Isocitrate dehydrogenase (IDH) active-site mutations cause a neomorphic enzyme activity that results in the formation of supraphysiologic concentrations of D-2-hydroxyglutarate (D-2HG). D-2HG is thought to be an oncometabolite that drives the formation of cancers in a variety of tissue types by altering the epigenetic state of progenitor cells by inhibiting enzymes involved in histone and DNA demethylation. This model has led to the development of pharmacologic inhibitors of mutant IDH activity for anticancer therapy, which are now being tested in several clinical trials. Emerging evidence in preclinical glioma models suggests that the epigenetic changes induced by D-2HG may persist even after mutant IDH activity is inhibited and D-2HG has returned to basal levels. Therefore, these results have raised questions as to whether the exploitation of downstream synthetic lethal vulnerabilities, rather than direct inhibition of mutant IDH1, will prove to be a superior therapeutic strategy. In this review, we summarize the preclinical evidence in gliomas and other models on the induction and persistence of D-2HG–induced hypermethylation of DNA and histones, and we examine emerging lines of evidence related to altered DNA repair mechanisms in mutant IDH tumors and their potential for therapeutic exploitation.

Mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) occur in the vast majority of grade II/III gliomas and secondary glioblastomas (GBM, grade IV gliomas; refs. 1–6). IDH1/2 mutations also occur in chondrosarcoma, hepatocellular carcinoma, acute myeloid leukemia (AML), intrahepatic cholangiocarcinoma, and thyroid cancers (7–10) and occur with relatively rare frequency in prostate cancers, melanomas, non–small cell lung cancers, and solid papillary carcinoma with reverse polarity breast cancers (9, 11–14). IDH1/2 mutations almost always occur as heterozygous missense substitutions in which a conserved arginine residue, located within the active site of IDH1/2 enzymes, is substituted to a different amino acid, with IDH1R132H being the most frequent mutation in glioma (1, 2, 15). Regardless of the specific amino acid substitution, mutations in Arg132 of IDH1 and Arg140 or Arg172 of IDH2 (IDHmut) cause a neomorphic enzyme activity in which α-ketoglutarate (αKG) is converted into the putative oncometabolite D-2-hydroxyglutrate (D-2HG; refs. 16, 17). In cells expressing IDHmut, D-2HG accumulates to supraphysiologic concentrations (i.e., millimolar levels) and inhibits a variety of αKG-dependent chromatin remodeling enzymes, including TET hydroxylases and lysine demethylases involved in histone demethylation (16, 18–22). On the basis of this evidence, IDH1/2 mutations are thought be initiating oncogenic events that cause epigenetic remodeling in neural progenitor cells, thus leading to an inhibition of normal cellular differentiation processes in a manner that promotes gliomagenesis. However, efforts to establish IDH1mut glioma cell lines have been challenging, and genetically engineered mouse models of IDH1 mutations have generally failed to promote gliomagenesis without concurrent expression of oncogenic drivers (23–27).

Genetic sequencing studies indicate that IDH1/2 mutations are early, truncal genetic events in the pathogenesis of malignant gliomas, and expression of IDH1R132H in neural progenitor cells induces DNA and histone hypermethylation that coincides with an inhibition of normal cellular differentiation (4–6). It is clear that a portion of grade II/III diffuse gliomas with IDH1/2 mutations can arise in the absence of known mitogenic driver alterations that are characteristic of higher-grade anaplastic gliomas and GBM (e.g., EGFR mutations, PI3K pathway–activating mutations, PDGFRA amplification), suggesting that IDH1 mutations are a driver of gliomagenesis in these grade II/III tumors and are therapeutically targetable (4, 6, 15). The vast majority of IDHmut grade II/III glioma also harbor secondary genetic alterations in either ATRX and TP53 (characteristic of astrocytoma) or CIC, FUBP1, chromosome 1p/19q codeletion, and the TERT promoter (characteristic of oligodendroglioma; refs. 4, 6, 15, 28). In addition, tertiary driver alterations ultimately arise as IDHmut lower-grade gliomas progress to anaplastic gliomas and secondary GBM (4, 5, 15, 28–30).

