáncer’ (AECC Scientific Foundation); European Union’s Horizon 2020 Research and Innovation Programme [grant number 825510, ESCALON]; COST Action European Cholangiocarcinoma Network, supported by COST (European Cooperation in Science and Technology; www.cost.eu), a funding agency for research and innovation networks.