IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment-Current State and Future Perspectives

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 16; p. 3754
• Main Authors: Crispo, Fabiana, Pietrafesa, Michele, Condelli, Valentina, Maddalena, Francesca, Bruno, Giuseppina, Piscazzi, Annamaria, Sgambato, Alessandro, Esposito, Franca, Landriscina, Matteo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.08.2020; MDPI
• Subjects: 2-hydroxyglutarate; Antineoplastic Agents - therapeutic use; Bile; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Biliary tract; Cancer therapies; Cell adhesion & migration; Cell cycle; Cell differentiation; Chemotherapy; Cholangiocarcinoma; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Deoxyribonucleic acid; Differentiation (biology); DNA; Epigenetics; Gene expression; Humans; IDH1 inhibitors; intrahepatic cholangiocarcinoma; isocitrate dehydrogenase; Isocitrate Dehydrogenase - antagonists & inhibitors; Ketoglutaric acid; Malignancy; Medical prognosis; Metabolism; Mortality; Mutation; Next-generation sequencing; Review; Tumors; United States > US; IDH1 inhibitors; 2-hydroxyglutarate; isocitrate dehydrogenase; intrahepatic cholangiocarcinoma
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25163754

Cholangiocarcinoma is a primary malignancy of the biliary tract characterized by late and unspecific symptoms, unfavorable prognosis, and few treatment options. The advent of next-generation sequencing has revealed potential targetable or actionable molecular alterations in biliary tumors. Among several identified genetic alterations, the mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some point mutations induce widespread epigenetic alterations by means of a gain-of-function of the enzyme, which becomes able to produce the oncometabolite 2-hydroxyglutarate, with inhibitory activity on α-ketoglutarate-dependent enzymes, such as DNA and histone demethylases. Thus, its accumulation produces changes in the expression of several key genes involved in cell differentiation and survival. At present, small-molecule inhibitors of mutated enzyme are under investigation in preclinical and clinical phases as promising innovative treatments for IDH1-mutated intrahepatic cholangiocarcinomas. This review examines the molecular rationale and the results of preclinical and early-phase studies on novel pharmacological agents targeting mutant in cholangiocarcinoma patients. Contextually, it will offer a starting point for discussion on combined therapies with metabolic and epigenetic drugs, to provide molecular support to target the interplay between metabolism and epigenetics, two hallmarks of cancer onset and progression.