In this review, we review the preclinical evidence in gliomas and other cancer cell types on the induction of epigenetic dysregulation in response to D-2HG and examine a number of studies that have investigated the extent to which these processes are reversible, with an emphasis on glioma models. In addition, we examine emerging lines of evidence related to altered DNA damage and repair mechanisms in IDHmut gliomas, particularly the use of PARP inhibitors. We summarize recent preclinical studies that have tested PARP inhibitors with or without alkylating agents and radiation, and discuss ongoing clinical trials testing these approaches. In depth discussions of the biology and metabolism of IDH mutations (31–33), their relevance to noninvasive diagnostics (34), their role in glioma classification (35), and pharmacologic efforts to target these mutations have been reviewed in detail elsewhere (36).

The first direct preclinical investigation of IDH1mut inhibition was published in 2013, when Rohle and colleagues reported that treatment with AGI-5198, an inhibitor of IDH1R132H, slowed growth of a subcutaneous IDH1mut glioma xenograft in mice, but did not inhibit growth of an IDH1WT xenograft (37). Following this initial report of preclinical efficacy by Rohle and colleagues, the efficacy of IDH1R132H inhibition in preclinical glioma models has been at best inconsistent and in some cases clearly ineffective, suggesting that the results presented by Rohle and colleagues in 2013 may not be robustly reproducible across a wide range of model systems and conditions (38–40). Hypothetically, one reason for the observed lack of efficacy in preclinical glioma models is that virtually all established IDH1mut glioma cell lines are derived from grade III or grade IV tumors that have acquired tertiary genetic alterations in mitogenic signaling pathways (29, 41). Such tertiary driver alterations may predominate over IDH1 mutations as drivers of high-grade gliomas (29), thus rendering the continued D-2HG production nonessential during disease progression.

On the other hand, multiple lines of evidence suggest that supraphysiological D-2HG levels produced by IDH1/2 mutations are sufficient to inhibit αKG-dependent lysine demethylases and TET dioxygenases involved in DNA demethylation, which results in hypermethylation of histones and DNA and an inhibition of cellular differentiation (19, 21, 22, 42, 43). Therefore, the extent to which epigenetic dysregulation induced by IDH1/2 mutations is reversible remains a key question, particularly for gliomas, where preclinical results with IDHmut inhibitors have been less promising.

In their initial study, Rohle and colleagues showed that treatment of mice with established TS603 xenografts with AGI-5198 slowed growth over a 21-day time course. The investigators observed that xenografts treated with AGI-5198 contained fewer nuclei that stained positive for histone H3 Lys9 trimethylation (H3K9me3) compared with untreated xenografts. However, there were no significant differences in DNA methylation after AGI-5198 treatment (although the TS603 cell line was confirmed to exhibit the glioma CpG island (CGI) methylator phenotype, G-CIMP; ref. 37). Shortly thereafter, Turcan and colleagues reported that the DNA methyltransferase inhibitor decitabine, but not AGI-5198, inhibited anchorage-independent growth of TS603 colonies and induced significant DNA demethylation in this cell line (44). In 2015, Tateishi and colleagues found that treatment of mice bearing MGG152 orthotopic xenografts with AGI-5198 did not result in any significant changes in animal survival, orthotopic xenograft size, or expression of the proliferative marker Ki-67 (38). Furthermore, inhibition of mutant IDH1 did not cause any detectable changes in H3K9me2 or H3K9me3 (38). Long-term incubation of IDH1mut gliomas cells with AGI-5198 (12-months) did not result in observable differences in H3K9me3 or H3K27me3 and did not alter genome-wide patterns of DNA methylation. In fact, rather than inhibiting growth of IDH1mut cell lines, Tateishi and colleagues reported a slight acceleration of proliferation after long-term incubation and significantly shorter survival of animals after transplantation of MGG152 cells (38). The results from these targeting studies collectively suggest that suppression of D-2HG via IDHmut inhibition is unlikely to induce major changes in DNA and histone methylation, in spite of the well documented efficacy in suppressing D-2HG levels.

