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IDH1 Targeting As a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

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IDH1 Targeting As a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives molecules Review IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives 1, 1, 1 1 Fabiana Crispo y , Michele Pietrafesa y , Valentina Condelli , Francesca Maddalena , Giuseppina Bruno 2, Annamaria Piscazzi 2, Alessandro Sgambato 1, Franca Esposito 3,* and Matteo Landriscina 1,2,* 1 Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (PZ), Italy; [email protected] (F.C.); [email protected] (M.P.); [email protected] (V.C.); [email protected] (F.M.); [email protected] (A.S.) 2 Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; [email protected] (G.B.); [email protected] (A.P.) 3 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy * Correspondence: [email protected] (F.E.); [email protected] (M.L.); Tel.: +39-081-746-3145 (F.E.); +39-088-173-6426 (M.L.) These authors have contributed equally to this work. y Received: 29 July 2020; Accepted: 17 August 2020; Published: 18 August 2020 Abstract: 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 IDH1 mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some IDH1 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 IDH1 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 IDH1 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. Keywords: intrahepatic cholangiocarcinoma; isocitrate dehydrogenase; 2-hydroxyglutarate; IDH1 inhibitors 1. Cholangiocarcinoma: From Classification to Treatment Strategies Cholangiocarcinoma (CCA) is a heterogeneous group of hepatobiliary malignancy that originates from biliary epithelium, at any portion of the tree, and shows features of cholangiocyte differentiation [1]. Cholangiocarcinoma represents almost 3% of all gastrointestinal tumors and the global CCA incidence rate shows geographic variation, probably as a result of differences in genetic characteristics and/or Molecules 2020, 25, 3754; doi:10.3390/molecules25163754 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 22 global CCA incidence rate shows geographic variation, probably as a result of differences in genetic characteristics and/or exposure to risk factors of the world’s populations [2]. Intriguingly, Eastern countries, particularly the northeast of Thailand, exhibit higher age-standardized incidence rates Molecules(ASIRs)2020 than, 25 in, 3754 the West (Europe, United States and Australia), where the incidence of this disease2 of 23is <6 per 100,000 cases [2], so much so that CCA is considered a rare cancer. Generally, a slightly smaller incidence and mortality is observed in women compared to men (the male-to-female ratio is exposure to risk factors of the world’s populations [2]. Intriguingly, Eastern countries, particularly 1:1.2–1.5) [3–5]. the northeast of Thailand, exhibit higher age-standardized incidence rates (ASIRs) than in the West On the basis of their anatomical location, CCAs can be classified into three clinically distinct (Europe, United States and Australia), where the incidence of this disease is <6 per 100,000 cases [2], types of cancers: intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) cholangiocarcinoma so much so that CCA is considered a rare cancer. Generally, a slightly smaller incidence and mortality (Figure 1). is observed in women compared to men (the male-to-female ratio is 1:1.2–1.5) [3–5]. On the basis of their anatomical location, CCAs can be classified into three clinically distinct types of cancers: intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) cholangiocarcinoma (Figure1). FigureFigure 1.1. The biliarybiliary tree,tree, basedbased onon anatomicalanatomical classification,classification, isis subdividedsubdivided intointo intrahepaticintrahepatic andand extrahepaticextrahepatic portions. portions. The The extrahepatic extrahepatic tract tract comprises comprises the the right right and and left hepatic left hepatic ducts, ducts, from whichfrom which arises aarises perihilar a perihilar CCA (pCCA), CCA (pCCA), the common the common bile duct thatbile accountsduct that for accounts distal CCA for distal (dCCA), CCA and (dCCA), the gallbladder. and the Thegallbladder. intrahepatic The counterpart intrahepatic derives counterpart from the deri second-orderves from bilethe ducts.second-order The sub-classification bile ducts. The of intrahepaticsub-classification CCA (iCCA)of intrahepatic is based CCA on the (iCCA) size of is the based duct on from the whichsize of thethe tumorduct from originates: which Thethe tumor small bileoriginates: duct type The arises small from bile duct the interlobular type arises from andseptal the interlobular ducts, while and the septal large ducts, duct typewhile arises the large from duct the segmentaltype arises ducts. from the segmental ducts. iCCAiCCA arisesarises inin thethe second-degreesecond-degree bilebile ducts,ducts, specificallyspecifically fromfrom segmentalsegmental bilebile ductsducts toto smallersmaller branchesbranches ofof thethe intrahepaticintrahepatic partpart ofof biliarybiliary tree.tree. In contrast, pCCA and dCCAdCCA areare cancerscancers ofof thethe extrahepaticextrahepatic biliarybiliary treetree becausebecause thethe firstfirst originatesoriginates fromfrom thethe rightright andand/or/or leftleft hepatichepatic ductduct andand/or/or thethe commoncommon hepatichepatic duct duct proximally proximally to theto cysticthe cystic duct origin,duct origin, while thewhile second the occurssecond below occurs the below insertion the ofinsertion the cystic of ductthe cystic into the duct common into the bile common duct, but bile not includingduct, but thenot ampullaincluding Vater the [1ampulla,6]. pCCA Vater accounts [1,6]. approximatelypCCA accounts 50–60% approximately of CCAs cases50–60% and of together CCAs cases with dCCAand together (20–30%) with represents dCCA (20–30%) 80–90% of represents all CCAs diagnosed80–90% of inall the CCAs United diagnosed States; the in remainingthe United 10–20% States; isthe represented remaining by 10–20% iCCA, whichis represented is the less by frequent iCCA, subtypewhich is of the CCA, less but frequent the second subtype most of common CCA, but primary the second intrahepatic most malignancycommon primary after hepatocellular intrahepatic carcinomamalignancy (HCC) after [hepatocellular5]. Although pCCA carcinoma and dCCA (HCC) represent [5]. Although the majority pCCA of and CCA dCCA cases, represent over the lastthe twomajority decades, of CCA iCCA cases, has shown over athe progressive last two increasedecades, of iCCA incidence has inshown the world, a progressive whereas the increase incidence of ratesincidence of other in the CCA world, subtypes whereas have the decreased incidence in the rate sames of periodother CCA [2,5]. subtypes have decreased in the sameThis period change [2,5]. in epidemiological trends is transforming the iCCA subtype into a global health problem that warrants attention and investigations for several reasons: (i) Incidence and mortality rates have risen significantly since the end of the past century; (ii) the knowledge about molecular mechanisms underlying iCCA onset is lacking and incomplete, thus a series of questions remain unanswered; (iii) this CCA subtype displays the highest inter-tumor heterogeneity, making its diagnosis Molecules 2020, 25, 3754 3 of 23 complex, subsequently affecting the prognosis and management of patients; (iv) no effective therapies are available—thus far, iCCA is recognized as an orphan-drug disease. Unlike pCCAs and dCCAs, which are mucin-producing adenocarcinomas (conventional type) or papillary tumors, iCCAs are characterized by highly variable morphological aspects, distinguishing a mucin-producing adenocarcinoma (bile duct (mucinous) type iCCAs or large bile duct type iCCAs), which originates from cholangiocytes and peribiliary glands, and a mixed subtype (bile ductular (mixed)-type iCCAs or small bile duct type iCCAs), in which areas of adenocarcinoma coexist with areas of hepatocytic differentiation, suggesting it originated from hepatic progenitor cells [2,6]. iCCA is characterized by clinical aggressiveness, like all CCA subtypes, but unlike pCCA and dCCA, it
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