Next Article in Journal
Evidences for a Role of Gut Microbiota in Pathogenesis and Management of Epilepsy
Next Article in Special Issue
Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer
Previous Article in Journal
Caspase-14—From Biomolecular Basics to Clinical Approach. A Review of Available Data
Previous Article in Special Issue
KRAS, A Prime Mediator in Pancreatic Lipid Synthesis through Extra Mitochondrial Glutamine and Citrate Metabolism
Review

From Metabolism to Genetics and Vice Versa: The Rising Role of Oncometabolites in Cancer Development and Therapy

1
Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
2
Medical Oncology and Cancer Prevention Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
*
Author to whom correspondence should be addressed.
Academic Editors: Karel Smetana and Michal Masarik
Int. J. Mol. Sci. 2021, 22(11), 5574; https://doi.org/10.3390/ijms22115574
Received: 23 April 2021 / Revised: 21 May 2021 / Accepted: 22 May 2021 / Published: 25 May 2021
(This article belongs to the Special Issue Advances in Cancer Metabolism and Tumour Microenvironment)

Abstract

Over the last decades, the study of cancer metabolism has returned to the forefront of cancer research and challenged the role of genetics in the understanding of cancer development. One of the major impulses of this new trend came from the discovery of oncometabolites, metabolic intermediates whose abnormal cellular accumulation triggers oncogenic signalling and tumorigenesis. These findings have led to reconsideration and support for the long-forgotten hypothesis of Warburg of altered metabolism as oncogenic driver of cancer and started a novel paradigm whereby mitochondrial metabolites play a pivotal role in malignant transformation. In this review, we describe the evolution of the cancer metabolism research from a historical perspective up to the oncometabolites discovery that spawned the new vision of cancer as a metabolic disease. The oncometabolites’ mechanisms of cellular transformation and their contribution to the development of new targeted cancer therapies together with their drawbacks are further reviewed and discussed.
Keywords: oncometabolites; cancer; metabolism; epigenetics; therapy; metabolomics oncometabolites; cancer; metabolism; epigenetics; therapy; metabolomics

1. The Rebirth of Cancer Metabolism

In early 1920, Otto Warburg made a very significant observation still acknowledged 98 years later that remarkably contributed to the recent renaissance of cancer metabolism research. During biochemical studies on sea urchin eggs, he noted a significant increase in oxygen consumption during fertilization [1], demonstrating for the first time that cellular replication and growth can induce changes in metabolism [2,3]. In further investigations on mice hepatoma tissue slices supplemented with glucose, he observed a 70-fold increase of lactic acid production independently from the presence of oxygen that would be named aerobic glycolysis or the “Warburg effect” [4]. Warburg attributed the cause of the impairment of cellular respiration to dysfunctional mitochondria and became convinced that defective metabolism was the main driver of carcinogenesis [2] as declared to the German Central Committee for Cancer Control in Stuttgart 1955 “… there is today no other explanation for the origin of cancer cells, either special or general. From this point of view, mutation and carcinogenic agent are not alternatives, but empty words, unless metabolically specified…” [5]. From its early beginning, Warburg’s theory found many opponents that considered the “Warburg effect” only an adaptation to hypoxic conditions due to the poor vascularization of the tumours. The biochemist Weinhouse confuted Warburg’s theory showing that cancer cells were able to accomplish oxidative phosphorylation like normal cells and, unlike Warburg, he sustained that dysfunctional mitochondria were not the cause but the consequence of upregulated glycolysis [6]. However, more quickly than expected, the debate ended and Warburg’s idea was considered old-fashioned. Meanwhile the genetic model of cancer based on the Somatic Mutation Theory (SMT) originally proposed by Theodor Boveri [7] became the most attractive. The attention on cancer metabolism was definitively taken away by the discoveries of oncogenes and tumour suppressor genes starting from the SRC oncogene initially isolated in Rous sarcoma retrovirus [8,9,10,11] and later in human cells [12]. The SRC oncogene was followed by MYC, ERBB/EGFR, and RAS oncogenes [13,14,15,16,17] whose identification in diverse human cancers [18,19] consolidated the view of cancer as a genetic disease. Only at the end of the 90s was an unexpected link found between the genes involved in cell proliferation and cellular energy metabolism that led to reconsideration of the importance of metabolism and Warburg’s theory in cancer development. In 1997 Dang et al. demonstrated that the transcription factor MYC, well known for its role in cell cycle and apoptosis, directly affected the expression of the lactate dehydrogenase-A gene (LDH-A), turning on the Warburg effect [20]. Independently, Craig Thompson et al. identified the cause that sustained the aerobic glycolysis in the alteration of the protein kinase B (Akt) signalling pathway commonly activated in human cancers in response to different transcription factors [21] including p53, hypoxia-inducible factor (HIF) and nuclear factor-κB (NF-κB), which were further found to be involved in cancer metabolic reprogramming [22,23,24]. The breakthrough for the Warburg revival coincided with the finding of specific mutated genes encoding for enzymes of the tricarboxylic acid (TCA) cycle as the succinate dehydrogenase (SDH) [25,26] and fumarate hydratase (FH) [27]. The loss of function (LoF) of these mitochondrial enzymes lead to the accumulation of their respective substrates, as succinate and fumarate, in different human cancer types, supporting the original role of mitochondria in cancer development. The observation that two mitochondrial enzymes could act as classic tumour suppressors [25,28] instilled the idea that oncogenes and tumour suppressor genes can also express their functions exclusively by reprogramming cellular metabolism. A few years later, the discovery of a specific defect in the enzymatic activity of the mitochondrial isocitrate dehydrogenase (IDH) [29,30,31] led to the tumour accumulation of 2-hydroxyglutarate (2-HG), further proving the importance of specific metabolites in tumorigenesis starting the oncometabolites era.

2. Oncometabolites: The Emerging of a New Paradigm

The cellular accumulation of succinate, fumarate and 2-HG promotes and sustains specific metabolic phenotypes that induce cancer development and growth. For these characteristics, they take the name of oncometabolites, defined as small molecules whose abnormal cellular accumulation is able to activate oncogenic signalling and promote a milieu favourable for the tumorigenesis. Interestingly, all of them are the result of genetic mutations encoding enzymes of the TCA cycle supporting the essential role of mitochondria as signalling hubs for key biological functions in both normal and cancer cells fate [32]. Despite oncometabolites cellular accumulation is associated with gene mutations, their oncogenic mechanisms go beyond genetics since they can directly act at all omics levels, altering cell signalling and regulating gene expression and protein functions as unique cancer phenotype modulating agents.

2.1. The Succinate

The identification of germline SDHD gene mutations both in hereditary paragangliomas (PGLs) [25] and pheochromocytomas (PCCs) [26] moved attention on the role of mitochondrial metabolism in cancer development again. The SDH genes (SDHA, SDHB, SDHC, SDHD) encode the subunits of the succinate dehydrogenase tetrameric complex also known as mitochondrial complex II, which is involved in the TCA cycle as well as in the aerobic electron transport chain (ETC) [33] (Figure 1). This latter is constituted by four subunits (SDHA, SDHB, SDHC, SDHD) assembled in two protein complexes. The SDHA and SDHB constitute the catalytic subunits responsible for the oxidative conversion of succinate to fumarate, while the SDHC and SDHD subunits have only a structural role as membrane anchor [34]. The defects in SDH activity raised from germline mutations on chromosome 1 or 11 can include missense, nonsense, frameshift, splicing defect, and deletion/insertion [35,36]. The LoF of SDH occurs by the loss of heterozygosity (LOH) due to the second allele deletion that arrests the succinate- fumarate conversion [37]. Cellular metabolomics investigations pointed out the specific accumulation of the succinate [38,39,40,41,42] in tumours that carry the LOH for the SDHx mutated genes including renal cell carcinoma, gastrointestinal stromal tumour, pituitary adenomas pancreatic neuroendocrine tumours [43,44,45,46,47,48] and PGLs [49]. The SDH immunohistochemistry (IHC) staining using specific SDHB antibodies has been proposed as test for the screening of SDHx mutations since the loss of SDHB subunit is correlated with any SDHx mutations [50]. However, the IHC presents some drawbacks linked to the heterogenic or weak diffuse SDHB immunostaining that may increase the risk for false-negative or positive cases [49,51,52]. Therefore, succinate accumulation or the phenotypic succinate/fumarate ratio, measured by liquid chromatography-mass spectrometry, has been proposed to improve the sensitivity and specificity of SDHx detection [41]. The LOH for the SDHx can be reviled non-invasively in vivo by proton 1H-MRS tomography through measuring differential succinate accumulation [53,54].
The common biochemical consequence of the succinate accumulation was the increased production of ROS likely due to the role played by the SDH in the ETC [55,56]. Different evidences showed an increase of oxidative stress in SDH mutant tumours which was associated with genomic instability and tumorigenesis [55,57,58,59]. However, succinate can also leave mitochondria and exert different effects on both the cytosolic and nuclear key enzymes directly involved in malignant transformation [60] as described in the following section.

2.2. The Fumarate

The FH gene encodes a key TCA cycle enzyme and its germinal mutations at chromosome locus 1q43 have been associated with the decrease of enzyme activity and fumarate cellular accumulation [61]. Among the FH mutations, the missense and frameshift [62,63] are the most common found in uterine fibroids, hereditary leiomyomatosis, and renal cell carcinoma syndrome (HLRCC) [27] and also in PGLs and PCCs [64,65]. These mutations indeed lead to significant reduced FH activity [66] or to the premature truncation of the protein [67]. The missense mutations mainly involved the conserved enzyme’s active site or subunits important for inter-intra interactions and protein stability [66,68]. The FH is a homotetrameric enzyme localized in both mitochondria and cytosol where it is involved in the reversible hydration of fumarate to malate as well as in the catabolism pathways of amino acids [69] (Figure 1). The early diagnosis of tumour FH genetic defects could be clinically detected by IHC of the protein or by metabolomics investigations to search for specific fumarate accumulation [41,70]. The FH immunostaining integrated with the IHC for succinated proteins [71,72,73,74] is the most used diagnostic test for detecting mitochondrial FH dysfunction identified by FH negative and 2-succinocysteine positive staining [72,74,75]. The FH and succinated proteins IHC are generally classified with “0” score for negative staining (total loss), “1+” or “2+” score for focal or diffuse staining with weak or strong intensity, respectively (partial loss) [74]. The fumarate/malate ratio could be also used for diagnostic purposes as well as other specific metabolic features consequent to fumarate cellular accumulation, including the reversal induction of the argininosuccinate lyase (ASL) activity [76,77].
The FH LoF induces a significant fumarate accumulation that leads to post-translational modifications, affecting proteins functions out of mitochondria and causing chromatin modulations altering epigenetic status and gene expression that drives malignant transformation through specific biochemical mechanisms detailed in further sections.

2.3. The R-2-Hydroxyglutarate

The involvement of R-2HG metabolite in cancer was ignored until 2008 when Parsons et al. sequenced over 20,000 genes in glioblastoma [31] finding in 12% of patients a somatic mutation in the isocitrate dehydrogenase (IDH) gene. Different metabolomics analyses in tumours tissues, as well as in cerebrospinal fluid, blood, and urine, demonstrated that the IDH gene mutation is associated with a huge cellular accumulation of the R-2HG [78,79,80,81,82,83,84]. Further studies found the same mutation also in II-III grade gliomas, in secondary glioblastoma [29,30], as well as in extra-brain cancers such as human acute myeloid leukaemia (AML) [85], intrahepatic cholangiocarcinoma [86], chondrosarcomas [87] and breast carcinoma [88,89,90]. The IDH is an important enzyme involved in the TCA cycle responsible for the reversible oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) (Figure 1). The IDH enzyme is present in three distinct isoforms that differ for localization and co-factors dependence: the homodimers IDH1 and IDH2 use nicotinamide adenine dinucleotide phosphate (NADP) cofactor and are localized in cytosol and mitochondria, respectively, while the heterotrimeric IDH3 isoform is dependent on NAD cofactor which confers a regulatory activity in function of the cell energy status and catalyses the forward reaction from isocitrate to α-KG. The most common cancer mutations involve the IDH1 and IDH2 isoforms and resulted to be mutually exclusive [91]. Their prevalence is different according to the cancer type since it was found that IDH1 has higher incidence rate than IDH2 in brain cancers [91,92], while in AML they are equally common [93], likely reflecting the differential tumour metabolic needs.
The IDH mutations concern the substitution of the arginine R132 (for IDH1), and R172 or R140 (for IDH2) with a histidine residue. The arginine substitution decreases the affinity for isocitrate substrate, resulting in a significantly slower rate of conversion to α-KG. Also, it increases the affinity for NADPH that confers a neomorphic activity to the enzyme allowing the further stereospecific conversion of α-KG into the R-2HG enantiomer [79]. The concentration of R-2HG metabolite in glioma cells carrying the mutated IDH1/2 can reach ~30 millimolar [79,94,95] saturating the mitochondrial R-2HG dehydrogenase responsible for its cellular removal [96]. Interestingly, even the IDH wild type tumour produced the enantiomer R-2HG, however its concentration resulted 100 fold less than IDH mutated tumours [96]. The IDH heterozygous mutation was found to be the necessary condition to reach such high R-2HG levels [97]. The IDH mutations have remarkable clinical utility allowing a better gliomas classification [98] that improves the current diagnosis and prognosis of this cancer disease [99,100,101,102]. Numerous investigations have focused on R-2HG as a surrogate biomarker for identifying IDH mutations. In AML the measurement of R-2HG can be carried out directly in patients’ serum or plasma where it resulted notably correlated with IDH mutations [103,104]. However, despite the good diagnostic power, the serum R-2HG level in AML has poor prognostic relevance not having been found associated with the overall clinical outcomes [105,106]. In glioma, advances in magnetic resonance spectroscopy (MRS) allowed researchers to effectively measure 2HG in vivo with good correlation with IDH mutation status [107,108,109,110,111,112], whereas MRS can measure total 2HG at the tissue level, chromatography coupled with mass spectrometry enables the specific quantification of R- and S-stereoisomers in the cerebrospinal fluid, serum and urine. However, its application has produced no concordant results since some studies found a positive correlation between high 2HG levels and mutation status [81,82,83,113,114] while others reported no difference between wild-type and mutant patients [115,116]. These discrepancies could be associated with the lack of standardized analytical methods or depend on patients’ pathological status since the blood-brain barrier integrity may be differentially compromised in gliomas patients [117,118], affecting the amount of 2HG that reaches blood and urine.
Beyond the IDH-mutated production, the cellular R-2HG was found to have other sources that further highlight its active role in cancer development [119] (Figure 1). In breast cancer, the oncogene phosphoglycerate dehydrogenase (PHGDH) was reportedly able to accumulate both S/R-2HG enantiomers from α-KG [120] as well as the overexpression of the mitochondrial hydroxyacid-oxoacid-transhydrogenase (HOT), which produces R-2HG as a consequence of the 4- hydroxybutyrate to succinic semialdehyde conversion [121,122] (Figure 1). Moreover, R-2HG seems to be derived from specific immune cells such as activated T helper (Th) 17 when they metabolically switch from oxidative phosphorylation to aerobic glycolysis in the response against the tumour [123]. All this evidence has reinforced the hypothesis that R-2HG involvement in tumorigenesis may be independent from IDH mutations, revealing insights on novel cancer targets.