Several recent studies have used spontaneous or genetically engineered loss of IDHmut expression to investigate the reversibility of D-2HG–induced hypermethylation. In 2017, Turcan and colleagues used constitutive and doxycycline-inducible expression of IDH1R132H in immortalized human astrocytes (IHA) to investigate the induction and reversibility of DNA hypermethylation, gene expression changes, and the histone methylation landscape (22). Using this approach, they compared the dynamic changes in the epigenetic landscape of their model system with the epigenetic state of gliomas and patient-derived cell lines, including TS603 (22). The investigators found that expression of IDH1R132H generated a small subpopulation (∼2%–6%) of IDH1R132H CD24+ cells, which exhibited a stem-like gene expression profile and formed significantly more colonies in soft agar relative to IDH1R132H CD24 IHAs (22). IDH1R132H expression induced progressive increases in H3K4me2, H3K4me3, H3K4me3, H3K9me2, H3K9me3, and H3K36me3, as well as significant increases in hypermethylated DNA loci at similar regions to hypermethylated loci in the IDH1R132H cell line TS603. Importantly, Turcan and colleagues found that the vast majority of methylated loci ultimately returned to basal levels following withdrawal of doxycycline (loss of IDH1R132H and D-2HG). However, unsupervised hierarchical clustering of DNA methylation in IHAs that had previously expressed IDH1R132H for 40 passages showed that it took approximately 20 passages after loss of IDH1R132H expression for these cells to cluster with IHAs that had never expressed IDH1R132H. Notably, a subset of IDH1R132H-induced methylated loci persisted even after long-term withdrawal of doxycycline for 40 passages (22).

In a longitudinal study of lower-grade gliomas, Mazor and colleagues reported recurrent copy-number alterations (CNA) at the IDH1 locus at recurrence, which were associated with lower D-2HG production, maintenance of G-CIMP phenotypes, and clonal expansion of IDH1 CNA (45). While the G-CIMP phenotype was retained in this study following loss of D-2HG production, the authors noted that CpG sites outside of CGIs, were associated with decreased methylation and hypomethylated CpG sites in samples with IDH1 CNAs. Although IDH1 mutations are generally retained at recurrence, the investigators noted that their data may indicate that loss of IDHmut is associated with an adaptive advantage, as those cells with IDH1 CNAs, and therefore reduced D-2HG production, were observed to clonally expand in recurrent gliomas and patient-derived xenografts after serial passaging (45). These data may indicate that continued D-2HG production is not required for progression of IDHmut gliomas.

Moure and colleagues recently used CRISPR/Cas9 gene editing to systematically delete individual IDH1 alleles in patient-derived glioma cells (46). In this study, the IDH1R132H allele was specifically deleted in three individual clones from a patient-derived IDH1R132H/WT astrocytoma cell line, and the IDH1WT allele was deleted from an IDH1R132H/WT secondary GBM cell line. In both cell lines, deletion of an individual IDH1 allele was sufficient to ablate D-2HG production without inhibiting cellular proliferation. Furthermore, MGMT promoter methylation and G-CIMP status was maintained in all clones, although there was a trend toward decreased methylation in clones that had lost D-2HG production, which was enriched in open sea genomic loci and CGI shores of transcription start sites (46).

