Frequency of IDH mutations in different types of gliomas.
Abstract
In 2009, the discovery of isocitrate dehydrogenase (IDH) mutations in gliomas is a powerful example of understanding of the relationship between tumor genetics and human diseases. IDHs, catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate with production of NADH/NADPH, is the key enzymes in the Krebs cycle. IDH mutations, which occur early in gliomagenesis, change the function of the enzymes, causing them to produce 2–hydroxyglutarate, and to not create NADPH. Gliomas with mutated IDH have improved prediction of patient outcomes compared to its with wild-type IDH. Thus, the WHO Classification of Tumors of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers (including the IDH mutations) – together with classic histological features – in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. The aim of this chapter is to review the findings on the epidemiology and significance of IDH mutations in human gliomas, from discovery to the current knowledge about their molecular pathogenesis.
Keywords
- IDH mutation
- gliomas
- Isocitrate dehydrogenase
- significance
- therapies
1. Introduction
Isocitrate dehydrogenase (IDH) is a key enzyme in the Krebs cycle and plays an important role in energy metabolism. This enzyme is involved in a number of cellular processes, such as mitochondrial oxidative phosphorylation, regulation of cellular redox status, glutamine metabolism as well as lipogenesis or glucose sensing.
In 2008, Parsons et al. discovered a link between
The aim of this chapter is to review the findings on the epidemiology and significance of
2. IDH enzymes
2.1 Normal enzymes
2.1.1 Genetics and classification enzymes
IDH is a small molecule protein which is mainly distributed in the liver, heart muscle and skeletal muscle. In humans, there are three isozymes of IDH, which differ in subcellular localization, structural organization, allosteric regulation, catalytic mechanism and cofactor requirement. These are IDH1, IDH2 and IDH3.
These isozymes are encoded by five separate genes. IDH1, encoded by
IDH2, which is found in mitochondrial, encoded by the
IDH3 is a multi-tetrameric enzyme (2α1β1γ) with α − subunits being catalytic and the β- and γ- subunits being believed to be regulatory [9, 10]. Since
2.1.2 Mechanism and function of IDH enzymes
IDH exists in NADP-dependent forms [2]. Both IDH1 and IDH2 exist as homodimers, share considerable sequence similarity (70% identity humans). IDH1 is highly expressed in the mammalian liver (IDH1 provides NADPH for peroxisomal fat and cholesterol synthesis) with only moderate to absent expression in other tissues, whereas IDH2 is highly expressed in heart, muscle, and activated lymphocytes [13].
The main function of IDH is to catalyze the oxidative decarboxylation of ICT to α-KG. This reaction also produces a molecule called NADPH, which is necessary for multiple cellular processes. The NADPH is involved in the breakdown of lipids for energy, and also protects cells from potentially harmful molecules called reactive oxygen species.
By providing mitochondrial NADPH for NADPH-dependent antioxidant enzymes, IDH maintains a pool of reduced glutathione and peroxiredoxin [14]. These molecules protect mitochondria from ROS-mediated oxidative damage, ensuing lipid peroxidation and DNA damage, and from stress induced by heat shock, cadmium, excess fructose, or tumor necrosis factor-α (TNF-α) [13, 14]. These data suggest that IDH is important for cell stress responses, mitochondrial bioenergetics, and macromolecular synthesis to support cell survival and growth.
2.2 Molecular pathogenesis of IDH mutations
2.2.1 Enzymatic properties of mutant IDHs
Mutations in
All
In addition, due to essential roles of IDHs in producing cytoplasmic and mitochondrial NADPH, tumor cell survival may also be dependent on basal IDH activities to maintain cytoplasmic and mitochondrial redox homeostasis.
2.2.2 Mutant IDH enzymes control cellular growth
A large body of evidence indicates that IDH mutation inhibits cell proliferation [18, 19, 20]. Theoretically, D-2HG inhibits ATP synthase, resulting in decreased mTOR (mammalian target of rapamycin) signaling and cell growth. Moreover, by inhibiting the FTO (fat mass and obesity-associated) demethylase activity, D-2HG promotes cell-cycle arrest, thereby increasing N6-methyladenosine modification of MYC/CEBPA (CCAAT/enhancer binding protein alpha) transcripts for destabilization and, thus, decreasing proliferative signaling [20].