3. Oncometabolites Mechanism of Cancer Induction

The cellular accumulation of oncometabolites initiates carcinogenesis and sustains the invasive neoplastic phenotype by interfering with important cellular metabolic signalling at both genomic and proteomic levels [124,125]. They have a common biochemical mechanism of interference which consists in the inhibition of the activity of the cellular α-KG dependent dioxygenases (α-KGDDs) [126,127,128], a wide family of enzymes that includes about 60 different isoforms involved in the control of epigenetic modifications and hypoxia responses [129]. The α-KGDDs are Fe (II) enzymes that catalyse oxidative hydroxylations of target substrates both at transcriptional and post-transcriptional levels. The hydroxylation at the methyl group represents the first step for the final methyl removal from histones and DNA, occurring through sequential oxidative formylation and decarboxylation reactions with consumption of O2 and α-KG and CO2 and succinate production [129] (Figure 2). Oncometabolites are all structurally similar to the α-KG substrate and compete with its active binding site inhibiting the activity of α-KGDDs. The inhibition of two specific α-KGDDs, such as the ten-eleven translocation (TETs) and Jumonji domain-containing histone-lysine demethylases (KDMs), induced by the high cellular concentration of succinate, fumarate or R-2HG can have relevant epigenetic consequences being strictly involved in the modulation of the chromatin and genome methylation status [130,131,132] (Figure 2). The KDMs are directly involved in the demethylation of the histones at lysine residues [132], while TETs catalyse the DNA demethylation of 5-methylcytosine regulating the transcription of the genes [133]. Thus, the competitive inhibition of KDMs and TETs by oncometabolites induces a typical hypermethylation phenotype [126,130,134,135,136] that affects the transcription of genes involved in DNA repair (MGMT, BRCA, ATM), apoptosis (DAPK, TMS1), cell cycle (p16INK4a, p15INK4b, Rb, p14ARF), carcinogen-metabolism (GSTP1), and cell-adherence (CDH1, CDH13), enabling cancer growth and proliferation [137,138]. Other genes are regulated specifically by either KDM or TET isoforms. The specific inhibition of the KDM4B isoform by oncometabolites resulted in the hypermethylation at histone 3 lysine 9 (H3K9) with consequent alteration of the pathway of homology-dependent repair (HDR) that prevents the recruitment of DNA repair factors [139]. The KDM4B inhibition was also found associated with aberrant activation of mTOR pathway in IDH mutant tumour [140,141]. Moreover, the TET inhibition was found correlated with impaired myeloid differentiation in AML due to hypermethylation in genes containing DNA binding motifs for transcription factors important for leukemogenesis [142]. The HIF-prolyl 4-hydroxylases (PHDs) is another α-KGDD inhibited by oncometabolites. It is responsible for the regulation of cellular stability of the HIF, a transcription factor targeting several genes mainly involved in angiogenesis, glycolysis, and apoptosis [143,144]. In normoxic conditions, HIF resulted hydroxylated by PHDs at prolines residues allowing its cellular degradation through the ubiquitin-proteasome system (Figure 2). The high oncometabolites concentration prevents the HIF hydroxylation stabilizing it in the active form inducting a pseudohypoxia status characterized by increased angiogenesis and glucose metabolism [37,145,146,147,148]. Independently by HIF mechanism, fumarate and succinate can additionally enhance hypoxia signalling via TETs epigenetic activation [149] and through ABL1 up-regulation and mTOR pathway [150]. Moreover, succinate itself can upregulate vascular endothelial growth factor (VEGF) through the activation of succinate receptor G protein-coupled receptor-91 (GPR91) further promoting tumour angiogenesis [151,152]. Unlike succinate and fumarate, the role of R-2HG in the induction of pseudohypoxia is controversial. Some studies have reported that it could both activate [153,154,155] and inactivate the PHDs [148,156], while others sustain no correlation between R-2HG and HIF activation in gliomas [157,158] suggesting that R-2HG may not be the main regulator of the HIF signalling pathway.
In addition to these features, each oncometabolite exerts distinct pathological functions that likely are associated with the specific cancer type where they accumulate. High cellular fumarate concentrations induce protein succination, a post-translational modification generated by the Michael addition of proteins’ cysteine thiols to fumarate with the production of S-(2-succino)-cysteine derivatives [159] (Figure 1). This irreversible protein modification can involve Kelch-like ECH-associated protein-1 (KEAP1) that normally exerts a negative control on the nuclear factor erythroid 2–related factor 2 (Nrf2) [160,161]. This latter is a regulator of cellular antioxidant systems and the KEAP1 succination triggers the Nrf2 related-genes up-regulation, making tumoral cells able to adapt to oxidative stress favouring cell proliferation and survival [162,163,164,165]. Conversely, fumarate succination of glutathione (GSH) causes a drop of the cellular NADPH levels which is associated with an enhancement of ROS production promoting cancer by cellular damage [166,167,168]. Another specific fumarate effect has been associated with urea cycle alteration since the fumarate accumulation reverses the ASL reaction with consequent arginosuccinate increase that makes FH-deficient cells auxotrophic for arginine [77]. Analogously to fumarate, succinate can induce succinylation of proteins, a characteristic post-translation modification mediated by succinyl coenzyme A whose level increased consequently the high cellular succinate accumulation in SDH-deficiency cells [169,170]. The nucleophilic addition of the ɛ-amino group of lysine to the succinyl-CoA generates succinyl-lysine proteins exchanging the positive charge on lysine which may alter protein structural conformational and protein-protein interactions [170]. Indeed, succinylation was reported to affect several biological protein targets such as nuclear histones [169,171] and mitochondrial proteins [172,173,174] that could alter the endoplasmic reticulum protein processing, increase the glucose metabolism and confer resistance to cell apoptosis to sustain cell growth [175,176] (Figure 1). The main sites of hypersuccinylation were identified in mitochondrial protein such as pyruvate dehydrogenase complex, ATP synthase, respiratory chain complexes I, III, and IV, cytochrome c oxidase but also in SHDB itself, with consequent impair in cellular respiration and increased recruit of BCL-2 to mitochondrial membrane preventing apoptosis [172,174,177].
Other oncogenic mechanisms specific of the R-2HG concern the selective inhibition of the α-KG-dependent branch chain amino acid transaminases 1 (BCAT1) and BCAT2 [178], decreasing glutamate levels and making cells auxotrophic for this amino acid as well as for glutamine necessary to continuously replenish the NADPH consumed by mutant IDH and essential to fuel the cellular anabolism that supports the tumour growth [179]. Whereas the inhibition of the ALKBH homolog, another α-KG-dependent enzyme, decreases the DNA repair activity accumulating DNA damage in cancer cells [180]. Both effects could explain the higher efficacy of glutaminase inhibitors and alkylating agents in IDH mutant cancer [181,182,183,184,185,186], as well as the best prognosis to temozolomide treatments in IDH, mutated glioma [181,186,187,188]. Conversely, R-2HG may induce drug resistance phenomena by inducing the overexpression of the homeobox protein NANOG increasing multidrug resistance protein 1 expression [189]. Another interesting R-2HG effect is represented by its immunosuppressive activity in the tumour microenvironment. The R-2HG can inhibit the chemotaxis mediated by signal transducer—activator of transcription 1 (STAT1) reducing the tumour infiltrating CD8+ cytotoxic T lymphocyte [190,191,192], and increasing the regulatory T-cell over the Th17 [193]. It also prevents T lymphocyte activation by suppressing the ATPase and reduces the nuclear factor of activated T cell (NFAT) expression [194,195] and inactivates the complement-mediated lysis and phagocytosis in gliomas cells [196]. All these aspects seem to suggest that R-2HG could contribute to tumour escape from the immune system surveillance and should be taken into account when immunotherapy strategies are considered in gliomas treatments.

4. Targeted Therapies

The role of oncometabolites in cancer has stimulated the development of novel targeted therapies that are mainly addressed to the inhibition of their accumulation and/or the constraint of their metabolic and epigenetic downstream effects. The first pharmacological strategy brought to the development of specific IDH inhibitors to decrease R-2HG production. This approach has been exclusively exploited for IDH over the SDH and FH targets because the IDH mutant enzyme gains a neomorphic function different from that of wild type. Moreover, compared with succinate and fumarate, which are involved in several physiological metabolic pathways, the R-2HG apparently does not have any known relevant physiological activities [197]. These features addressed the development of numerous drugs for the mutated IDH form, which mainly acts as allosteric inhibitors (Table 1) [198,199,200,201,202,203]. Most of these drugs were designed and developed by the emerging Agios Pharmaceutical and two of them, enasidenib and ivosidenib, have found a place in clinics.
Enasidenib (IDHIFA®, AG-221, Celgene Corporation) was the first IDH inhibitor approved by the Food and Drug Administration (FDA) for the treatment of relapsed or refractory (R/R) AML with IDH2 mutation [201]. Phase I/II clinical trial (NCT01915498), conducted in 239 patients showed promising results with an overall response rate of 40.3% with 19.3% of patients who achieved a complete response [201]. Moreover, the drug exhibits a good toxicological profile., Like other targeted therapy they are characterized by few side effects that includes nausea, vomiting, diarrhoea, jaundice and decreased appetite [204]. Currently, ongoing clinical trials are investigating the use of enasidenib alone or in combination with standard chemotherapy drugs such as azacitidine in the treatment of hematologic malignancies as well as in glioma, cholangiocarcinoma, and chondrosarcoma (ClinicalTrials.gov NCT03683433, NCT02677922, NCT03839771) [205]. The other IDH inhibitor ivosidenib (Tibsovo®, AG-120, Agios Pharmaceuticals, Inc.) received FDA approval for the treatment of R/R AML carrying the IDH1 mutated form [200]. The result of a single-arm study (NCT02074839) provided valuable data regarding its efficacy and safety; indeed, 30.4% of patients achieved a complete or partial remission with a median response duration of 8.2 months [206]. In addition, 37% of AML patients became transfusion independent, and 21% had no residual detectable IDH1 mutations [206]. The IDH1 inhibitor showed a favourable toxicity profile including fatigue, anaemia, nausea, diarrhoea, with a few relevant specific side effects such as alteration in heart rhythm and increase of serum aminotransferase levels [207]. Ivosidenib was also recently approved as first-line of treatment for newly diagnosed AML in patients over 75 years old [208] while preliminary results from phase III clinical trials seem to prove its clinical activity also in IDH1 mutated cholangiocarcinoma [209]. Other small IDH inhibitors such as olutasidenib (FT-2102) are currently under investigation in phase I/II clinical trials for AML and myelodysplastic syndrome [202] as well as vorasidenib (AG-881), a pan inhibitor of both IDH1/2 enzymes, has been evaluated in glioma (NCT04164901) [199]. Despite the promising results of these IDH inhibitors, some studies reported clinical cases of acquired resistance, which was found associated with the occurrence of a new second-site IDH2 mutations in trans or in cis at the level of the drug binding site [210], or with the emergence of an additional mutation that restored the R-2HG synthesis [211], while others exhibited the isoform switching phenomena from IDH1 to IDH2 and vice versa [212]. Moreover, the use of IDH inhibitors presents several challenges and their clinical application needs to be carefully evaluated. The R-2HG rise leads to concomitant NADPH consumption that may alter the ox-red cancer status making IDH-mutated cells more sensitive to standard chemo and radiotherapy due to the ROS burst [213,214,215,216,217]. In the same context, the DNA damage repair inhibition mediated by R-2HG makes IDH mutated tumours more vulnerable to alkylating drug treatment [218]. These specific biochemical features of IDH mutated cells can suggest that IDH inhibitors treatment may not be always advantageous and must be carefully evaluated on the basis of specific tumour metabolic characteristics [218,219,220,221].
An interesting new therapeutic strategy targeting IDH mutated cancers is represented by the development of IDH immune vaccines [222,223]. This approach is based on the evidence that glioma patients developed a Th-1 response against IDH1(R132H)+ tumours [222,223,224,225]. This inspired the development of a targeted- mutant IDH neoepitope vaccine to potentiate the response of the immune system against IDH mutated tumours. Two clinical trials are currently ongoing to test such immune strategy (NCT02193347, NCT02454634) [222,223]. The latter study has recently ended phase I, demonstrating the safety profile of peptide vaccine in grade III and IV astrocytomas patients [226].
Besides the inhibition of oncometabolite production, the other pharmacological approaches contrast the oncometabolites downstream effects. For instance, the glutaminase inhibitors were effective in reducing the growth of SDH and FH-deficient cancers [227,228,229] by lowering the glutamine needed to replenish TCA intermediates [227,229] including the R-2HG in IDH mutant tumours [230,231,232]. Conversely, high doses of α-KG may restore the hydroxylation activity of α-KGDDs enzymes by sweeping the oncometabolites in the binding site. However, only a few preclinical studies confirmed that the α-KG excess can effectively restore the PDHs as well as the TETs activity [136,233]. Another more established therapeutic option consisted of the use of demethylating agents to reverse the hypermethylated phenotype. In this context, the use of 5-azacitidine and its derivative decitabine were shown to reduce the methylation in SDH knock-out cells [136,234] as well as in IDH mutated gliomas [235,236,237,238]. This activity has been translated in clinical setting by reporting a better overall survival in IDH mutated AML patients treated with azacitidine/decitabine in combination with the BCL-2 inhibitor venetoclax [239,240]. The combination of azacitidine and different IDH inhibitors showed complete remission in AML patients suggesting a synergetic activity between the two drugs [200,201,202,241]. Following these promising results, other novel hypomethylating agents such as guadecitabine are currently under investigation in a phase II trial in SDH-deficient PCCs (ClinicalTrials.gov, NCT03165721).

5. Conclusions

Behind ATP production, billions of endosymbiotic evolutions led mitochondria to play a key role in the fine tuning of eukaryotic cell signalling and in determining the cellular fate. The discovery of the oncometabolites fumarate, succinate, and R-2HG, all belonging to the TCA cycle, have overwhelmingly reproposed the original Warburg theory according to which metabolic defect in mitochondria may be at the base of cancer development. The pivotal role of oncometabolites in driving malignant transformation through epigenetic modulation and pseudohypoxia effect goes beyond the genetics mechanisms underlying the overall importance of the metabolism studies for the comprehensive understanding of cancer cell development and progression. So far, the overall metabolic mechanisms of cancer disease remain to be fully understood, however, the elucidation of specific metabolic characteristics pointed out by oncometabolites inspired novel targeted therapeutic approaches that paved the way for controlling cancer growth by rewiring cancer cell metabolism.

