TY - JOUR
T1 - IDH signalling pathway in cholangiocarcinoma
T2 - From biological rationale to therapeutic targeting
AU - Salati, Massimiliano
AU - Caputo, Francesco
AU - Baldessari, Cinzia
AU - Galassi, Barbara
AU - Grossi, Francesco
AU - Dominici, Massimo
AU - Ghidini, Michele
N1 - Funding Information:
Financed by Italian fiscal contribution ?5x1000? 2016 devolved to Fondazione IRCCS Ca? Granda Ospedale Maggiore Policlinico.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - Biliary tract cancers are anatomically distinct and genetically diverse tumors, evenly characterized by poor response to standard treatments and a bleak outlook. The advent of comprehensive genomic profiling using next-generation sequencing has unveiled a plethora of potentially actionable aberrations, changing the view of biliary tract cancers from an “orphan” to a “target-rich” disease. Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials. Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations. In this review article, we will focus on the IDH1/IDH2 pathway, discussing the preclinical rationale of its targeting as well as the promises and challenges of the clinical development of IDH inhibitors in biliary tract cancers.
AB - Biliary tract cancers are anatomically distinct and genetically diverse tumors, evenly characterized by poor response to standard treatments and a bleak outlook. The advent of comprehensive genomic profiling using next-generation sequencing has unveiled a plethora of potentially actionable aberrations, changing the view of biliary tract cancers from an “orphan” to a “target-rich” disease. Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials. Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations. In this review article, we will focus on the IDH1/IDH2 pathway, discussing the preclinical rationale of its targeting as well as the promises and challenges of the clinical development of IDH inhibitors in biliary tract cancers.
KW - Biliary cancer
KW - Cholangiocarcinoma
KW - Gallbladder cancer
KW - IDH
KW - Ivosidenib
KW - Precision medicine
KW - Targeted therapy
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U2 - 10.3390/cancers12113310
DO - 10.3390/cancers12113310
M3 - Review article
AN - SCOPUS:85096670380
VL - 12
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 11
M1 - 3310
ER -