Precision medicine in cholangiocarcinoma

Abstract

Cholangiocarcinoma is one of the epithelial cancers with the poorest prognosis and the narrowest therapeutic choice in humans. Compared with other cancer types, cholangiocarcinoma has been often neglected by oncology and liver research studies, thereby leaving many issues unsolved. Apart from the early and marked aggressiveness, one of the main reasons of the still unsatisfying clinical management of cholangiocarcinoma is its wide tumor heterogeneity needing more than other diseases a 'precision medicine' approach. In this regard, in the last few years there has been an awakening of interest aimed at dissecting the complex molecular and genomic profile of cholangiocarcinoma. Thus, a range of molecular players have been recently identified as putative mechanistic determinants of cholangiocarcinoma invasiveness, encompassing tyrosine kinase receptors, metabolic enzymes, transcription factors, small GTPases, ubiquitin ligases, and chromatin-remodelling proteins, whose aberrant expression may derive from stochastic mutations as well as from pro-oncogenic paracrine signals released by the stromal microenvironment, which is particularly exuberant in cholangiocarcinoma. Herein, we sought to overview the most relevant observations unravelling the genomic landscape of cholangiocarcinoma, and the prognostic and predictive biomarkers that consequently have been emerging. Then, we will discuss innovative treatment approaches derived from conventional chemotherapy, targeted therapies, antiangiogenic therapies and immunotherapy, and how they are opening new avenues towards a precision medicine in cholangiocarcinoma.

The tumour microenvironment and immune milieu of cholangiocarcinoma

“…154,155 To further explain the disappointment with angiogenesis inhibitors, it must be underlined that quite surprisingly, the main route of CCA dissemination through the lymphatic vascular system has not been considered yet for selective targeting. 156 Interestingly, in a xenograft model of iCCA, targeting VEGFR-3 receptor (cognate of the main lymphangiogenic growth factor VEGF-C) markedly reduced tumour-associated lymphangiogenesis. 34 Further investigations should also focus on the identification of CCA subgroups (eg patients with enhanced PDGF-BB level) who might benefit from angiogenesis inhibitors.…”

Medical treatment for cholangiocarcinoma

“…PD‐1/PD‐L1 and CTLA‐4 checkpoints are negative regulators of local inflammatory response against tumour cells . Discovering specific histological and molecular biomarkers predictive of response to immune checkpoint inhibitors (ICI) is the current challenge . The immunohistochemical expression of PD‐L1 is considered a biomarker associated with response to anti‐PD‐L1 antibodies and a better OS in a number of tumour types .…”

“…Antibodies blocking the interaction of PD-1 and CTLA-4 with their specific ligands have been successful in the treatment of several haematological and solid malignancies and their evaluation is also emerging in CCA. 87 PD-1/PD-L1 and CTLA-4 checkpoints are negative regulators of local inflammatory response against tumour cells. 88 Discovering specific histological and molecular biomarkers predictive of response to immune checkpoint inhibitors (ICI) is the current challenge.…”

“…88 Discovering specific histological and molecular biomarkers predictive of response to immune checkpoint inhibitors (ICI) is the current challenge. 87 The immunohistochemical expression of PD-L1 is considered a biomarker associated with response to anti-PD-L1 antibodies and a better OS in a number of tumour types. [89][90][91] PD-L1 may be expressed not only on tumour cells, but also on immune infiltrating cells.…”

Implications of Immunotherapy in Hepatobiliary Tumors

“…Among other epithelial cancers, CC exhibits a very poor prognosis and limited systemic treatment options [54]. It can be divided into intrahepatic, perihilar, and distal CC [55].…”