There is a study in mice indicating that IDH1R132H homozygous expression in neural progenitor cells (NPCs) results in extensive cerebral hemorrhage and perinatal lethality [21]. On molecular levels, high-level accumulation of D-2HG inhibits prolyl-hydroxylation and subsequent maturation of collagen. Immature collagens accumulate, resulting in an aberrantly formed basement membrane and the initiation of an endoplasmic reticulum (ER) stress response. As a result, mice developed hydrocephalus and grossly dilated lateral ventricles.
Collectively, these studies provide strong evidence that IDH mutation targets various signaling pathways to inhibit glial cell proliferation.
2.3 IDH mutation involvement human cancers
Mutations in
Mutations targeting IDH in different types of tumors share four distinct biochemical features. First of all,
Second, the vast majority of
From what has been mentioned so far, the most likely model is as follows: substitution of two arginine residues on both monomers inactivates both forward oxidative decarboxylation and reverse reductive carboxylation reactions while the presence of one arginine fully inhibits the forward oxidative decarboxylation reaction but changes the product of the reverse reductive carboxylation reaction to be D-2HG instead of ICT.
It is conceivable that the Mut-Mut dimer is totally, while the Wt-Mut dimer increases the production of D-2HG from 2KG through the reverse reaction and does not interconvert ICT and 2KG. Since D-2HG is thought to inactivate 2KG utilizing enzymes, it is possible that it also inhibits the Wt-Wt dimer form and that might explain the dominant negative effect of heterozygous arginine substitution (Figure 3) [24, 25].
Third, nearly all
Lastly, the mutual exclusivity seen in mutant
2.4 IDH mutations in human gliomas
Glioma stem cells are small numbers of tumor cells that act as stem cells in glial cells. According to the “seed and soil” theory put forward by Paget, if the tumor microenvironment is soil, then glioma stem cells are seeds.
The IDH mutations enhance function in glial tumor cells, leading to the accumulation and secretion of large amounts of the oncometabolite, D-2HG, which ultimately inhibits the catalytic activity of α-KG-dependent dioxygenase, damaging the key steps in angiogenesis, hypoxic stress, and mature differentiation of cells. These processes are closely related to the occurrence and development of tumors. However, researches showed that D-2HG is a weak competitive inhibitor of α-KG. Thus, it can only be observed to inhibit the differentiation of glioma stem cells when the accumulation of D-2HG is high. Therefore, the formation of gliomas requires not only seeds (glioma stem cells) but also soil (tumor microenvironment).
It was found that the
Interestingly, VEGF is initiated transcription by HIF-1α, and hypoxia can cause an increase in VEGF. IDH mutants can modulate VEGF to promote tumor microchip formation by inhibiting HIF-1α degradation. Moreover, quick growth of tumors will rapidly consume the surrounding energy and nutrients. Thus, HIF-1α is a stably expressed surrounding tumor.
With the appropriate soil, glioma tumor stem cells grow rapidly and continue to invade the surrounding tissues, ultimately accelerating the growth of gliomas.
In contrast to diffuse gliomas,
Aggregate data from multiple preclinical and clinical studies have shown that
These changes relate to the histological classification of the disease. For example, diffuse astrocytomas, mutant
Type of IDH | IDH1/2 | IDH1/2 | IDH1 | IDH1/2 | IDH1 |
---|---|---|---|---|---|
Yan et al [29] | Hartmann et al [26] | Ichimura et al [33] | Park et al [34] | Watanabe et al [35] | |
Pilocytic astrocytoma | 0% | 0% | 0% | 10% | |
Diffuse astrocytoma | 90% | 74% | 59% | >80% | 88% |
Anaplastic astrocytoma | 73% | 65% | 52% | 78% | |
Secondary glioblastoma | 85% | 50% | >95% | 82% | |
Primary glioblastoma | 5% | 3% | 5% | ||
Oligodendroglioma | 84% | 87% | 68% | 100% | 79% |
Anaplastic oligodendroglioma | 94% | 75% | 60% | 75% | |
Oligoastrocytoma | 100% | 83% | 50% | 94% | |
Anaplastic oligoastrocytoma | 100% | 72% | 78% | 71% |
3. Clinical indications involving the discovery of IDH-mutated glioma
3.1 Diagnosis
The latest WHO classification of CNS tumors using the integrated phenotypic and molecular parameters (including the
There are wo features make
Practical guidelines are available for detection of
As the indirect method to confirm
All of the above methods have in common the need for tissue samples. Thus, surgery or biopsy of the tumor is necessary. This is a diagnostic difficulty. Therefore, recently, studies on non-invasive methods are being carried out, in which diagnosis by magnetic resonance spectroscopy (MRS) and amide proton transfer-weighted (APTw) have been shown to be promising [40, 41, 42]. In IDH mutant gliomas, D-2HG accumulates to sufficient levels as a brain metabolite, which renders its visibility on MRS. Therefore, this may provide crucial longitudinal data for the determination of disease progression and therapy response.