Collectively, results from studies using pharmacologic inhibition of IDHmut or genetic deletion of IDHmut alleles indicates that glioma recurrence and patient-derived cell line proliferation can occur in the absence of continued D-2HG production (38, 44–46). Furthermore, many of the hypermethylated features of IDHmut gliomas are maintained in the absence of D-2HG and may require many cell divisions to revert to baseline levels (22). Given these observations, it is tempting to conclude that pharmacologic inhibition of IDHmut alone may not be an effective way of preventing tumor recurrence or slowing tumor progression. However, one important caveat to that interpretation is that essentially all available glioma cell lines and xenografts used to study IDHmut to date are derived from anaplastic gliomas or secondary GBMs that have acquired tertiary driver alterations (29, 41). Therefore, it is critically important to note that because we do not have patient-derived preclinical models of IDHmut lower-grade gliomas that do not also harbor tertiary driver alterations, there is an absence of preclinical evidence over whether patients with corresponding lower-grade diffuse gliomas could benefit from mutant IDH1/2 inhibition. In other words, we cannot rule out the possibility that there remains a therapeutic opportunity for IDHmut small-molecule inhibitors for the treatment of IDHmut grade II/III gliomas that have not yet acquired driver alterations in mitogenic-signaling oncogenic driver genes. In addition, several studies have now reported that D-2HG produced by IDHmut may elicit immunosuppressive effects (47–50). Such effects may be mediated by epigenetic regulation of glioma gene expression and effects on tumor-infiltrating immune cells within the glioma microenvironment. Therefore, it remains to be determined whether the combination of IDHmut inhibition and antiglioma immunotherapy may be a viable therapeutic strategy.

Owing in large part to the limited promise of directly targeting IDH1mut in preclinical glioma models (25, 38–40, 44), numerous studies published over the past several years have investigated synthetic lethal/sick approaches as alternatives for treating IDH1/2 mutant gliomas (38, 51, 52). In particular, several recent studies have identified dysregulated DNA damage and repair processes in IDHmut gliomas, and these findings have prompted the design of novel strategies to target these tumor-specific properties for therapeutic purposes, including the commencement of several clinical trials to test the use of PARP inhibitors in combination with temozolomide (TMZ) or radiation (27, 52–54).

The initial study by Sulkowski and colleagues used HCT116 colorectal cancer cells, HeLa cells, and HEL (human erythroid leukemia) cells expressing IDH1WT or IDH1R132H and found that D-2HG produced by IDH1R132H impaired homologous recombination (HR) efficiency in these cell lines, thus conferring sensitivity to PARP1/2 inhibitors (52). The investigators also reported that IDHmut patient-derived glioma cells exhibit elevated basal levels of DNA damage, and that IDHmut patient-derived glioma cells, as well as IDH1WT cells treated with cell-permeable D-2HG, are more sensitive to the PARP1/2 inhibitor BMN-673 (talazoparib). Subsequently, Molenaar and colleagues reported that IDHmut was similarly associated with sensitivity to PARP inhibitors in AML cells and that this sensitivity could be reversed by pharmacological inhibition of IDHmut (54). A separate study, using a panel of IDHWT and IDHmut chondrosarcoma cell lines, found that sensitivity to talazoparib varied between cell lines and was independent of IDHmut status (55). Notably, this study showed that talazoparib treatment acted synergistically with either TMZ or irradiation, but also noted that the observed talazoparib-mediated radiosensitizing effect was partially reversed when IDHmut was inhibited in the JJ012 cell line (55). Using a panel of glioma cell lines, Tateishi and colleagues found that TMZ treatment induced activation of PARP and decreased levels of NAD+, which could then be further exploited by inhibiting NAD+ biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) inhibition (53). In this study, addition of PARP inhibitors reversed the TMZ-induced sensitizing effect to NAMPT inhibition.

More recently, Higuchi and colleagues used isogenic pairs of glioma cells with or without RNAi-mediated MSH6 deficiency to model the emergence of mismatch repair (MMR) defects that is associated with resistance to alkylating agents in GBM (56). In this study, the investigators found that PARP inhibition alone did not significantly alter cell viability and this occurred independent of IDHmut and MSH6 status. However, PARP inhibition was sufficient to reverse TMZ resistance that was acquired via MSH6 depletion (MMR deficiency; ref. 56). Most recently, Wang and colleagues used a combination of genetically engineered astrocytes, glioma cell lines, and a cholangiocarcinoma cell line to investigate the relationship between IDHmut status, PARP inhibitor sensitivity, and the response to radiotherapy. The investigators found that PARP inhibitor treatment enhanced the efficacy of radiotherapy in mice bearing IDH1R132H TS603 xenografts, as well as IDHmut murine gliomas generated using the RCAS-TVA system (57). The PARP inhibitor–mediated radiosensitizing effect was not observed in IDHWT xenografts (58).