Author Contributions

Conceptualization, G.C., E.D.G.; writing—original draft preparation, G.C., E.D.G.; writing—review and editing, G.M, A.S. (Asia Saorin), A.S. (Agostino Steffan); visualization, G.C., E.D.G., G.M., A.S. (Asia Saorin), A.S. (Agostino Steffan); funding acquisition, G.C., A.S. (Agostino Steffan). All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Italian Ministry of Health (Ricerca Corrente).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Warburg, O. Beobachtungen über die oxydationsprozesse im seeigelei. Biol. Chem. 1908, 57, 1–16. [Google Scholar] [CrossRef]
  2. Warburg, O. On Respiratory Impairment in Cancer Cells. Science 1956, 124, 269–270. [Google Scholar] [PubMed]
  3. Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 1927, 8, 519–530. [Google Scholar] [CrossRef] [PubMed]
  4. Warburg, O.; Minami, S. Versuche an Überlebendem Carcinom-gewebe. Klin. Wochenschr. 1923, 2, 776–777. [Google Scholar] [CrossRef]
  5. Warburg, O. On the Origin of Cancer Cells. Science 1956, 123, 309–314. [Google Scholar] [CrossRef]
  6. Weinhouse, S. Studies on the Fate of Isotopically Labeled Metabolites in the Oxidative Metabolism of Tumors. Cancer Res. 1951, 11, 585–591. [Google Scholar]
  7. Boveri, T. The Origin of Malignant Tumors; The Williams & Wilkins Company: Baltimore, MD, USA, 1929. [Google Scholar]
  8. Duesberg, P.H.; Vogt, P.K. Differences between the Ribonucleic Acids of Transforming and Nontransforming Avian Tumor Viruses. Proc. Natl. Acad. Sci. USA 1970, 67, 1673–1680. [Google Scholar] [CrossRef]
  9. Martin, G.S. Rous Sarcoma Virus: A Function Required for the Maintenance of the Transformed State. Nature 1970, 227, 1021–1023. [Google Scholar] [CrossRef]
  10. Rous, P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 1911, 13, 397–411. [Google Scholar] [CrossRef]
  11. Toyoshima, K.; Vogt, P.K. Temperature Sensitive Mutants of an Avian Sarcoma Virus. Virology 1969, 39, 930–931. [Google Scholar] [CrossRef]
  12. Stehelin, D.; Varmus, H.E.; Bishop, J.M.; Vogt, P.K. DNA Related to the Transforming Gene(s) of Avian Sarcoma Viruses Is Present in Normal Avian DNA. Nature 1976, 260, 170–173. [Google Scholar] [CrossRef]
  13. Kirsten, W.H.; Mayer, L.A. Morphologic Responses to a Murine Erythroblastosis Virus. J. Natl. Cancer Inst. 1967, 39, 311–335. [Google Scholar]
  14. Harvey, J.J. An unidentified virus which causes the rapid production of tumours in mice. Nature 1964, 204, 1104–1105. [Google Scholar] [CrossRef]
  15. Der, C.J.; Krontiris, T.G.; Cooper, G.M. Transforming Genes of Human Bladder and Lung Carcinoma Cell Lines Are Homologous to the Ras Genes of Harvey and Kirsten Sarcoma Viruses. Proc. Natl. Acad. Sci. USA 1982, 79, 3637–3640. [Google Scholar] [CrossRef]
  16. Parada, L.F.; Tabin, C.J.; Shih, C.; Weinberg, R.A. Human EJ Bladder Carcinoma Oncogene Is Homologue of Harvey Sarcoma Virus Ras Gene. Nature 1982, 297, 474–478. [Google Scholar] [CrossRef]
  17. Santos, E.; Martin-Zanca, D.; Reddy, E.P.; Pierotti, M.A.; Della Porta, G.; Barbacid, M. Malignant Activation of a K-Ras Oncogene in Lung Carcinoma but Not in Normal Tissue of the Same Patient. Science 1984, 223, 661–664. [Google Scholar] [CrossRef]
  18. Dalla-Favera, R.; Bregni, M.; Erikson, J.; Patterson, D.; Gallo, R.C.; Croce, C.M. Human C-Myc Onc Gene Is Located on the Region of Chromosome 8 That Is Translocated in Burkitt Lymphoma Cells. Proc. Natl. Acad. Sci. USA 1982, 79, 7824–7827. [Google Scholar] [CrossRef]
  19. Schwab, M.; Ellison, J.; Busch, M.; Rosenau, W.; Varmus, H.E.; Bishop, J.M. Enhanced Expression of the Human Gene N-Myc Consequent to Amplification of DNA May Contribute to Malignant Progression of Neuroblastoma. Proc. Natl. Acad. Sci. USA 1984, 81, 4940–4944. [Google Scholar] [CrossRef]
  20. Shim, H.; Dolde, C.; Lewis, B.C.; Wu, C.S.; Dang, G.; Jungmann, R.A.; Dalla-Favera, R.; Dang, C.V. C-Myc Transactivation of LDH-A: Implications for Tumor Metabolism and Growth. Proc. Natl. Acad. Sci. USA 1997, 94, 6658–6663. [Google Scholar] [CrossRef]
  21. Elstrom, R.L.; Bauer, D.E.; Buzzai, M.; Karnauskas, R.; Harris, M.H.; Plas, D.R.; Zhuang, H.; Cinalli, R.M.; Alavi, A.; Rudin, C.M.; et al. Akt Stimulates Aerobic Glycolysis in Cancer Cells. Cancer Res. 2004, 64, 3892–3899. [Google Scholar] [CrossRef]
  22. Levine, A.J.; Puzio-Kuter, A.M. The Control of the Metabolic Switch in Cancers by Oncogenes and Tumor Suppressor Genes. Science 2010, 330, 1340–1344. [Google Scholar] [CrossRef]
  23. Schwartzenberg-Bar-Yoseph, F.; Armoni, M.; Karnieli, E. The Tumor Suppressor P53 Down-Regulates Glucose Transporters GLUT1 and GLUT4 Gene Expression. Cancer Res. 2004, 64, 2627–2633. [Google Scholar] [CrossRef]
  24. Ying, H.; Kimmelman, A.C.; Lyssiotis, C.A.; Hua, S.; Chu, G.C.; Fletcher-Sananikone, E.; Locasale, J.W.; Son, J.; Zhang, H.; Coloff, J.L.; et al. Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism. Cell 2012, 149, 656–670. [Google Scholar] [CrossRef]
  25. Baysal, B.E.; Ferrell, R.E.; Willett-Brozick, J.E.; Lawrence, E.C.; Myssiorek, D.; Bosch, A.; van der Mey, A.; Taschner, P.E.; Rubinstein, W.S.; Myers, E.N.; et al. Mutations in SDHD, a Mitochondrial Complex II Gene, in Hereditary Paraganglioma. Science 2000, 287, 848–851. [Google Scholar] [CrossRef]
  26. Astuti, D.; Latif, F.; Dallol, A.; Dahia, P.L.; Douglas, F.; George, E.; Sköldberg, F.; Husebye, E.S.; Eng, C.; Maher, E.R. Gene Mutations in the Succinate Dehydrogenase Subunit SDHB Cause Susceptibility to Familial Pheochromocytoma and to Familial Paraganglioma. Am. J. Hum. Genet. 2001, 69, 49–54. [Google Scholar] [CrossRef]
  27. Tomlinson, I.P.M.; Alam, N.A.; Rowan, A.J.; Barclay, E.; Jaeger, E.E.M.; Kelsell, D.; Leigh, I.; Gorman, P.; Lamlum, H.; Rahman, S.; et al. Germline Mutations in FH Predispose to Dominantly Inherited Uterine Fibroids, Skin Leiomyomata and Papillary Renal Cell Cancer. Nat. Genet. 2002, 30, 406–410. [Google Scholar] [CrossRef]
  28. Gottlieb, E.; Tomlinson, I.P.M. Mitochondrial Tumour Suppressors: A Genetic and Biochemical Update. Nat. Rev. Cancer 2005, 5, 857–866. [Google Scholar] [CrossRef]
  29. Balss, J.; Meyer, J.; Mueller, W.; Korshunov, A.; Hartmann, C.; von Deimling, A. Analysis of the IDH1 Codon 132 Mutation in Brain Tumors. Acta Neuropathol. 2008, 116, 597–602. [Google Scholar] [CrossRef]
  30. Kang, M.R.; Kim, M.S.; Oh, J.E.; Kim, Y.R.; Song, S.Y.; Seo, S.I.; Lee, J.Y.; Yoo, N.J.; Lee, S.H. Mutational Analysis of IDH1 Codon 132 in Glioblastomas and Other Common Cancers. Int. J. Cancer 2009, 125, 353–355. [Google Scholar] [CrossRef]
  31. Parsons, D.W.; Jones, S.; Zhang, X.; Lin, J.C.-H.; Leary, R.J.; Angenendt, P.; Mankoo, P.; Carter, H.; Siu, I.-M.; Gallia, G.L.; et al. An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 2008, 321, 1807–1812. [Google Scholar] [CrossRef]
  32. Missiroli, S.; Perrone, M.; Genovese, I.; Pinton, P.; Giorgi, C. Cancer Metabolism and Mitochondria: Finding Novel Mechanisms to Fight Tumours. EBioMedicine 2020, 59. [Google Scholar] [CrossRef] [PubMed]
  33. Lancaster, C.R.D. Succinate:Quinone Oxidoreductases: An Overview. Biochim. Biophys. Acta (BBA) Bioenerg 2002, 1553, 1–6. [Google Scholar] [CrossRef]
  34. Van Vranken, J.G.; Na, U.; Winge, D.R.; Rutter, J. Protein-Mediated Assembly of Succinate Dehydrogenase and Its Cofactors. Crit. Rev. Biochem. Mol. Biol. 2015, 50, 168–180. [Google Scholar] [CrossRef] [PubMed]
  35. Barbara, P.; Stratakis, C.A. Sdh mutations in tumourigenesis and inherited endocrine tumours. J. Intern. Med. 2009, 266, 19–42. [Google Scholar] [CrossRef]
  36. Dannenberg, H.; Speel, E.J.; Zhao, J.; Saremaslani, P.; van Der Harst, E.; Roth, J.; Heitz, P.U.; Bonjer, H.J.; Dinjens, W.N.; Mooi, W.J.; et al. Losses of Chromosomes 1p and 3q Are Early Genetic Events in the Development of Sporadic Pheochromocytomas. Am. J. Pathol. 2000, 157, 353–359. [Google Scholar] [CrossRef]
  37. Pollard, P.J.; Brière, J.J.; Alam, N.A.; Barwell, J.; Barclay, E.; Wortham, N.C.; Hunt, T.; Mitchell, M.; Olpin, S.; Moat, S.J.; et al. Accumulation of Krebs Cycle Intermediates and Over-Expression of HIF1alpha in Tumours Which Result from Germline FH and SDH Mutations. Hum. Mol. Genet. 2005, 14, 2231–2239. [Google Scholar] [CrossRef]
  38. Imperiale, A.; Moussallieh, F.-M.; Roche, P.; Battini, S.; Cicek, A.E.; Sebag, F.; Brunaud, L.; Barlier, A.; Elbayed, K.; Loundou, A.; et al. Metabolome Profiling by HRMAS NMR Spectroscopy of Pheochromocytomas and Paragangliomas Detects SDH Deficiency: Clinical and Pathophysiological Implications. Neoplasia 2015, 17, 55–65. [Google Scholar] [CrossRef]
  39. Kim, E.; Wright, M.J.P.; Sioson, L.; Novos, T.; Gill, A.J.; Benn, D.E.; White, C.; Dwight, T.; Clifton-Bligh, R.J. Utility of the Succinate:Fumarate Ratio for Assessing SDH Dysfunction in Different Tumor Types. Mol. Genet. Metab. Rep. 2016, 10, 45–49. [Google Scholar] [CrossRef]
  40. Lendvai, N.; Pawlosky, R.; Bullova, P.; Eisenhofer, G.; Patocs, A.; Veech, R.L.; Pacak, K. Succinate-to-Fumarate Ratio as a New Metabolic Marker to Detect the Presence of SDHB/D-Related Paraganglioma: Initial Experimental and Ex Vivo Findings. Endocrinology 2014, 155, 27–32. [Google Scholar] [CrossRef]
  41. Richter, S.; Gieldon, L.; Pang, Y.; Peitzsch, M.; Huynh, T.; Leton, R.; Viana, B.; Ercolino, T.; Mangelis, A.; Rapizzi, E.; et al. Metabolome-Guided Genomics to Identify Mutations in Isocitrate Dehydrogenase, Fumarate Hydratase and Succinate Dehydrogenase Genes in Pheochromocytoma and Paraganglioma. Genet. Med. 2019, 21, 705–717. [Google Scholar] [CrossRef]
  42. Richter, S.; Peitzsch, M.; Rapizzi, E.; Lenders, J.W.; Qin, N.; de Cubas, A.A.; Schiavi, F.; Rao, J.U.; Beuschlein, F.; Quinkler, M.; et al. Krebs Cycle Metabolite Profiling for Identification and Stratification of Pheochromocytomas/Paragangliomas Due to Succinate Dehydrogenase Deficiency. J. Clin. Endocrinol. Metab. 2014, 99, 3903–3911. [Google Scholar] [CrossRef]
  43. Aghamir, S.M.K.; Heshmat, R.; Ebrahimi, M.; Ketabchi, S.E.; Dizaji, S.P.; Khatami, F. The Impact of Succinate Dehydrogenase Gene (SDH) Mutations in Renal Cell Carcinoma (RCC): A Systematic Review. OTT 2019, 12, 7929–7940. [Google Scholar] [CrossRef]
  44. Niemeijer, N.D.; Papathomas, T.G.; Korpershoek, E.; de Krijger, R.R.; Oudijk, L.; Morreau, H.; Bayley, J.-P.; Hes, F.J.; Jansen, J.C.; Dinjens, W.N.M.; et al. Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum. J. Clin. Endocrinol. Metab. 2015, 100, E1386–E1393. [Google Scholar] [CrossRef]
  45. Shi, S.-S.; Wang, Y.-F.; Bao, W.; Ye, S.-B.; Wu, N.; Wang, X.; Xia, Q.-Y.; Li, R.; Shen, Q.; Zhou, X.-J. Genetic and Epigenetic Alterations of SDH Genes in Patients with Sporadic Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors. Pathol. Int. 2019, 69, 350–359. [Google Scholar] [CrossRef]
  46. Williamson, S.R.; Eble, J.N.; Amin, M.B.; Gupta, N.S.; Smith, S.C.; Sholl, L.M.; Montironi, R.; Hirsch, M.S.; Hornick, J.L. Succinate Dehydrogenase-Deficient Renal Cell Carcinoma: Detailed Characterization of 11 Tumors Defining a Unique Subtype of Renal Cell Carcinoma. Mod. Pathol. 2015, 28, 80–94. [Google Scholar] [CrossRef]
  47. Xekouki, P.; Szarek, E.; Bullova, P.; Giubellino, A.; Quezado, M.; Mastroyannis, S.A.; Mastorakos, P.; Wassif, C.A.; Raygada, M.; Rentia, N.; et al. Pituitary Adenoma with Paraganglioma/Pheochromocytoma (3PAs) and Succinate Dehydrogenase Defects in Humans and Mice. J. Clin. Endocrinol. Metab. 2015, 100, E710–E719. [Google Scholar] [CrossRef]
  48. Zhao, Y.; Feng, F.; Guo, Q.-H.; Wang, Y.-P.; Zhao, R. Role of Succinate Dehydrogenase Deficiency and Oncometabolites in Gastrointestinal Stromal Tumors. World J. Gastroenterol. 2020, 26, 5074–5089. [Google Scholar] [CrossRef]
  49. Snezhkina, A.V.; Kalinin, D.V.; Pavlov, V.S.; Lukyanova, E.N.; Golovyuk, A.L.; Fedorova, M.S.; Pudova, E.A.; Savvateeva, M.V.; Stepanov, O.A.; Poloznikov, A.A.; et al. Immunohistochemistry and Mutation Analysis of SDHx Genes in Carotid Paragangliomas. Int. J. Mol. Sci. 2020, 21, 6950. [Google Scholar] [CrossRef]
  50. van Nederveen, F.H.; Gaal, J.; Favier, J.; Korpershoek, E.; Oldenburg, R.A.; de Bruyn, E.M.C.A.; Sleddens, H.F.B.M.; Derkx, P.; Rivière, J.; Dannenberg, H.; et al. An Immunohistochemical Procedure to Detect Patients with Paraganglioma and Phaeochromocytoma with Germline SDHB, SDHC, or SDHD Gene Mutations: A Retrospective and Prospective Analysis. Lancet Oncol. 2009, 10, 764–771. [Google Scholar] [CrossRef]