Identification of
3.2 Prognostic
Generally,
Furthermore, in the SongTao study,
In 2009, using a large clinical dataset, Yan et al. reported that GBM patients with
The median OS was 65 months for gliomas patients with
Extensive meta-analysis (2,190 cases) confirmed
Several studies have explained that the favorable prognosis of IDH mutant gliomas is due to their increased sensitivity to chemotherapy and radiotherapy [47, 53]. IDH mutant gliomas likely harbour defects in multiple DNA repair pathways, which render them vulnerable to radiotherapy- or chemotherapy-induced DNA damage [54, 55]. These findings indicate that IDH mutation could serve as an important predictive factor for treatment response among glioma patients.
3.2.1 Novel therapies
Glioma is the most frequent brain tumor and has a notably high mortality and disability rate. For its complex pathogenesis, the surgical and drug-assisted treatments do not seem to be effective. Therefore, it is of great significance to find new targets for diagnosis and treatment. The detection of IDH mutations in gliomas offers bases to research new therapies.
Some studies indicated that IDH-mutated gliomas maintain the IDH-mutated allele even after acquiring oncogenic driver mutations [56, 57]. This may show that IDH-mutated gliomas may remain vulnerable to the targeted therapies developed specifically for IDH mutations even at progression or after malignant transformation to higher grade glioma. The therapeutic effects may be further enhanced by combining different targeted therapies or with traditional chemotherapeutics or radiation.
3.2.2 IDH-mutated inhibitors
Since the neomorphic activity of IDH mutants is correlated with malignant transformation, direct targeting of the mutant enzymes becomes a heavily pursued strategy.
Over the past decade, several attempts have been made to find and develop small molecular compounds that directly inhibit the IDH-mutated enzymes. Some synthetic inhibitors reported as AGI-5198, ivosidenib (AG-120) and vorasidenib (AG-881), demonstrated effective and safe in treating IDH-mutated myeloid malignancies and solid tumors, including glioma [58, 59, 60]. BAY1436032, another IDH-mutant inhibitor, had shown tumor-suppressing effects as experimental therapeutics for the treatment of AML and astrocytoma in animal models [61, 62]. Recently, ivosidenib and vorasidenib have been approved by the Food and Drug Administration as a therapeutic option for IDH-mutated AML.
Despite the promising success of the IDH-mutated inhibitors, a number of studies have indicated the potential limitations of their application. As discussed above, IDH-mutated enzymes enhance sensitivity to chemotherapy and radiotherapy. So that, using these inhibitors reduces D-2HG production and relieves the burden on the multiple DNA repair pathways, resulting in chemoresistance. For example, AGI-5198 might increase their resistance to genotoxic therapies, such as radiation and chemo agents [63, 64].
Overall, targeting IDH-mutated activity is a straightforward strategy and has shown efficacy gliomas in humans. However, whether inhibition of mutant IDH and subsequent reduction in D-2HG production are sufficient to halt tumor growth in gliomas and other solid tumors remains unclear. In addition, whether these drugs will cross the blood brain barrier for admission to IDH mutant glioma cells is a question that requires further studies.
3.2.3 Targeting redox homoeostasis
Redox homeostasis has been reported to be greatly affected by IDH mutations, notably elevated levels of oxidative stress. Targeting redox homeostasis may be effective in gliomas with IDH mutations. In fact, in IDH-mutated gliomas, the synthesis of NAD is largely compromised. As a result, tumor cells rely on a path of salvation to create NAD. Consequently, the IDH-mutated gliomas cells can be extremely sensitive to the blockade of the salvage pathway.
In addition, one study demonstrated that levels of glutamate, glutamine and glutathione decreased in tumor regions in patients with IDH-mutated glioma, compared with levels in contralateral regions. Furthermore, the glutathione level negatively correlates with the level of D-2HG, suggesting that glutathione is required for IDH-mutated cells to maintain redox homoeostasis [65]. An animal preclinical study has shown that inhibiting glutamine metabolism using the glutaminase inhibitor CB-839 leads to impaired redox homoeostasis and makes IDH-mutated glioma sensitivity to radiotherapy [66].
