<i>IDH1</i> Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives
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 sev...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/16/3754 |
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| author | Fabiana Crispo Michele Pietrafesa Valentina Condelli Francesca Maddalena Giuseppina Bruno Annamaria Piscazzi Alessandro Sgambato Franca Esposito Matteo Landriscina |
| author_facet | Fabiana Crispo Michele Pietrafesa Valentina Condelli Francesca Maddalena Giuseppina Bruno Annamaria Piscazzi Alessandro Sgambato Franca Esposito Matteo Landriscina |
| author_sort | Fabiana Crispo |
| collection | DOAJ |
| description | 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 <i>IDH1</i> mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some <i>IDH1</i> 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 <i>IDH1</i> 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 <i>IDH1</i> 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. |
| first_indexed | 2024-03-10T17:16:44Z |
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| id | doaj.art-e75a858fb11e46fcaccf73d283e63b70 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T17:16:44Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e75a858fb11e46fcaccf73d283e63b702023-11-20T10:28:56ZengMDPI AGMolecules1420-30492020-08-012516375410.3390/molecules25163754<i>IDH1</i> Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future PerspectivesFabiana Crispo0Michele Pietrafesa1Valentina Condelli2Francesca Maddalena3Giuseppina Bruno4Annamaria Piscazzi5Alessandro Sgambato6Franca Esposito7Matteo Landriscina8Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), ItalyMedical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, ItalyMedical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), ItalyCholangiocarcinoma 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 <i>IDH1</i> mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some <i>IDH1</i> 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 <i>IDH1</i> 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 <i>IDH1</i> 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.https://www.mdpi.com/1420-3049/25/16/3754intrahepatic cholangiocarcinomaisocitrate dehydrogenase2-hydroxyglutarate<i>IDH1</i> inhibitors |
| spellingShingle | Fabiana Crispo Michele Pietrafesa Valentina Condelli Francesca Maddalena Giuseppina Bruno Annamaria Piscazzi Alessandro Sgambato Franca Esposito Matteo Landriscina <i>IDH1</i> Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives Molecules intrahepatic cholangiocarcinoma isocitrate dehydrogenase 2-hydroxyglutarate <i>IDH1</i> inhibitors |
| title | <i>IDH1</i> Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives |
| title_full | <i>IDH1</i> Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives |
| title_fullStr | <i>IDH1</i> Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives |
| title_full_unstemmed | <i>IDH1</i> Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives |
| title_short | <i>IDH1</i> Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives |
| title_sort | i idh1 i targeting as a new potential option for intrahepatic cholangiocarcinoma treatment current state and future perspectives |
| topic | intrahepatic cholangiocarcinoma isocitrate dehydrogenase 2-hydroxyglutarate <i>IDH1</i> inhibitors |
| url | https://www.mdpi.com/1420-3049/25/16/3754 |
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