  51. Papathomas, T.G.; Oudijk, L.; Persu, A.; Gill, A.J.; van Nederveen, F.; Tischler, A.S.; Tissier, F.; Volante, M.; Matias-Guiu, X.; Smid, M.; et al. SDHB/SDHA Immunohistochemistry in Pheochromocytomas and Paragangliomas: A Multicenter Interobserver Variation Analysis Using Virtual Microscopy: A Multinational Study of the European Network for the Study of Adrenal Tumors ([email protected]). Mod. Pathol. 2015, 28, 807–821. [Google Scholar] [CrossRef]
  52. Santi, R.; Rapizzi, E.; Canu, L.; Ercolino, T.; Baroni, G.; Fucci, R.; Costa, G.; Mannelli, M.; Nesi, G. Potential Pitfalls of SDH Immunohistochemical Detection in Paragangliomas and Phaeochromocytomas Harbouring Germline SDHx Gene Mutation. Anticancer Res. 2017, 37, 805–812. [Google Scholar] [CrossRef]
  53. Casey, R.T.; McLean, M.A.; Madhu, B.; Challis, B.G.; Ten Hoopen, R.; Roberts, T.; Clark, G.R.; Pittfield, D.; Simpson, H.L.; Bulusu, V.R.; et al. Translating in Vivo Metabolomic Analysis of Succinate Dehydrogenase Deficient Tumours into Clinical Utility. JCO Precis Oncol. 2018, 2, 1–12. [Google Scholar] [CrossRef]
  54. Lussey-Lepoutre, C.; Bellucci, A.; Morin, A.; Buffet, A.; Amar, L.; Janin, M.; Ottolenghi, C.; Zinzindohoué, F.; Autret, G.; Burnichon, N.; et al. In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma. Clin. Cancer Res. 2016, 22, 1120–1129. [Google Scholar] [CrossRef]
  55. Guzy, R.D.; Sharma, B.; Bell, E.; Chandel, N.S.; Schumacker, P.T. Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis. Mol. Cell Biol. 2008, 28, 718–731. [Google Scholar] [CrossRef]
  56. Yankovskaya, V.; Horsefield, R.; Törnroth, S.; Luna-Chavez, C.; Miyoshi, H.; Léger, C.; Byrne, B.; Cecchini, G.; Iwata, S. Architecture of Succinate Dehydrogenase and Reactive Oxygen Species Generation. Science 2003, 299, 700–704. [Google Scholar] [CrossRef] [PubMed]
  57. Ishii, T.; Yasuda, K.; Akatsuka, A.; Hino, O.; Hartman, P.S.; Ishii, N. A Mutation in the SDHC Gene of Complex II Increases Oxidative Stress, Resulting in Apoptosis and Tumorigenesis. Cancer Res. 2005, 65, 203–209. [Google Scholar] [PubMed]
  58. Owens, K.M.; Aykin-Burns, N.; Dayal, D.; Coleman, M.C.; Domann, F.E.; Spitz, D.R. Genomic Instability Induced by Mutant Succinate Dehydrogenase Subunit D (SDHD) Is Mediated by O2(-•) and H2O2. Free Radic. Biol. Med. 2012, 52, 160–166. [Google Scholar] [CrossRef] [PubMed]
  59. Slane, B.G.; Aykin-Burns, N.; Smith, B.J.; Kalen, A.L.; Goswami, P.C.; Domann, F.E.; Spitz, D.R. Mutation of Succinate Dehydrogenase Subunit C Results in Increased O2.-, Oxidative Stress, and Genomic Instability. Cancer Res. 2006, 66, 7615–7620. [Google Scholar] [CrossRef]
  60. Flavahan, W.A.; Drier, Y.; Johnstone, S.E.; Hemming, M.L.; Tarjan, D.R.; Hegazi, E.; Shareef, S.J.; Javed, N.M.; Raut, C.P.; Eschle, B.K.; et al. Altered Chromosomal Topology Drives Oncogenic Programs in SDH-Deficient GISTs. Nature 2019, 575, 229–233. [Google Scholar] [CrossRef]
  61. Wyvekens, N.; Valtcheva, N.; Mischo, A.; Helmchen, B.; Hermanns, T.; Choschzick, M.; Hötker, A.M.; Rauch, A.; Mühleisen, B.; Akhoundova, D.; et al. Novel Morphological and Genetic Features of Fumarate Hydratase Deficient Renal Cell Carcinoma in HLRCC Syndrome Patients with a Tailored Therapeutic Approach. Genes Chromosomes Cancer 2020, 59, 611–619. [Google Scholar] [CrossRef]
  62. Bayley, J.-P.; Launonen, V.; Tomlinson, I.P. The FH Mutation Database: An Online Database of Fumarate Hydratase Mutations Involved in the MCUL (HLRCC) Tumor Syndrome and Congenital Fumarase Deficiency. BMC Med. Genet. 2008, 9, 20. [Google Scholar] [CrossRef]
  63. Sánchez-Heras, A.B.; Castillejo, A.; García-Díaz, J.D.; Robledo, M.; Teulé, A.; Sánchez, R.; Zúñiga, Á.; Lastra, E.; Durán, M.; Llort, G.; et al. Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization. Cancers 2020, 12, 3277. [Google Scholar] [CrossRef]
  64. Castro-Vega, L.J.; Buffet, A.; De Cubas, A.A.; Cascón, A.; Menara, M.; Khalifa, E.; Amar, L.; Azriel, S.; Bourdeau, I.; Chabre, O.; et al. Germline Mutations in FH Confer Predisposition to Malignant Pheochromocytomas and Paragangliomas. Hum. Mol. Genet. 2014, 23, 2440–2446. [Google Scholar] [CrossRef]
  65. Clark, G.R.; Sciacovelli, M.; Gaude, E.; Walsh, D.M.; Kirby, G.; Simpson, M.A.; Trembath, R.C.; Berg, J.N.; Woodward, E.R.; Kinning, E.; et al. Germline FH Mutations Presenting with Pheochromocytoma. J. Clin. Endocrinol. Metab. 2014, 99, E2046–E2050. [Google Scholar] [CrossRef]
  66. Alam, N.A.; Rowan, A.J.; Wortham, N.C.; Pollard, P.J.; Mitchell, M.; Tyrer, J.P.; Barclay, E.; Calonje, E.; Manek, S.; Adams, S.J.; et al. Genetic and Functional Analyses of FH Mutations in Multiple Cutaneous and Uterine Leiomyomatosis, Hereditary Leiomyomatosis and Renal Cancer, and Fumarate Hydratase Deficiency. Hum. Mol. Genet. 2003, 12, 1241–1252. [Google Scholar] [CrossRef]
  67. Toro, J.R.; Nickerson, M.L.; Wei, M.-H.; Warren, M.B.; Glenn, G.M.; Turner, M.L.; Stewart, L.; Duray, P.; Tourre, O.; Sharma, N.; et al. Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America. Am. J. Hum. Genet. 2003, 73, 95–106. [Google Scholar] [CrossRef]
  68. Picaud, S.; Kavanagh, K.L.; Yue, W.W.; Lee, W.H.; Muller-Knapp, S.; Gileadi, O.; Sacchettini, J.; Oppermann, U. Structural Basis of Fumarate Hydratase Deficiency. J. Inherit. Metab. Dis. 2011, 34, 671–676. [Google Scholar] [CrossRef]
  69. Estévez, M.; Skarda, J.; Spencer, J.; Banaszak, L.; Weaver, T.M. X-Ray Crystallographic and Kinetic Correlation of a Clinically Observed Human Fumarase Mutation. Protein Sci 2002, 11, 1552–1557. [Google Scholar] [CrossRef]
  70. Casey, R.T.; McLean, M.A.; Challis, B.G.; McVeigh, T.P.; Warren, A.Y.; Mendil, L.; Houghton, R.; Sanctis, S.D.; Kosmoliaptsis, V.; Sandford, R.N.; et al. Fumarate Metabolic Signature for the Detection of Reed Syndrome in Humans. Clin. Cancer Res. 2020, 26, 391–396. [Google Scholar] [CrossRef] [PubMed]
  71. Buelow, B.; Cohen, J.; Nagymanyoki, Z.; Frizzell, N.; Joseph, N.M.; McCalmont, T.; Garg, K. Immunohistochemistry for 2-Succinocysteine (2SC) and Fumarate Hydratase (FH) in Cutaneous Leiomyomas May Aid in Identification of Patients With HLRCC (Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome). Am. J. Surg. Pathol. 2016, 40, 982–988. [Google Scholar] [CrossRef] [PubMed]
  72. Chen, Y.-B.; Brannon, A.R.; Toubaji, A.; Dudas, M.E.; Won, H.H.; Al-Ahmadie, H.A.; Fine, S.W.; Gopalan, A.; Frizzell, N.; Voss, M.H.; et al. Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome-Associated Renal Cancer: Recognition of the Syndrome by Pathologic Features and the Utility of Detecting Aberrant Succination by Immunohistochemistry. Am. J. Surg. Pathol. 2014, 38, 627–637. [Google Scholar] [CrossRef] [PubMed]
  73. Joseph, N.M.; Solomon, D.A.; Frizzell, N.; Rabban, J.T.; Zaloudek, C.; Garg, K. Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas from Young Patients. Am. J. Surg. Pathol. 2015, 39, 1529–1539. [Google Scholar] [CrossRef] [PubMed]
  74. Trpkov, K.; Hes, O.; Agaimy, A.; Bonert, M.; Martinek, P.; Magi-Galluzzi, C.; Kristiansen, G.; Lüders, C.; Nesi, G.; Compérat, E.; et al. Fumarate Hydratase-Deficient Renal Cell Carcinoma Is Strongly Correlated with Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome. Am. J. Surg. Pathol. 2016, 40, 865–875. [Google Scholar] [CrossRef] [PubMed]
  75. Carter, C.S.; Skala, S.L.; Chinnaiyan, A.M.; McHugh, J.B.; Siddiqui, J.; Cao, X.; Dhanasekaran, S.M.; Fullen, D.R.; Lagstein, A.; Chan, M.P.; et al. Immunohistochemical Characterization of Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) in Cutaneous Leiomyomas for Detection of Familial Cancer Syndromes. Am. J. Surg. Pathol. 2017, 41, 801–809. [Google Scholar] [CrossRef]
  76. Heinonen, H.-R.; Mehine, M.; Mäkinen, N.; Pasanen, A.; Pitkänen, E.; Karhu, A.; Sarvilinna, N.S.; Sjöberg, J.; Heikinheimo, O.; Bützow, R.; et al. Global Metabolomic Profiling of Uterine Leiomyomas. Br. J. Cancer 2017, 117, 1855–1864. [Google Scholar] [CrossRef]
  77. Zheng, L.; MacKenzie, E.D.; Karim, S.A.; Hedley, A.; Blyth, K.; Kalna, G.; Watson, D.G.; Szlosarek, P.; Frezza, C.; Gottlieb, E. Reversed Argininosuccinate Lyase Activity in Fumarate Hydratase-Deficient Cancer Cells. Cancer Metab. 2013, 1, 12. [Google Scholar] [CrossRef]
  78. Borger, D.R.; Goyal, L.; Yau, T.; Poon, R.T.; Ancukiewicz, M.; Deshpande, V.; Christiani, D.C.; Liebman, H.M.; Yang, H.; Kim, H.; et al. Circulating Oncometabolite 2-Hydroxyglutarate Is a Potential Surrogate Biomarker in Patients with Isocitrate Dehydrogenase-Mutant Intrahepatic Cholangiocarcinoma. Clin. Cancer Res. 2014, 20, 1884–1890. [Google Scholar] [CrossRef]
  79. Dang, L.; White, D.W.; Gross, S.; Bennett, B.D.; Bittinger, M.A.; Driggers, E.M.; Fantin, V.R.; Jang, H.G.; Jin, S.; Keenan, M.C.; et al. Cancer-Associated IDH1 Mutations Produce 2-Hydroxyglutarate. Nature 2009, 462, 739–744. [Google Scholar] [CrossRef]
  80. Delahousse, J.; Verlingue, L.; Broutin, S.; Legoupil, C.; Touat, M.; Doucet, L.; Ammari, S.; Lacroix, L.; Ducreux, M.; Scoazec, J.-Y.; et al. Circulating Oncometabolite D-2-Hydroxyglutarate Enantiomer Is a Surrogate Marker of Isocitrate Dehydrogenase-Mutated Intrahepatic Cholangiocarcinomas. Eur. J. Cancer 2018, 90, 83–91. [Google Scholar] [CrossRef]
  81. Lombardi, G.; Corona, G.; Bellu, L.; Puppa, A.D.; Pambuku, A.; Fiduccia, P.; Bertorelle, R.; Gardiman, M.P.; D’Avella, D.; Toffoli, G.; et al. Diagnostic Value of Plasma and Urinary 2-Hydroxyglutarate to Identify Patients With Isocitrate Dehydrogenase-Mutated Glioma. Oncologist 2015, 20, 562–567. [Google Scholar] [CrossRef]
  82. Natsumeda, M.; Igarashi, H.; Nomura, T.; Ogura, R.; Tsukamoto, Y.; Kobayashi, T.; Aoki, H.; Okamoto, K.; Kakita, A.; Takahashi, H.; et al. Accumulation of 2-Hydroxyglutarate in Gliomas Correlates with Survival: A Study by 3.0-Tesla Magnetic Resonance Spectroscopy. Acta Neuropathol. Commun. 2014, 2, 158. [Google Scholar] [CrossRef]
  83. Sim, H.-W.; Nejad, R.; Zhang, W.; Nassiri, F.; Mason, W.; Aldape, K.D.; Zadeh, G.; Chen, E.X. Tissue 2-Hydroxyglutarate as a Biomarker for Isocitrate Dehydrogenase Mutations in Gliomas. Clin. Cancer Res. 2019, 25, 3366–3373. [Google Scholar] [CrossRef]
  84. Winter, H.; Kaisaki, P.J.; Harvey, J.; Giacopuzzi, E.; Ferla, M.P.; Pentony, M.M.; Knight, S.J.L.; Sharma, R.A.; Taylor, J.C.; McCullagh, J.S.O. Identification of Circulating Genomic and Metabolic Biomarkers in Intrahepatic Cholangiocarcinoma. Cancers 2019, 11, 1895. [Google Scholar] [CrossRef]
  85. Mardis, E.R.; Ding, L.; Dooling, D.J.; Larson, D.E.; McLellan, M.D.; Chen, K.; Koboldt, D.C.; Fulton, R.S.; Delehaunty, K.D.; McGrath, S.D.; et al. Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome. N. Engl. J. Med. 2009, 361, 1058–1066. [Google Scholar] [CrossRef]
  86. Borger, D.R.; Tanabe, K.K.; Fan, K.C.; Lopez, H.U.; Fantin, V.R.; Straley, K.S.; Schenkein, D.P.; Hezel, A.F.; Ancukiewicz, M.; Liebman, H.M.; et al. Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and IDH2 in Cholangiocarcinoma Identified through Broad-Based Tumor Genotyping. Oncologist 2012, 17, 72–79. [Google Scholar] [CrossRef]
  87. Amary, M.F.; Bacsi, K.; Maggiani, F.; Damato, S.; Halai, D.; Berisha, F.; Pollock, R.; O’Donnell, P.; Grigoriadis, A.; Diss, T.; et al. IDH1 and IDH2 Mutations Are Frequent Events in Central Chondrosarcoma and Central and Periosteal Chondromas but Not in Other Mesenchymal Tumours. J. Pathol. 2011, 224, 334–343. [Google Scholar] [CrossRef]
  88. Chiang, S.; Weigelt, B.; Wen, H.-C.; Pareja, F.; Raghavendra, A.; Martelotto, L.G.; Burke, K.A.; Basili, T.; Li, A.; Geyer, F.C.; et al. IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity. Cancer Res. 2016, 76, 7118–7129. [Google Scholar] [CrossRef]
  89. Fathi, A.T.; Sadrzadeh, H.; Comander, A.H.; Higgins, M.J.; Bardia, A.; Perry, A.; Burke, M.; Silver, R.; Matulis, C.R.; Straley, K.S.; et al. Isocitrate Dehydrogenase 1 (IDH1) Mutation in Breast Adenocarcinoma Is Associated with Elevated Levels of Serum and Urine 2-Hydroxyglutarate. Oncologist 2014, 19, 602–607. [Google Scholar] [CrossRef]
  90. Minemura, H.; Takagi, K.; Sato, A.; Yamaguchi, M.; Hayashi, C.; Miki, Y.; Harada-Shoji, N.; Miyashita, M.; Sasano, H.; Suzuki, T. Isoforms of IDH in Breast Carcinoma: IDH2 as a Potent Prognostic Factor Associated with Proliferation in Estrogen-Receptor Positive Cases. Breast Cancer 2021. [Google Scholar] [CrossRef]