Since the disruption of redox homoeostasis results in potent cytotoxicity accompanied by tumor suppression, current therapeutic compounds are mostly at the preclinical stage and show considerable systemic toxicity. Nevertheless, developing the next generation of therapeutic compounds with both potency and selectivity will be of great help for targeting redox imbalance in IDH-mutated malignancies.
3.2.4 Immunotherapies
With evidence that IDH mutation is an early event in tumorigenesis and is present homogenously in all glioma tumor cells at specific codons. These mutations are ideal immunotherapy targets.
In fact, there are increasing evidences that the IDH mutation might play critical roles in altering the immunological microenvironment of the tumor, as shown by an inhibition of tumor-infiltrating lymphocytes, cytotoxic T cells and natural killer cells [67, 68]. Additionally, the presence of IDH mutation correlates with a decrease in the expression of PD-L1 (Programmed Death-Ligand 1). Decreased expression of PD-L1 in IDH-mutated gliomas implies a stronger T cell activation, because PD-L1 is a cellular surface protein that modulates the immune system and promotes self-tolerance through inhibition T cell activity [69].
The combination with the IDH-mutated inhibitors shows an improvement in the efficacy of PD-1-resistant derived immunotherapy, which induces intracellular CD4 + T-cell proliferation. The result is a reduction in tumor size and a prolonged survival. Further studies are currently under investigation, promising to bring positive results.
3.2.5 Vaccines
Vaccination is the most effective measure of disease prevention and control. In many low-grade glioma patients, the spontaneous immune response to IDH1 mutation has been found [70]. The use of the self-immune response to tumor treatment has also been a heavily researched subject in recent years and provides evidences that is worth the wait. For example, in animal experiments, it was found that the vaccine not only was able to prevent from IDH1 mutant cells growing in the brain, but also did not destroy the normal physiological function of the IDH1 enzyme [70].
Specifically, a phase 1 clinical trial is ongoing to confirm the safety and therapeutic efficacy of the IDH1 R132H mutant peptide vaccine (NOA-16) in newly diagnosed grade III and IV gliomas with IDH1 mutation. The first reported results demonstrated the safety and immunogenicity of NOA-16, with 80% of patients having mutation-specific T cell immune responses, and 87% of the patients displaying humoral immune responses; no deaths have been reported [71].
It is difficult to completely remove gliomas by surgery and drugs, so they often recur. Moreover, the recurrent gliomas after clearance generally tend to be more resistant and invasive. Vaccines can play a maintenance role in these cases. So finding a suitable vaccine will greatly benefit patients and help them escape the magic spell of glioma recurrence.
3.2.6 Other therapies
In addition to the treatments outlined above, there are other methods base on vulnerability of IDH-mutant cells to NAD+ depletion, hypoxia-inducible factor-1? (HIF-1?) pathway of IDH mutation or mammalian target of rapamycin (mTOR) signaling pathway. These are all new methods, are preclinical models and promise to bring about a change in treatment for gliomas with IDH mutations.
It is generally known that trials of IDH mutant inhibitors, vaccines, immunotherapies and so on in IDH mutant gliomas and recurrent gliomas have been conducted. Meanwhile, old drugs for other tumors have also been developed to treat gliomas with IDH mutations, such as azacitidine, nivolumab, and temozolomide.
In summary, targeting the distinctive vulnerabilities of IDH-mutated glioma has been shown to be successful, as cancer cells are less likely to compensate for the loss of essential biological pathways. However, development of further studies is needed for more convincing evidence to apply these novel therapies to treatment.
4. Conclusion
The discovery of the IDH mutation not only adds to the landscape of glioma genetics but also supports diagnosis and prognosis. For IDH-mutated gliomas, numerous attempts have been made to define selective and effective therapeutics that target the biological signatures, with the aim of improving standard treatments.
From the above mentioned biological bases, IDH mutation is an important target for the prevention and treatment of gliomas. However, due to the short and uncertain clinical trial duration, most clinical trials of vaccines, IDH inhibitors or other methods are still underway. Much research still needs to be completed. However, we believe that the great potential of these new treatments offers hope in patients with gliomas.
Finally, a major obstacle in IDH-mutated glioma is that the critical oncogenic drivers of this disease remain controversial. One of the main questions remains the molecular pathogenesis of WHO grade II and III gliomas without IDH mutations, which often do not show changes in genes typically associated with gliomas. In-depth investigation of critical molecular pathways will be of great importance to develop highly potent and selectivity treatment.
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