  91. Yan, H.; Parsons, D.W.; Jin, G.; McLendon, R.; Rasheed, B.A.; Yuan, W.; Kos, I.; Batinic-Haberle, I.; Jones, S.; Riggins, G.J.; et al. IDH1 and IDH2 Mutations in Gliomas. N. Engl. J. Med. 2009, 360, 765–773. [Google Scholar] [CrossRef]
  92. Wang, H.-Y.; Tang, K.; Liang, T.-Y.; Zhang, W.-Z.; Li, J.-Y.; Wang, W.; Hu, H.-M.; Li, M.-Y.; Wang, H.-Q.; He, X.-Z.; et al. The Comparison of Clinical and Biological Characteristics between IDH1 and IDH2 Mutations in Gliomas. J. Exp. Clin. Cancer Res. 2016, 35, 86. [Google Scholar] [CrossRef] [PubMed]
  93. Shen, Y.; Zhu, Y.-M.; Fan, X.; Shi, J.-Y.; Wang, Q.-R.; Yan, X.-J.; Gu, Z.-H.; Wang, Y.-Y.; Chen, B.; Jiang, C.-L.; et al. Gene Mutation Patterns and Their Prognostic Impact in a Cohort of 1185 Patients with Acute Myeloid Leukemia. Blood 2011, 118, 5593–5603. [Google Scholar] [CrossRef] [PubMed]
  94. Choi, C.; Ganji, S.K.; DeBerardinis, R.J.; Hatanpaa, K.J.; Rakheja, D.; Kovacs, Z.; Yang, X.-L.; Mashimo, T.; Raisanen, J.M.; Marin-Valencia, I.; et al. 2-Hydroxyglutarate Detection by Magnetic Resonance Spectroscopy in IDH-Mutated Patients with Gliomas. Nat. Med. 2012, 18, 624–629. [Google Scholar] [CrossRef] [PubMed]
  95. Gross, S.; Cairns, R.A.; Minden, M.D.; Driggers, E.M.; Bittinger, M.A.; Jang, H.G.; Sasaki, M.; Jin, S.; Schenkein, D.P.; Su, S.M.; et al. Cancer-Associated Metabolite 2-Hydroxyglutarate Accumulates in Acute Myelogenous Leukemia with Isocitrate Dehydrogenase 1 and 2 Mutations. J. Exp. Med. 2010, 207, 339–344. [Google Scholar] [CrossRef]
  96. Lin, A.-P.; Abbas, S.; Kim, S.-W.; Ortega, M.; Bouamar, H.; Escobedo, Y.; Varadarajan, P.; Qin, Y.; Sudderth, J.; Schulz, E.; et al. D2HGDH Regulates Alpha-Ketoglutarate Levels and Dioxygenase Function by Modulating IDH2. Nat. Commun. 2015, 6, 7768. [Google Scholar] [CrossRef]
  97. Jin, G.; Reitman, Z.J.; Duncan, C.G.; Spasojevic, I.; Gooden, D.M.; Rasheed, B.A.; Yang, R.; Lopez, G.Y.; He, Y.; McLendon, R.E.; et al. Disruption of Wild Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas. Cancer Res. 2013, 73, 496–501. [Google Scholar] [CrossRef]
  98. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathol. 2016, 131, 803–820. [Google Scholar] [CrossRef]
  99. Bleeker, F.E.; Atai, N.A.; Lamba, S.; Jonker, A.; Rijkeboer, D.; Bosch, K.S.; Tigchelaar, W.; Troost, D.; Vandertop, W.P.; Bardelli, A.; et al. The Prognostic IDH1(R132) Mutation Is Associated with Reduced NADP+-Dependent IDH Activity in Glioblastoma. Acta Neuropathol. 2010, 119, 487–494. [Google Scholar] [CrossRef]
  100. Hartmann, C.; Hentschel, B.; Wick, W.; Capper, D.; Felsberg, J.; Simon, M.; Westphal, M.; Schackert, G.; Meyermann, R.; Pietsch, T.; et al. Patients with IDH1 Wild Type Anaplastic Astrocytomas Exhibit Worse Prognosis than IDH1-Mutated Glioblastomas, and IDH1 Mutation Status Accounts for the Unfavorable Prognostic Effect of Higher Age: Implications for Classification of Gliomas. Acta Neuropathol. 2010, 120, 707–718. [Google Scholar] [CrossRef]
  101. Sanson, M.; Marie, Y.; Paris, S.; Idbaih, A.; Laffaire, J.; Ducray, F.; El Hallani, S.; Boisselier, B.; Mokhtari, K.; Hoang-Xuan, K.; et al. Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas. J. Clin. Oncol. 2009, 27, 4150–4154. [Google Scholar] [CrossRef]
  102. Wang, F.; Zheng, Z.; Guan, J.; Qi, D.; Zhou, S.; Shen, X.; Wang, F.; Wenkert, D.; Kirmani, B.; Solouki, T.; et al. Identification of a Panel of Genes as a Prognostic Biomarker for Glioblastoma. EBioMedicine 2018, 37, 68–77. [Google Scholar] [CrossRef]
  103. DiNardo, C.D.; Propert, K.J.; Loren, A.W.; Paietta, E.; Sun, Z.; Levine, R.L.; Straley, K.S.; Yen, K.; Patel, J.P.; Agresta, S.; et al. Serum 2-Hydroxyglutarate Levels Predict Isocitrate Dehydrogenase Mutations and Clinical Outcome in Acute Myeloid Leukemia. Blood 2013, 121, 4917–4924. [Google Scholar] [CrossRef]
  104. Miller, A.; Tong, A.W.; Sweetman, L.; Theiss, A.; Murtaza, M.; Daoud, Y.; Wong, L. Characterization of Acute Myeloid Leukaemia (AML) Patients with Elevated Peripheral Blood Plasma D-2-Hydroxyglutarate (D-2HG) and/or Isocitrate Dehydrogenase (IDH) Mutational Status. Blood 2017, 130, 3923. [Google Scholar] [CrossRef]
  105. Balss, J.; Thiede, C.; Bochtler, T.; Okun, J.G.; Saadati, M.; Benner, A.; Pusch, S.; Ehninger, G.; Schaich, M.; Ho, A.D.; et al. Pretreatment d -2-Hydroxyglutarate Serum Levels Negatively Impact on Outcome in IDH1-Mutated Acute Myeloid Leukemia. Leukemia 2016, 30, 782–788. [Google Scholar] [CrossRef]
  106. Brunner, A.M.; Neuberg, D.S.; Wander, S.A.; Sadrzadeh, H.; Ballen, K.K.; Amrein, P.C.; Attar, E.; Hobbs, G.S.; Chen, Y.-B.; Perry, A.; et al. Isocitrate Dehydrogenase 1 and 2 Mutations, 2-Hydroxyglutarate Levels, and Response to Standard Chemotherapy for Patients with Newly Diagnosed Acute Myeloid Leukemia. Cancer 2019, 125, 541–549. [Google Scholar] [CrossRef]
  107. Andronesi, O.C.; Kim, G.S.; Gerstner, E.; Batchelor, T.; Tzika, A.A.; Fantin, V.R.; Vander Heiden, M.G.; Sorensen, A.G. Detection of 2-Hydroxyglutarate in IDH-Mutated Glioma Patients by in Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy. Sci. Transl. Med. 2012, 4, 116ra4. [Google Scholar] [CrossRef]
  108. Branzoli, F.; Di Stefano, A.L.; Capelle, L.; Ottolenghi, C.; Valabrègue, R.; Deelchand, D.K.; Bielle, F.; Villa, C.; Baussart, B.; Lehéricy, S.; et al. Highly Specific Determination of IDH Status Using Edited in Vivo Magnetic Resonance Spectroscopy. Neuro-oncology 2018, 20, 907–916. [Google Scholar] [CrossRef]
  109. Choi, C.; Raisanen, J.M.; Ganji, S.K.; Zhang, S.; McNeil, S.S.; An, Z.; Madan, A.; Hatanpaa, K.J.; Vemireddy, V.; Sheppard, C.A.; et al. Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma. J. Clin. Oncol. 2016, 34, 4030–4039. [Google Scholar] [CrossRef]
  110. Esmaeili, M.; Vettukattil, R.; Bathen, T.F. 2-Hydroxyglutarate as a Magnetic Resonance Biomarker for Glioma Subtyping. Transl. Oncol. 2013, 6, 92–98. [Google Scholar] [CrossRef]
  111. Tietze, A.; Choi, C.; Mickey, B.; Maher, E.A.; Parm Ulhøi, B.; Sangill, R.; Lassen-Ramshad, Y.; Lukacova, S.; Østergaard, L.; von Oettingen, G.; et al. Noninvasive Assessment of Isocitrate Dehydrogenase Mutation Status in Cerebral Gliomas by Magnetic Resonance Spectroscopy in a Clinical Setting. J. Neurosurg. 2018, 128, 391–398. [Google Scholar] [CrossRef]
  112. Radoul, M.; Hong, D.; Gillespie, A.M.; Najac, C.; Viswanath, P.; Pieper, R.O.; Costello, J.F.; Luchman, H.A.; Ronen, S.M. Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma. Metabolites 2021, 11, 109. [Google Scholar] [CrossRef] [PubMed]
  113. Ballester, L.Y.; Lu, G.; Zorofchian, S.; Vantaku, V.; Putluri, V.; Yan, Y.; Arevalo, O.; Zhu, P.; Riascos, R.F.; Sreekumar, A.; et al. Analysis of Cerebrospinal Fluid Metabolites in Patients with Primary or Metastatic Central Nervous System Tumors. Acta Neuropathol. Commun. 2018, 6, 85. [Google Scholar] [CrossRef] [PubMed]
  114. Kalinina, J.; Ahn, J.; Devi, N.S.; Wang, L.; Li, Y.; Olson, J.J.; Glantz, M.; Smith, T.; Kim, E.L.; Giese, A.; et al. Selective Detection of the D-Enantiomer of 2-Hydroxyglutarate in the CSF of Glioma Patients with Mutated Isocitrate Dehydrogenase. Clin. Cancer Res. 2016, 22, 6256–6265. [Google Scholar] [CrossRef] [PubMed]
  115. Cuccarini, V.; Antelmi, L.; Pollo, B.; Paterra, R.; Calatozzolo, C.; Nigri, A.; DiMeco, F.; Eoli, M.; Finocchiaro, G.; Brenna, G.; et al. In Vivo 2-Hydroxyglutarate-Proton Magnetic Resonance Spectroscopy (3 T, PRESS Technique) in Treatment-Naïve Suspect Lower-Grade Gliomas: Feasibility and Accuracy in a Clinical Setting. Neurol. Sci. 2020, 41, 347–355. [Google Scholar] [CrossRef]
  116. Fathi, A.T.; Nahed, B.V.; Wander, S.A.; Iafrate, A.J.; Borger, D.R.; Hu, R.; Thabet, A.; Cahill, D.P.; Perry, A.M.; Joseph, C.P.; et al. Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma. Oncologist 2016, 21, 214–219. [Google Scholar] [CrossRef]
  117. Belykh, E.; Shaffer, K.V.; Lin, C.; Byvaltsev, V.A.; Preul, M.C.; Chen, L. Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors. Front. Oncol. 2020, 10. [Google Scholar] [CrossRef]
  118. Nduom, E.K.; Yang, C.; Merrill, M.J.; Zhuang, Z.; Lonser, R.R. Characterization of the Blood-Brain Barrier of Metastatic and Primary Malignant Neoplasms. J. Neurosurg. 2013, 119, 427–433. [Google Scholar] [CrossRef]
  119. Engqvist, M.K.M.; Eßer, C.; Maier, A.; Lercher, M.J.; Maurino, V.G. Mitochondrial 2-Hydroxyglutarate Metabolism. Mitochondrion 2014, 19 Pt B, 275–281. [Google Scholar] [CrossRef]
  120. Fan, J.; Teng, X.; Liu, L.; Mattaini, K.R.; Looper, R.E.; VanderHeiden, M.G.; Rabinowitz, J.D. Human Phosphoglycerate Dehydrogenase Produces the Oncometabolite D-2-Hydroxyglutarate. ACS Chem. Biol. 2015, 10, 510. [Google Scholar] [CrossRef]
  121. Mishra, P.; Tang, W.; Putluri, V.; Dorsey, T.H.; Jin, F.; Wang, F.; Zhu, D.; Amable, L.; Deng, T.; Zhang, S.; et al. ADHFE1 Is a Breast Cancer Oncogene and Induces Metabolic Reprogramming. J. Clin. Investig. 2018, 128, 323–340. [Google Scholar] [CrossRef]
  122. Struys, E.A.; Verhoeven, N.M.; Brunengraber, H.; Jakobs, C. Investigations by Mass Isotopomer Analysis of the Formation of D-2-Hydroxyglutarate by Cultured Lymphoblasts from Two Patients with D-2-Hydroxyglutaric Aciduria. FEBS Lett. 2004, 557, 115–120. [Google Scholar] [CrossRef]
  123. Xu, T.; Stewart, K.M.; Wang, X.; Liu, K.; Xie, M.; Ryu, J.K.; Li, K.; Ma, T.; Wang, H.; Ni, L.; et al. Metabolic Control of TH17 and Induced Treg Cell Balance by an Epigenetic Mechanism. Nature 2017, 548, 228–233. [Google Scholar] [CrossRef]
  124. Pavlova, N.N.; Thompson, C.B. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016, 23, 27–47. [Google Scholar] [CrossRef]
  125. Colvin, H.; Nishida, N.; Konno, M.; Haraguchi, N.; Takahashi, H.; Nishimura, J.; Hata, T.; Kawamoto, K.; Asai, A.; Tsunekuni, K.; et al. Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and Is Associated with Distant Metastasis in Colorectal Cancer. Sci. Rep. 2016, 6, 36289. [Google Scholar] [CrossRef]
  126. Hoekstra, A.S.; de Graaff, M.A.; Briaire-de Bruijn, I.H.; Ras, C.; Seifar, R.M.; van Minderhout, I.; Cornelisse, C.J.; Hogendoorn, P.C.W.; Breuning, M.H.; Suijker, J.; et al. Inactivation of SDH and FH Cause Loss of 5hmC and Increased H3K9me3 in Paraganglioma/Pheochromocytoma and Smooth Muscle Tumors. Oncotarget 2015, 6, 38777–38788. [Google Scholar] [CrossRef]
  127. Xiao, M.; Yang, H.; Xu, W.; Ma, S.; Lin, H.; Zhu, H.; Liu, L.; Liu, Y.; Yang, C.; Xu, Y.; et al. Inhibition of α-KG-Dependent Histone and DNA Demethylases by Fumarate and Succinate That Are Accumulated in Mutations of FH and SDH Tumor Suppressors. Genes Dev. 2012, 26, 1326–1338. [Google Scholar] [CrossRef]
  128. Xu, W.; Yang, H.; Liu, Y.; Yang, Y.; Wang, P.; Kim, S.-H.; Ito, S.; Yang, C.; Wang, P.; Xiao, M.-T.; et al. Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases. Cancer Cell 2011, 19, 17–30. [Google Scholar] [CrossRef]
  129. Martinez, S.; Hausinger, R.P. Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-Dependent Oxygenases. J. Biol. Chem. 2015, 290, 20702–20711. [Google Scholar] [CrossRef]
  130. Liu, L.; Hu, K.; Feng, J.; Wang, H.; Fu, S.; Wang, B.; Wang, L.; Xu, Y.; Yu, X.; Huang, H. The Oncometabolite R-2-Hydroxyglutarate Dysregulates the Differentiation of Human Mesenchymal Stromal Cells via Inducing DNA Hypermethylation. BMC Cancer 2021, 21, 36. [Google Scholar] [CrossRef]
  131. Scourzic, L.; Mouly, E.; Bernard, O.A. TET Proteins and the Control of Cytosine Demethylation in Cancer. Genome Med. 2015, 7, 9. [Google Scholar] [CrossRef]
  132. Tsukada, Y.; Fang, J.; Erdjument-Bromage, H.; Warren, M.E.; Borchers, C.H.; Tempst, P.; Zhang, Y. Histone Demethylation by a Family of JmjC Domain-Containing Proteins. Nature 2006, 439, 811–816. [Google Scholar] [CrossRef]
  133. Tahiliani, M.; Koh, K.P.; Shen, Y.; Pastor, W.A.; Bandukwala, H.; Brudno, Y.; Agarwal, S.; Iyer, L.M.; Liu, D.R.; Aravind, L.; et al. Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1. Science 2009, 324, 930–935. [Google Scholar] [CrossRef]
  134. Tarhonskaya, H.; Nowak, R.P.; Johansson, C.; Szykowska, A.; Tumber, A.; Hancock, R.L.; Lang, P.; Flashman, E.; Oppermann, U.; Schofield, C.J.; et al. Studies on the Interaction of the Histone Demethylase KDM5B with Tricarboxylic Acid Cycle Intermediates. J. Mol. Biol. 2017, 429, 2895–2906. [Google Scholar] [CrossRef] [PubMed]
  135. Malta, T.M.; de Souza, C.F.; Sabedot, T.S.; Silva, T.C.; Mosella, M.S.; Kalkanis, S.N.; Snyder, J.; Castro, A.V.B.; Noushmehr, H. Glioma CpG Island Methylator Phenotype (G-CIMP): Biological and Clinical Implications. Neuro Oncol. 2018, 20, 608–620. [Google Scholar] [CrossRef] [PubMed]
  136. Letouzé, E.; Martinelli, C.; Loriot, C.; Burnichon, N.; Abermil, N.; Ottolenghi, C.; Janin, M.; Menara, M.; Nguyen, A.T.; Benit, P.; et al. SDH Mutations Establish a Hypermethylator Phenotype in Paraganglioma. Cancer Cell 2013, 23, 739–752. [Google Scholar] [CrossRef] [PubMed]
  137. Illiano, M.; Conte, M.; Salzillo, A.; Ragone, A.; Spina, A.; Nebbioso, A.; Altucci, L.; Sapio, L.; Naviglio, S. The KDM Inhibitor GSKJ4 Triggers CREB Downregulation via a Protein Kinase A and Proteasome-Dependent Mechanism in Human Acute Myeloid Leukemia Cells. Front. Oncol. 2020, 10. [Google Scholar] [CrossRef] [PubMed]
  138. Inoue, S.; Li, W.Y.; Tseng, A.; Beerman, I.; Elia, A.J.; Bendall, S.C.; Lemonnier, F.; Kron, K.J.; Cescon, D.W.; Hao, Z.; et al. Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. Cancer Cell 2016, 30, 337–348. [Google Scholar] [CrossRef]
  139. Sulkowski, P.L.; Oeck, S.; Dow, J.; Economos, N.G.; Mirfakhraie, L.; Liu, Y.; Noronha, K.; Bao, X.; Li, J.; Shuch, B.M.; et al. Oncometabolites Suppress DNA Repair by Disrupting Local Chromatin Signaling. Nature 2020, 582, 586–591. [Google Scholar] [CrossRef]
  140. Batsios, G.; Viswanath, P.; Subramani, E.; Najac, C.; Gillespie, A.M.; Santos, R.D.; Molloy, A.R.; Pieper, R.O.; Ronen, S.M. PI3K/MTOR Inhibition of IDH1 Mutant Glioma Leads to Reduced 2HG Production That Is Associated with Increased Survival. Sci. Rep. 2019, 9, 10521. [Google Scholar] [CrossRef]
  141. Carbonneau, M.; Gagné, L.M.; Lalonde, M.-E.; Germain, M.-A.; Motorina, A.; Guiot, M.-C.; Secco, B.; Vincent, E.E.; Tumber, A.; Hulea, L.; et al. The Oncometabolite 2-Hydroxyglutarate Activates the MTOR Signalling Pathway. Nat. Commun. 2016, 7. [Google Scholar] [CrossRef]
  142. Figueroa, M.E.; Abdel-Wahab, O.; Lu, C.; Ward, P.S.; Patel, J.; Shih, A.; Li, Y.; Bhagwat, N.; Vasanthakumar, A.; Fernandez, H.F.; et al. Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation. Cancer Cell 2010, 18, 553–567. [Google Scholar] [CrossRef]
  143. LaGory, E.L.; Giaccia, A.J. The Ever-Expanding Role of HIF in Tumour and Stromal Biology. Nat. Cell Biol. 2016, 18, 356–365. [Google Scholar] [CrossRef]
  144. Semenza, G.L. Targeting HIF-1 for Cancer Therapy. Nat. Rev. Cancer 2003, 3, 721–732. [Google Scholar] [CrossRef]
  145. Bernardo-Castiñeira, C.; Sáenz-de-Santa-María, I.; Valdés, N.; Astudillo, A.; Balbín, M.; Pitiot, A.S.; Jiménez-Fonseca, P.; Scola, B.; Tena, I.; Molina-Garrido, M.-J.; et al. Clinical Significance and Peculiarities of Succinate Dehydrogenase B and Hypoxia Inducible Factor 1α Expression in Parasympathetic versus Sympathetic Paragangliomas. Head Neck 2019, 41, 79–91. [Google Scholar] [CrossRef]
  146. Isaacs, J.S.; Jung, Y.J.; Mole, D.R.; Lee, S.; Torres-Cabala, C.; Chung, Y.-L.; Merino, M.; Trepel, J.; Zbar, B.; Toro, J.; et al. HIF Overexpression Correlates with Biallelic Loss of Fumarate Hydratase in Renal Cancer: Novel Role of Fumarate in Regulation of HIF Stability. Cancer Cell 2005, 8, 143–153. [Google Scholar] [CrossRef]
  147. Selak, M.A.; Armour, S.M.; MacKenzie, E.D.; Boulahbel, H.; Watson, D.G.; Mansfield, K.D.; Pan, Y.; Simon, M.C.; Thompson, C.B.; Gottlieb, E. Succinate Links TCA Cycle Dysfunction to Oncogenesis by Inhibiting HIF-Alpha Prolyl Hydroxylase. Cancer Cell 2005, 7, 77–85. [Google Scholar] [CrossRef]
  148. Yalaza, C.; Ak, H.; Cagli, M.S.; Ozgiray, E.; Atay, S.; Aydin, H.H. R132H Mutation in IDH1 Gene Is Associated with Increased Tumor HIF1-Alpha and Serum VEGF Levels in Primary Glioblastoma Multiforme. Ann. Clin. Lab. Sci. 2017, 47, 362–364. [Google Scholar]
  149. Laukka, T.; Mariani, C.J.; Ihantola, T.; Cao, J.Z.; Hokkanen, J.; Kaelin, W.G.; Godley, L.A.; Koivunen, P. Fumarate and Succinate Regulate Expression of Hypoxia-Inducible Genes via TET Enzymes. J. Biol. Chem. 2016, 291, 4256–4265. [Google Scholar] [CrossRef]
  150. Sourbier, C.; Ricketts, C.J.; Matsumoto, S.; Crooks, D.R.; Liao, P.-J.; Mannes, P.Z.; Yang, Y.; Wei, M.-H.; Srivastava, G.; Ghosh, S.; et al. Targeting ABL1-Mediated Oxidative Stress Adaptation in Fumarate Hydratase-Deficient Cancer. Cancer Cell 2014, 26, 840–850. [Google Scholar] [CrossRef]
  151. Mu, X.; Zhao, T.; Xu, C.; Shi, W.; Geng, B.; Shen, J.; Zhang, C.; Pan, J.; Yang, J.; Hu, S.; et al. Oncometabolite Succinate Promotes Angiogenesis by Upregulating VEGF Expression through GPR91-Mediated STAT3 and ERK Activation. Oncotarget 2017, 8, 13174–13185. [Google Scholar] [CrossRef]
  152. Sapieha, P.; Sirinyan, M.; Hamel, D.; Zaniolo, K.; Joyal, J.-S.; Cho, J.-H.; Honoré, J.-C.; Kermorvant-Duchemin, E.; Varma, D.R.; Tremblay, S.; et al. The Succinate Receptor GPR91 in Neurons Has a Major Role in Retinal Angiogenesis. Nat. Med. 2008, 14, 1067–1076. [Google Scholar] [CrossRef]
  153. Burr, S.P.; Costa, A.S.H.; Grice, G.L.; Timms, R.T.; Lobb, I.T.; Freisinger, P.; Dodd, R.B.; Dougan, G.; Lehner, P.J.; Frezza, C.; et al. Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1α Stability in Aerobic Conditions. Cell Metab. 2016, 24, 740–752. [Google Scholar] [CrossRef]
  154. Koivunen, P.; Lee, S.; Duncan, C.G.; Lopez, G.; Lu, G.; Ramkissoon, S.; Losman, J.A.; Joensuu, P.; Bergmann, U.; Gross, S.; et al. Transformation by the (R)-Enantiomer of 2-Hydroxyglutarate Linked to EGLN Activation. Nature 2012, 483, 484–488. [Google Scholar] [CrossRef]
  155. Koivunen, P.; Hirsilä, M.; Remes, A.M.; Hassinen, I.E.; Kivirikko, K.I.; Myllyharju, J. Inhibition of Hypoxia-Inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates: Possible Links between Cell Metabolism and Stabilization of HIF. J. Biol. Chem. 2007, 282, 4524–4532. [Google Scholar] [CrossRef] [PubMed]
  156. Zhao, S.; Lin, Y.; Xu, W.; Jiang, W.; Zha, Z.; Wang, P.; Yu, W.; Li, Z.; Gong, L.; Peng, Y.; et al. Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1alpha. Science 2009, 324, 261–265. [Google Scholar] [CrossRef]
  157. Metellus, P.; Colin, C.; Taieb, D.; Guedj, E.; Nanni-Metellus, I.; de Paula, A.M.; Colavolpe, C.; Fuentes, S.; Dufour, H.; Barrie, M.; et al. IDH Mutation Status Impact on in Vivo Hypoxia Biomarkers Expression: New Insights from a Clinical, Nuclear Imaging and Immunohistochemical Study in 33 Glioma Patients. J. Neurooncol. 2011, 105, 591–600. [Google Scholar] [CrossRef]
  158. Williams, S.C.; Karajannis, M.A.; Chiriboga, L.; Golfinos, J.G.; von Deimling, A.; Zagzag, D. R132H-Mutation of Isocitrate Dehydrogenase-1 Is Not Sufficient for HIF-1α Upregulation in Adult Glioma. Acta Neuropathol. 2011, 121, 279–281. [Google Scholar] [CrossRef]
  159. Alderson, N.L.; Wang, Y.; Blatnik, M.; Frizzell, N.; Walla, M.D.; Lyons, T.J.; Alt, N.; Carson, J.A.; Nagai, R.; Thorpe, S.R.; et al. S-(2-Succinyl)Cysteine: A Novel Chemical Modification of Tissue Proteins by a Krebs Cycle Intermediate. Arch. Biochem. Biophys. 2006, 450, 1–8. [Google Scholar] [CrossRef] [PubMed]
  160. Sun, Z.; Zhang, S.; Chan, J.Y.; Zhang, D.D. Keap1 Controls Postinduction Repression of the Nrf2-Mediated Antioxidant Response by Escorting Nuclear Export of Nrf2. Mol. Cell Biol. 2007, 27, 6334–6349. [Google Scholar] [CrossRef] [PubMed]
  161. Suzuki, T.; Muramatsu, A.; Saito, R.; Iso, T.; Shibata, T.; Kuwata, K.; Kawaguchi, S.-I.; Iwawaki, T.; Adachi, S.; Suda, H.; et al. Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1. Cell Rep. 2019, 28, 746–758.e4. [Google Scholar] [CrossRef] [PubMed]
  162. Kinch, L.; Grishin, N.V.; Brugarolas, J. Succination of Keap1 and Activation of Nrf2-Dependent Antioxidant Pathways in FH-Deficient Papillary Renal Cell Carcinoma Type 2. Cancer Cell 2011, 20, 418–420. [Google Scholar] [CrossRef]
  163. DeNicola, G.M.; Karreth, F.A.; Humpton, T.J.; Gopinathan, A.; Wei, C.; Frese, K.; Mangal, D.; Yu, K.H.; Yeo, C.J.; Calhoun, E.S.; et al. Oncogene-Induced Nrf2 Transcription Promotes ROS Detoxification and Tumorigenesis. Nature 2011, 475, 106–109. [Google Scholar] [CrossRef]
  164. Yamamoto, M.; Kensler, T.W.; Motohashi, H. The KEAP1-NRF2 System: A Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiol. Rev. 2018, 98, 1169–1203. [Google Scholar] [CrossRef]
  165. Panieri, E.; Telkoparan-Akillilar, P.; Suzen, S.; Saso, L. The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives. Biomolecules 2020, 10, 791. [Google Scholar] [CrossRef]
  166. Sullivan, L.B.; Martinez-Garcia, E.; Nguyen, H.; Mullen, A.R.; Dufour, E.; Sudarshan, S.; Licht, J.D.; Deberardinis, R.J.; Chandel, N.S. The Proto-Oncometabolite Fumarate Binds Glutathione to Amplify ROS-Dependent Signaling. Mol. Cell 2013, 51, 236–248. [Google Scholar] [CrossRef]
  167. Zheng, L.; Cardaci, S.; Jerby, L.; MacKenzie, E.D.; Sciacovelli, M.; Johnson, T.I.; Gaude, E.; King, A.; Leach, J.D.G.; Edrada-Ebel, R.; et al. Fumarate Induces Redox-Dependent Senescence by Modifying Glutathione Metabolism. Nat. Commun. 2015, 6, 6001. [Google Scholar] [CrossRef]
  168. Kudryavtseva, A.V.; Krasnov, G.S.; Dmitriev, A.A.; Alekseev, B.Y.; Kardymon, O.L.; Sadritdinova, A.F.; Fedorova, M.S.; Pokrovsky, A.V.; Melnikova, N.V.; Kaprin, A.D.; et al. Mitochondrial Dysfunction and Oxidative Stress in Aging and Cancer. Oncotarget 2016, 7, 44879–44905. [Google Scholar] [CrossRef]
  169. Smestad, J.; Erber, L.; Chen, Y.; Maher, L.J. Chromatin Succinylation Correlates with Active Gene Expression and Is Perturbed by Defective TCA Cycle Metabolism. iScience 2018, 2, 63–75. [Google Scholar] [CrossRef]
  170. Zhang, Z.; Tan, M.; Xie, Z.; Dai, L.; Chen, Y.; Zhao, Y. Identification of Lysine Succinylation as a New Post-Translational Modification. Nat. Chem. Biol. 2011, 7, 58–63. [Google Scholar] [CrossRef]
  171. Li, L.; Shi, L.; Yang, S.; Yan, R.; Zhang, D.; Yang, J.; He, L.; Li, W.; Yi, X.; Sun, L.; et al. SIRT7 Is a Histone Desuccinylase That Functionally Links to Chromatin Compaction and Genome Stability. Nat. Commun. 2016, 7, 12235. [Google Scholar] [CrossRef]
  172. Park, J.; Chen, Y.; Tishkoff, D.X.; Peng, C.; Tan, M.; Dai, L.; Xie, Z.; Zhang, Y.; Zwaans, B.M.M.; Skinner, M.E.; et al. SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways. Mol. Cell 2013, 50, 919–930. [Google Scholar] [CrossRef] [PubMed]
  173. Sreedhar, A.; Wiese, E.K.; Hitosugi, T. Enzymatic and Metabolic Regulation of Lysine Succinylation. Genes Dis. 2019, 7, 166–171. [Google Scholar] [CrossRef] [PubMed]
  174. Yang, Y.; Gibson, G.E. Succinylation Links Metabolism to Protein Functions. Neurochem. Res. 2019, 44, 2346–2359. [Google Scholar] [CrossRef] [PubMed]
  175. Liu, C.; Liu, Y.; Chen, L.; Zhang, M.; Li, W.; Cheng, H.; Zhang, B. Quantitative Proteome and Lysine Succinylome Analyses Provide Insights into Metabolic Regulation in Breast Cancer. Breast Cancer 2019, 26, 93–105. [Google Scholar] [CrossRef] [PubMed]
  176. Huang, K.-Y.; Hsu, J.B.-K.; Lee, T.-Y. Characterization and Identification of Lysine Succinylation Sites Based on Deep Learning Method. Sci. Rep. 2019, 9, 16175. [Google Scholar] [CrossRef] [PubMed]
  177. Li, F.; He, X.; Ye, D.; Lin, Y.; Yu, H.; Yao, C.; Huang, L.; Zhang, J.; Wang, F.; Xu, S.; et al. NADP+-IDH Mutations Promote Hypersuccinylation That Impairs Mitochondria Respiration and Induces Apoptosis Resistance. Mol. Cell 2015, 60, 661–675. [Google Scholar] [CrossRef] [PubMed]
  178. McBrayer, S.K.; Mayers, J.R.; DiNatale, G.J.; Shi, D.D.; Khanal, J.; Chakraborty, A.A.; Sarosiek, K.A.; Briggs, K.J.; Robbins, A.K.; Sewastianik, T.; et al. Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 2018, 175, 101–116.e25. [Google Scholar] [CrossRef]
  179. Chen, R.; Nishimura, M.C.; Kharbanda, S.; Peale, F.; Deng, Y.; Daemen, A.; Forrest, W.F.; Kwong, M.; Hedehus, M.; Hatzivassiliou, G.; et al. Hominoid-Specific Enzyme GLUD2 Promotes Growth of IDH1R132H Glioma. Proc. Natl. Acad. Sci. USA 2014, 111, 14217–14222. [Google Scholar] [CrossRef]
  180. Wang, P.; Wu, J.; Ma, S.; Zhang, L.; Yao, J.; Hoadley, K.A.; Wilkerson, M.D.; Perou, C.M.; Guan, K.-L.; Ye, D.; et al. Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. Cell Rep. 2015, 13, 2353–2361. [Google Scholar] [CrossRef]
  181. Alimohammadi, E.; Bagheri, S.R.; Taheri, S.; Dayani, M.; Abdi, A. The Impact of Extended Adjuvant Temozolomide in Newly Diagnosed Glioblastoma Multiforme: A Meta-Analysis and Systematic Review. Oncol. Rev. 2020, 14, 461. [Google Scholar] [CrossRef]
  182. Emadi, A.; Jun, S.A.; Tsukamoto, T.; Fathi, A.T.; Minden, M.D.; Dang, C.V. Inhibition of Glutaminase Selectively Suppresses the Growth of Primary Acute Myeloid Leukemia Cells with IDH Mutations. Exp. Hematol. 2014, 42, 247–251. [Google Scholar] [CrossRef]
  183. Ohka, F.; Ito, M.; Ranjit, M.; Senga, T.; Motomura, A.; Motomura, K.; Saito, K.; Kato, K.; Kato, Y.; Wakabayashi, T.; et al. Quantitative Metabolome Analysis Profiles Activation of Glutaminolysis in Glioma with IDH1 Mutation. Tumour. Biol. 2014, 35, 5911–5920. [Google Scholar] [CrossRef]
  184. Matre, P.; Velez, J.; Jacamo, R.; Qi, Y.; Su, X.; Cai, T.; Chan, M.; Lodi, A.; Sweeney, S.; Ma, H.; et al. Inhibiting Glutaminase in Acute Myeloid Leukemia: Metabolic Dependency of Selected AML Subtypes. Oncotarget 2016, 7, 79722–79735. [Google Scholar] [CrossRef]
  185. Ruiz-Rodado, V.; Lita, A.; Dowdy, T.; Celiku, O.; Saldana, A.C.; Wang, H.; Yang, C.Z.; Chari, R.; Li, A.; Zhang, W.; et al. Metabolic Plasticity of IDH1-Mutant Glioma Cell Lines Is Responsible for Low Sensitivity to Glutaminase Inhibition. Cancer Metab. 2020, 8, 23. [Google Scholar] [CrossRef]
  186. Tateishi, K.; Higuchi, F.; Miller, J.J.; Koerner, M.V.A.; Lelic, N.; Shankar, G.M.; Tanaka, S.; Fisher, D.E.; Batchelor, T.T.; Iafrate, A.J.; et al. The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1-Mutant Cancers and Potentiates NAD+ Depletion-Mediated Cytotoxicity. Cancer Res. 2017, 77, 4102–4115. [Google Scholar] [CrossRef]
  187. SongTao, Q.; Lei, Y.; Si, G.; YanQing, D.; HuiXia, H.; XueLin, Z.; LanXiao, W.; Fei, Y. IDH Mutations Predict Longer Survival and Response to Temozolomide in Secondary Glioblastoma. Cancer Sci. 2012, 103, 269–273. [Google Scholar] [CrossRef]
  188. Yang, P.; Zhang, W.; Wang, Y.; Peng, X.; Chen, B.; Qiu, X.; Li, G.; Li, S.; Wu, C.; Yao, K.; et al. IDH Mutation and MGMT Promoter Methylation in Glioblastoma: Results of a Prospective Registry. Oncotarget 2015, 6, 40896–40906. [Google Scholar] [CrossRef]
  189. Kim, G.-H.; Choi, S.Y.; Oh, T.-I.; Kan, S.-Y.; Kang, H.; Lee, S.; Oh, T.; Ko, H.M.; Lim, J.-H. IDH1R132H Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells. Int. J. Mol. Sci. 2019, 20, 2679. [Google Scholar] [CrossRef]
  190. Kohanbash, G.; Carrera, D.A.; Shrivastav, S.; Ahn, B.J.; Jahan, N.; Mazor, T.; Chheda, Z.S.; Downey, K.M.; Watchmaker, P.B.; Beppler, C.; et al. Isocitrate Dehydrogenase Mutations Suppress STAT1 and CD8+ T Cell Accumulation in Gliomas. J. Clin. Investig. 2017, 127, 1425–1437. [Google Scholar] [CrossRef]
  191. Amankulor, N.M.; Kim, Y.; Arora, S.; Kargl, J.; Szulzewsky, F.; Hanke, M.; Margineantu, D.H.; Rao, A.; Bolouri, H.; Delrow, J.; et al. Mutant IDH1 Regulates the Tumor-Associated Immune System in Gliomas. Genes Dev. 2017, 31, 774–786. [Google Scholar] [CrossRef]
  192. Cejalvo, T.; Gargini, R.; Segura-Collar, B.; Mata-Martínez, P.; Herranz, B.; Cantero, D.; Ruano, Y.; García-Pérez, D.; Pérez-Núñez, Á.; Ramos, A.; et al. Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype. Cancers 2020, 12, 3230. [Google Scholar] [CrossRef]
  193. Böttcher, M.; Renner, K.; Berger, R.; Mentz, K.; Thomas, S.; Cardenas-Conejo, Z.E.; Dettmer, K.; Oefner, P.J.; Mackensen, A.; Kreutz, M.; et al. D-2-Hydroxyglutarate Interferes with HIF-1α Stability Skewing T-Cell Metabolism towards Oxidative Phosphorylation and Impairing Th17 Polarization. Oncoimmunology 2018, 7, e1445454. [Google Scholar] [CrossRef]
  194. Bunse, L.; Pusch, S.; Bunse, T.; Sahm, F.; Sanghvi, K.; Friedrich, M.; Alansary, D.; Sonner, J.K.; Green, E.; Deumelandt, K.; et al. Suppression of Antitumor T Cell Immunity by the Oncometabolite (R)-2-Hydroxyglutarate. Nat. Med. 2018, 24, 1192–1203. [Google Scholar] [CrossRef]
  195. Zhang, L.; Romero, P. Metabolic Control of CD8+ T Cell Fate Decisions and Antitumor Immunity. Trends Mol. Med. 2018, 24, 30–48. [Google Scholar] [CrossRef]
  196. Zhang, L.; Sorensen, M.D.; Kristensen, B.W.; Reifenberger, G.; McIntyre, T.M.; Lin, F. D-2-Hydroxyglutarate Is an Intercellular Mediator in IDH-Mutant Gliomas Inhibiting Complement and T Cells. Clin. Cancer Res. 2018, 24, 5381–5391. [Google Scholar] [CrossRef]
  197. Grimolizzi, F.; Arranz, L. Multiple Faces of Succinate beyond Metabolism in Blood. Haematologica 2018, 103, 1586–1592. [Google Scholar] [CrossRef]
  198. Cho, Y.S.; Levell, J.R.; Liu, G.; Caferro, T.; Sutton, J.; Shafer, C.M.; Costales, A.; Manning, J.R.; Zhao, Q.; Sendzik, M.; et al. Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor. ACS Med. Chem. Lett. 2017, 8, 1116–1121. [Google Scholar] [CrossRef] [PubMed]
  199. Ma, R.; Yun, C.-H. Crystal Structures of Pan-IDH Inhibitor AG-881 in Complex with Mutant Human IDH1 and IDH2. Biochem. Biophys. Res. Commun. 2018, 503, 2912–2917. [Google Scholar] [CrossRef] [PubMed]
  200. Norsworthy, K.J.; Luo, L.; Hsu, V.; Gudi, R.; Dorff, S.E.; Przepiorka, D.; Deisseroth, A.; Shen, Y.-L.; Sheth, C.M.; Charlab, R.; et al. FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation. Clin. Cancer Res. 2019, 25, 3205–3209. [Google Scholar] [CrossRef] [PubMed]
  201. Stein, E.M.; DiNardo, C.D.; Pollyea, D.A.; Fathi, A.T.; Roboz, G.J.; Altman, J.K.; Stone, R.M.; DeAngelo, D.J.; Levine, R.L.; Flinn, I.W.; et al. Enasidenib in Mutant IDH2 Relapsed or Refractory Acute Myeloid Leukemia. Blood 2017, 130, 722–731. [Google Scholar] [CrossRef] [PubMed]
  202. Watts, J.M.; Baer, M.R.; Yang, J.; Prebet, T.; Lee, S.; Schiller, G.J.; Dinner, S.; Pigneux, A.; Montesinos, P.; Wang, E.S.; et al. Olutasidenib (FT-2102), an IDH1m Inhibitor as a Single Agent or in Combination with Azacitidine, Induces Deep Clinical Responses with Mutation Clearance in Patients with Acute Myeloid Leukemia Treated in a Phase 1 Dose Escalation and Expansion Study. Blood 2019, 134, 231. [Google Scholar] [CrossRef]
  203. Dang, L.; Su, S.-S.M. Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development. Annu. Rev. Biochem. 2017, 86, 305–331. [Google Scholar] [CrossRef]
  204. IDHIFA® (Enasidenib) Tablets, for Oral Use Initial U.S. Approval: 2017. Available online: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a5b4cdf0-3fa8-4c6c-80f6-8d8a00e3a5b6&type=display (accessed on 12 May 2021).
  205. DiNardo, C.D.; Schuh, A.C.; Stein, E.M.; Fernandez, P.M.; Wei, A.; De Botton, S.; Zeidan, A.M.; Fathi, A.T.; Quek, L.; Kantarjian, H.M.; et al. Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate Dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study. Blood 2019, 134, 643. [Google Scholar] [CrossRef]
  206. DiNardo, C.D.; Stein, E.M.; de Botton, S.; Roboz, G.J.; Altman, J.K.; Mims, A.S.; Swords, R.; Collins, R.H.; Mannis, G.N.; Pollyea, D.A.; et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N. Engl. J. Med. 2018, 378, 2386–2398. [Google Scholar] [CrossRef]
  207. TIBSOVO® (Ivosidenib Tablets). Available online: https://www.tibsovo.com/treatment/#possible-side-effects (accessed on 13 May 2021).
  208. Research, C. for D.E. and FDA Approves Ivosidenib as First-Line Treatment for AML with IDH1 Mutation. FDA 2019. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-first-line-treatment-aml-idh1-mutation (accessed on 12 March 2021).
  209. Abou-Alfa, G.K.; Macarulla, T.; Javle, M.M.; Kelley, R.K.; Lubner, S.J.; Adeva, J.; Cleary, J.M.; Catenacci, D.V.; Borad, M.J.; Bridgewater, J.; et al. Ivosidenib in IDH1-Mutant, Chemotherapy-Refractory Cholangiocarcinoma (ClarIDHy): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Study. Lancet Oncol. 2020, 21, 796–807. [Google Scholar] [CrossRef]
  210. Intlekofer, A.M.; Shih, A.H.; Wang, B.; Nazir, A.; Rustenburg, A.S.; Albanese, S.K.; Patel, M.; Famulare, C.; Correa, F.M.; Takemoto, N.; et al. Acquired Resistance to IDH Inhibition through Trans or Cis Dimer-Interface Mutations. Nature 2018, 559, 125–129. [Google Scholar] [CrossRef]
  211. Oltvai, Z.N.; Harley, S.E.; Koes, D.; Michel, S.; Warlick, E.D.; Nelson, A.C.; Yohe, S.; Mroz, P. Assessing Acquired Resistance to IDH1 Inhibitor Therapy by Full-Exon IDH1 Sequencing and Structural Modeling. Cold Spring Harb. Mol. Case Stud. 2021, 7, a006007. [Google Scholar] [CrossRef]
  212. Harding, J.J.; Lowery, M.A.; Shih, A.H.; Schvartzman, J.M.; Hou, S.; Famulare, C.; Patel, M.; Roshal, M.; Do, R.K.; Zehir, A.; et al. Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition. Cancer Discov. 2018, 8, 1540–1547. [Google Scholar] [CrossRef]
  213. Kessler, J.; Hohmann, T.; Güttler, A.; Petrenko, M.; Ostheimer, C.; Hohmann, U.; Bache, M.; Dehghani, F.; Vordermark, D. Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms. Cancers 2019, 11, 889. [Google Scholar] [CrossRef]
  214. Li, K.; Ouyang, L.; He, M.; Luo, M.; Cai, W.; Tu, Y.; Pi, R.; Liu, A. IDH1 R132H Mutation Regulates Glioma Chemosensitivity through Nrf2 Pathway. Oncotarget 2017, 8, 28865–28879. [Google Scholar] [CrossRef]
  215. Lin, L.; Cai, J.; Tan, Z.; Meng, X.; Li, R.; Li, Y.; Jiang, C. Mutant IDH1 Enhances Temozolomide Sensitivity via Regulation of the ATM/CHK2 Pathway in Glioma. Cancer Res. Treat. 2020. [Google Scholar] [CrossRef]
  216. Shi, J.; Sun, B.; Shi, W.; Zuo, H.; Cui, D.; Ni, L.; Chen, J. Decreasing GSH and Increasing ROS in Chemosensitivity Gliomas with IDH1 Mutation. Tumour. Biol. 2015, 36, 655–662. [Google Scholar] [CrossRef]
  217. Yu, D.; Liu, Y.; Zhou, Y.; Ruiz-Rodado, V.; Larion, M.; Xu, G.; Yang, C. Triptolide Suppresses IDH1-Mutated Malignancy via Nrf2-Driven Glutathione Metabolism. Proc. Natl. Acad. Sci. USA 2020, 117, 9964–9972. [Google Scholar] [CrossRef]
  218. Cairncross, J.G.; Wang, M.; Jenkins, R.B.; Shaw, E.G.; Giannini, C.; Brachman, D.G.; Buckner, J.C.; Fink, K.L.; Souhami, L.; Laperriere, N.J.; et al. Benefit from Procarbazine, Lomustine, and Vincristine in Oligodendroglial Tumors Is Associated with Mutation of IDH. J. Clin. Oncol. 2014, 32, 783–790. [Google Scholar] [CrossRef] [PubMed]
  219. Mohrenz, I.V.; Antonietti, P.; Pusch, S.; Capper, D.; Balss, J.; Voigt, S.; Weissert, S.; Mukrowsky, A.; Frank, J.; Senft, C.; et al. Isocitrate Dehydrogenase 1 Mutant R132H Sensitizes Glioma Cells to BCNU-Induced Oxidative Stress and Cell Death. Apoptosis 2013, 18, 1416–1425. [Google Scholar] [CrossRef] [PubMed]
  220. Molenaar, R.J.; Botman, D.; Smits, M.A.; Hira, V.V.; van Lith, S.A.; Stap, J.; Henneman, P.; Khurshed, M.; Lenting, K.; Mul, A.N.; et al. Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198. Cancer Res. 2015, 75, 4790–4802. [Google Scholar] [CrossRef] [PubMed]
  221. Tran, A.N.; Lai, A.; Li, S.; Pope, W.B.; Teixeira, S.; Harris, R.J.; Woodworth, D.C.; Nghiemphu, P.L.; Cloughesy, T.F.; Ellingson, B.M. Increased Sensitivity to Radiochemotherapy in IDH1 Mutant Glioblastoma as Demonstrated by Serial Quantitative MR Volumetry. Neuro Oncol. 2014, 16, 414–420. [Google Scholar] [CrossRef] [PubMed]
  222. Platten, M.; Schilling, D.; Bunse, L.; Wick, A.; Bunse, T.; Riehl, D.; Karapanagiotou-Schenkel, I.; Harting, I.; Sahm, F.; Schmitt, A.; et al. A Mutation-Specific Peptide Vaccine Targeting IDH1R132H in Patients with Newly Diagnosed Malignant Astrocytomas: A First-in-Man Multicenter Phase I Clinical Trial of the German Neurooncology Working Group (NOA-16). JCO 2018, 36, 2001. [Google Scholar] [CrossRef]
  223. Schumacher, T.; Bunse, L.; Pusch, S.; Sahm, F.; Wiestler, B.; Quandt, J.; Menn, O.; Osswald, M.; Oezen, I.; Ott, M.; et al. A Vaccine Targeting Mutant IDH1 Induces Antitumour Immunity. Nature 2014, 512, 324–327. [Google Scholar] [CrossRef]
  224. Hilf, N.; Kuttruff-Coqui, S.; Frenzel, K.; Bukur, V.; Stevanović, S.; Gouttefangeas, C.; Platten, M.; Tabatabai, G.; Dutoit, V.; van der Burg, S.H.; et al. Actively Personalized Vaccination Trial for Newly Diagnosed Glioblastoma. Nature 2019, 565, 240–245. [Google Scholar] [CrossRef]
  225. Pollack, I.F.; Jakacki, R.I.; Butterfield, L.H.; Hamilton, R.L.; Panigrahy, A.; Normolle, D.P.; Connelly, A.K.; Dibridge, S.; Mason, G.; Whiteside, T.L.; et al. Antigen-Specific Immunoreactivity and Clinical Outcome Following Vaccination with Glioma-Associated Antigen Peptides in Children with Recurrent High-Grade Gliomas: Results of a Pilot Study. J. Neurooncol. 2016, 130, 517–527. [Google Scholar] [CrossRef]
  226. Platten, M.; Bunse, L.; Wick, A.; Bunse, T.; Le Cornet, L.; Harting, I.; Sahm, F.; Sanghvi, K.; Tan, C.L.; Poschke, I.; et al. A Vaccine Targeting Mutant IDH1 in Newly Diagnosed Glioma. Nature 2021, 1–6. [Google Scholar] [CrossRef]
  227. Calithera Biosciences, Inc. Ph1 Study of the Safety, PK, and PDn of Escalating Oral Doses of the Glutaminase Inhibitor CB-839, as a Single Agent and in Combination with Standard Chemotherapy in Patients With Advanced and/or Treatment-Refractory Solid Tumors. 2020. Available online: https://clinicaltrials.gov/ct2/show/NCT02071862 (accessed on 12 March 2021).
  228. Kitazawa, S.; Ebara, S.; Ando, A.; Baba, Y.; Satomi, Y.; Soga, T.; Hara, T. Succinate Dehydrogenase B-Deficient Cancer Cells Are Highly Sensitive to Bromodomain and Extra-Terminal Inhibitors. Oncotarget 2017, 8, 28922–28938. [Google Scholar] [CrossRef]
  229. Sarkadi, B.; Meszaros, K.; Krencz, I.; Canu, L.; Krokker, L.; Zakarias, S.; Barna, G.; Sebestyen, A.; Papay, J.; Hujber, Z.; et al. Glutaminases as a Novel Target for SDHB-Associated Pheochromocytomas/Paragangliomas. Cancers 2020, 12, 599. [Google Scholar] [CrossRef]
  230. Salamanca-Cardona, L.; Shah, H.; Poot, A.J.; Correa, F.M.; Di Gialleonardo, V.; Lui, H.; Miloushev, V.Z.; Granlund, K.L.; Tee, S.S.; Cross, J.R.; et al. In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors. Cell Metab. 2017, 26, 830–841.e3. [Google Scholar] [CrossRef]
  231. Terunuma, A.; Putluri, N.; Mishra, P.; Mathé, E.A.; Dorsey, T.H.; Yi, M.; Wallace, T.A.; Issaq, H.J.; Zhou, M.; Killian, J.K.; et al. MYC-Driven Accumulation of 2-Hydroxyglutarate Is Associated with Breast Cancer Prognosis. J. Clin. Investig. 2014, 124, 398–412. [Google Scholar] [CrossRef]
  232. Yamashita, A.S.; da Costa Rosa, M.; Stumpo, V.; Rais, R.; Slusher, B.S.; Riggins, G.J. The Glutamine Antagonist Prodrug JHU-083 Slows Malignant Glioma Growth and Disrupts MTOR Signaling. Neurooncol. Adv. 2021, 3, vdaa149. [Google Scholar] [CrossRef]
  233. MacKenzie, E.D.; Selak, M.A.; Tennant, D.A.; Payne, L.J.; Crosby, S.; Frederiksen, C.M.; Watson, D.G.; Gottlieb, E. Cell-Permeating α-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells. Mol. Cell. Biol. 2007, 27, 3282–3289. [Google Scholar] [CrossRef]
  234. Loriot, C.; Domingues, M.; Berger, A.; Menara, M.; Ruel, M.; Morin, A.; Castro-Vega, L.-J.; Letouzé, É.; Martinelli, C.; Bemelmans, A.-P.; et al. Deciphering the Molecular Basis of Invasiveness in Sdhb-Deficient Cells. Oncotarget 2015, 6, 32955–32965. [Google Scholar] [CrossRef]
  235. Borodovsky, A.; Salmasi, V.; Turcan, S.; Fabius, A.W.M.; Baia, G.S.; Eberhart, C.G.; Weingart, J.D.; Gallia, G.L.; Baylin, S.B.; Chan, T.A.; et al. 5-Azacytidine Reduces Methylation, Promotes Differentiation and Induces Tumor Regression in a Patient-Derived IDH1 Mutant Glioma Xenograft. Oncotarget 2013, 4, 1737–1747. [Google Scholar] [CrossRef]
  236. Federici, L.; Capelle, L.; Annereau, M.; Bielle, F.; Willekens, C.; Dehais, C.; Laigle-Donadey, F.; Hoang-Xuan, K.; Delattre, J.-Y.; Idbaih, A.; et al. 5-Azacitidine in Patients with IDH1/2-Mutant Recurrent Glioma. Neuro Oncol. 2020, 22, 1226–1228. [Google Scholar] [CrossRef]
  237. Turcan, S.; Fabius, A.W.M.; Borodovsky, A.; Pedraza, A.; Brennan, C.; Huse, J.; Viale, A.; Riggins, G.J.; Chan, T.A. Efficient Induction of Differentiation and Growth Inhibition in IDH1 Mutant Glioma Cells by the DNMT Inhibitor Decitabine. Oncotarget 2013, 4, 1729–1736. [Google Scholar] [CrossRef] [PubMed]
  238. Yamashita, A.S.; da Costa Rosa, M.; Borodovsky, A.; Festuccia, W.T.; Chan, T.; Riggins, G.J. Demethylation and Epigenetic Modification with 5-Azacytidine Reduces IDH1 Mutant Glioma Growth in Combination with Temozolomide. Neuro Oncol. 2019, 21, 189–200. [Google Scholar] [CrossRef] [PubMed]
  239. DiNardo, C.D.; Pratz, K.; Pullarkat, V.; Jonas, B.A.; Arellano, M.; Becker, P.S.; Frankfurt, O.; Konopleva, M.; Wei, A.H.; Kantarjian, H.M.; et al. Venetoclax Combined with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia. Blood 2019, 133, 7–17. [Google Scholar] [CrossRef] [PubMed]
  240. Pollyea, D.A.; Stevens, B.M.; Jones, C.L.; Winters, A.; Pei, S.; Minhajuddin, M.; D’Alessandro, A.; Culp-Hill, R.; Riemondy, K.A.; Gillen, A.E.; et al. Venetoclax with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Patients with Acute Myeloid Leukemia. Nat. Med. 2018, 24, 1859–1866. [Google Scholar] [CrossRef] [PubMed]
  241. Chaturvedi, A.; Gupta, C.; Goparaju, R.; Gabdoulline, R.; Kaulfuss, S.; Görlich, K.; Schottmann, R.; Panknin, O.; Wagner, M.; Geffers, R.; et al. Synergistic Activity of IDH1 Inhibitor Bay-1436032 with Azacitidine in IDH1 Mutant Acute Myeloid Leukemia. Blood 2017, 130, 1352. [Google Scholar] [CrossRef]
  242. Yen, K.; Travins, J.; Wang, F.; David, M.D.; Artin, E.; Straley, K.; Padyana, A.; Gross, S.; DeLaBarre, B.; Tobin, E.; et al. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations. Cancer Discov. 2017, 7, 478–493. [Google Scholar] [CrossRef] [PubMed]
  243. Deng, G.; Shen, J.; Yin, M.; McManus, J.; Mathieu, M.; Gee, P.; He, T.; Shi, C.; Bedel, O.; McLean, L.R.; et al. Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule. J. Biol. Chem. 2015, 290, 762–774. [Google Scholar] [CrossRef]
  244. Chaturvedi, A.; Herbst, L.; Pusch, S.; Klett, L.; Goparaju, R.; Stichel, D.; Kaulfuss, S.; Panknin, O.; Zimmermann, K.; Toschi, L.; et al. Pan-Mutant-IDH1 Inhibitor BAY1436032 Is Highly Effective against Human IDH1 Mutant Acute Myeloid Leukemia in Vivo. Leukemia 2017, 31, 2020–2028. [Google Scholar] [CrossRef]
  245. Heuser, M.; Palmisiano, N.; Mantzaris, I.; Mims, A.; DiNardo, C.; Silverman, L.R.; Wang, E.S.; Fiedler, W.; Baldus, C.; Schwind, S.; et al. Safety and Efficacy of BAY1436032 in IDH1-Mutant AML: Phase I Study Results. Leukemia 2020, 34, 2903–2913. [Google Scholar] [CrossRef]
  246. Pusch, S.; Krausert, S.; Fischer, V.; Balss, J.; Ott, M.; Schrimpf, D.; Capper, D.; Sahm, F.; Eisel, J.; Beck, A.-C.; et al. Pan-Mutant IDH1 Inhibitor BAY 1436032 for Effective Treatment of IDH1 Mutant Astrocytoma in Vivo. Acta Neuropathol. 2017, 133, 629–644. [Google Scholar] [CrossRef]
  247. Li, L.; Paz, A.C.; Wilky, B.A.; Johnson, B.; Galoian, K.; Rosenberg, A.; Hu, G.; Tinoco, G.; Bodamer, O.; Trent, J.C. Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells. PLoS ONE 2015, 10. [Google Scholar] [CrossRef]
  248. Rohle, D.; Popovici-Muller, J.; Palaskas, N.; Turcan, S.; Grommes, C.; Campos, C.; Tsoi, J.; Clark, O.; Oldrini, B.; Komisopoulou, E.; et al. An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. Science 2013, 340, 626–630. [Google Scholar] [CrossRef]
  249. Urban, D.J.; Martinez, N.J.; Davis, M.I.; Brimacombe, K.R.; Cheff, D.M.; Lee, T.D.; Henderson, M.J.; Titus, S.A.; Pragani, R.; Rohde, J.M.; et al. Assessing Inhibitors of Mutant Isocitrate Dehydrogenase Using a Suite of Pre-Clinical Discovery Assays. Sci. Rep. 2017, 7, 12758. [Google Scholar] [CrossRef]
  250. Wang, F.; Travins, J.; DeLaBarre, B.; Penard-Lacronique, V.; Schalm, S.; Hansen, E.; Straley, K.; Kernytsky, A.; Liu, W.; Gliser, C.; et al. Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation. Science 2013, 340, 622–626. [Google Scholar] [CrossRef]
  251. Okoye-Okafor, U.C.; Bartholdy, B.; Cartier, J.; Gao, E.N.; Pietrak, B.; Rendina, A.R.; Rominger, C.; Quinn, C.; Smallwood, A.; Wiggall, K.J.; et al. New IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia. Nat. Chem. Biol. 2015, 11, 878–886. [Google Scholar] [CrossRef]
Figure 1. Oncometabolites production and reactions. Loss of function of mutated SDH and FH enzymes leads to the accumulation of succinate and fumarate that triggers post-translational proteins modifications such as succinylation and succination, respectively. The R-2HG derives mainly from the neomorphic catalytic activity of the mutated mitochondrial IDH2 and cytosolic IDH1, and less from non-canonical reactions involving the PHDGH and HOT enzymes. FH, fumarate hydratase; SDH, succinate dehydrogenase; α-KG, α-ketoglutarate; R-2HG, R-2-hydroxyglutarate; PHDGH, phosphoglycerate dehydrogenase; HOT, hydroxyacid-oxoacid-transhydrogenase; 4-BH, 4- hydroxybutyrate; SSA, succinic semialdehyde; AS, argininosuccinate; ARG, arginine.
Figure 1. Oncometabolites production and reactions. Loss of function of mutated SDH and FH enzymes leads to the accumulation of succinate and fumarate that triggers post-translational proteins modifications such as succinylation and succination, respectively. The R-2HG derives mainly from the neomorphic catalytic activity of the mutated mitochondrial IDH2 and cytosolic IDH1, and less from non-canonical reactions involving the PHDGH and HOT enzymes. FH, fumarate hydratase; SDH, succinate dehydrogenase; α-KG, α-ketoglutarate; R-2HG, R-2-hydroxyglutarate; PHDGH, phosphoglycerate dehydrogenase; HOT, hydroxyacid-oxoacid-transhydrogenase; 4-BH, 4- hydroxybutyrate; SSA, succinic semialdehyde; AS, argininosuccinate; ARG, arginine.
Ijms 22 05574 g001
Figure 2. Oncometabolites epigenetic and pseudohypoxia effects. Oncometabolites act as competitive inhibitors of αKG-dependent dioxygenases (αKGDDs) such as the KDMs and TETs families responsible for the modulation of chromatin by demethylation of histones and DNA CpG islands, respectively. The inhibition of PHDs blocks the HIF proline hydroxylation for the ubiquitin-proteasome degradation leading to HIF stabilization and activation of the hypoxia signalling pathway establishing a pseudo-hypoxic phenotype. KDMs, lysine histone demethylases; TETs, ten-eleven translocation; K, lysine; C, cytosine; P, proline; PHDs, prolyl hydroxylases; HIF, hypoxia-inducible factor; Ub, ubiquitin.
Figure 2. Oncometabolites epigenetic and pseudohypoxia effects. Oncometabolites act as competitive inhibitors of αKG-dependent dioxygenases (αKGDDs) such as the KDMs and TETs families responsible for the modulation of chromatin by demethylation of histones and DNA CpG islands, respectively. The inhibition of PHDs blocks the HIF proline hydroxylation for the ubiquitin-proteasome degradation leading to HIF stabilization and activation of the hypoxia signalling pathway establishing a pseudo-hypoxic phenotype. KDMs, lysine histone demethylases; TETs, ten-eleven translocation; K, lysine; C, cytosine; P, proline; PHDs, prolyl hydroxylases; HIF, hypoxia-inducible factor; Ub, ubiquitin.
Ijms 22 05574 g002
Table 1. Targeted therapies for IDH mutation.
Table 1. Targeted therapies for IDH mutation.
DrugPhaseTargetMechanism of ActionRef.
Enasidenib
(AG-221)
Ijms 22 05574 i001
FDA approvalIDH2Reversible, allosteric non-competitive inhibition via stabilization of the mutated IDH non-catalytic open conformation that prevents R-2HG formation [242].[201]
Ivosidenib
(AG-120)
Ijms 22 05574 i002
FDA approvalIDH1Reversible, allosteric inhibition of IDH1 R132 mutants competing with the cofactor Mg ion and preventing the formation of the catalytically active protein conformation [243][200]
Olutasidenib
(FT-2102)
Ijms 22 05574 i003
I/IIIDH1Competitive inhibition at isocitrate-binding pocket
blocking the conformational changes necessary for the catalysis.
[202]
BAY-1436032
Ijms 22 05574 i004
IIDH1Non-competitive, allosteric inhibition by binding at the interface of two monomers and stabilization of open inactive conformation.[244,245,246]
Vorasidenib (AG-881)
Ijms 22 05574 i005
IIIIDH1/2Non-competitive, allosteric inhibition by binding at the interface of two monomers and stabilization of open inactive conformation.[199]
IDH-305
Ijms 22 05574 i006
IIDH1Allosteric, non-competitive inhibition via stabilization of open, inactive enzyme dimer conformation (steric hindrance).[198]
AGI-5198
Ijms 22 05574 i007
Pre-clinicalIDH1Allosteric, competitive inhibition of α-KG.[247,248]
AGI-6780
Ijms 22 05574 i008
Pre-clinicalIDH2Allosteric inhibition by binding at the monomers interface preventing the transition for the active enzyme conformation.[249,250]
GSK321
Ijms 22 05574 i009
Pre-clinicalIDH1Allosteric inhibition by blocking the enzyme in the inactive conformation.[251]
PEPIDH1M vaccineIIDH1T-helper-1 (TH1) responses are activated by presentation to major histocompatibility complexes (MHC) class II of the peptide encompassing the immunogenic epitope of the mutated IDH region.[223]
IDH1 peptide vaccineIIDH1IDH1(R132H)-specific
peptide vaccine enhances T helper cell responses
against tumours in synergism with the mutated IDH immunogenic epitope.
[222,226]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Back to TopTop