Collectively, the findings described above have moved rapidly from initial reports to translation into the clinic, with at least two clinical trials underway to investigate the role of PARP inhibitors in combination with TMZ for the treatment of IDHmut gliomas (NCT03914742, NCT03749187; Table 1). It is important to note, however, that the preclinical results have been somewhat varied with respect to IDHmut status and PARP inhibitor sensitivity across different model systems and cell types. Furthermore, the benefit of PARP inhibition for glioma therapy appears to be most promising in combination with either TMZ or radiotherapy and available evidence to date suggests that this may not necessarily be specific to IDHmut gliomas (56, 58). Furthermore, the use of PARP inhibitors in IDHmut astroctyomas based on a putative HR-mediated DNA repair defect is somewhat unclear (52), as the vast majority of IDH1mut astrocytomas produce high levels of D-2HG while maintaining cellular immortality via alternative lengthening of telomeres, a mechanism of telomere maintenance that utilizes HR to maintain telomere length (15, 59, 60). Therefore, it is unclear whether D-2HG produced in IDH1mut astrocytomas impairs HR efficiency in this glioma subtype.

Table 1.

Ongoing clinical trials for the treatment of IDHmut gliomas.

NCT NumberStatusConditionsInterventionsPhasesStrategy
NCT03666559 Not yet recruiting Recurrent IDH1/2-mutated glioma Azacitidine Phase II Chemotherapya 
NCT03030066 Active, not recruiting Glioma with IDH1-R132 mutation DS-1001b Not applicable IDHmut inhibition 
NCT02481154 Active, not recruiting Solid tumor with IDH1 or IDH2 mutation AG881 Phase I IDHmut inhibition 
NCT02073994 Active, not recruiting Cholangiocarcinoma, chondrosarcoma, glioma, other advanced solid tumors AG-120 Phase I IDHmut inhibition 
NCT03914742 Not yet recruiting Recurrent glioma and glioblastoma with IDH1/2 mutations PARP inhibitor BGB-290; temozolomide; conventional surgery Phase I/phase II Synthetic lethal/sick 
NCT02333513 Unknown status Recurrent high-grade glioma Lomustine/vincristine/procarbazine Not applicable Chemotherapy 
NCT03684811 Recruiting Glioma/glioblastoma; hepatobiliary tumors; chondrosarcoma; intrahepatic cholangiocarcinoma; other solid tumors with IDH1 mutations FT-2102; azacitidine; nivolumab; gemcitabine; and cisplatin Phase I|phase II IDHmut inhibition 
NCT03749187 Recruiting Newly diagnosed or recurrent grade I–IV gliomas with IDH1/2 mutations in adolescents and young adults (ages 13–25) Drug: PARP inhibitor BGB-290|drug: temozolomide Phase I Synthetic lethal/sick 
NCT03343197 Active, not recruiting Glioma AG-120; AG881 Phase I  
NCT04056910 Not yet recruiting Advanced solid tumor; contrast-enhancing IDH-mutant glioma Ivosidenib; nivolumab Phase II IDHmut inhibition; Immunotherapy 
NCT02496741 Unknown status Glioma, cholangiocarcinoma, chondrosarcoma Metformin and chloroquine combination Phase I|phase II Synthetic lethal/sick 
NCT03718767 Recruiting Recurrent glioma with IDH mutation Nivolumab Phase II Immunotherapy 
NCT02746081 Active, not recruiting Solid tumors BAY1436032 Phase I IDHmut inhibition 
NCT01358058 Active, not recruiting Low-grade glioma, WHO grade 3 glioma IDH1/2 mutation and/or 1p/19q codeletion Proton radiation Not applicable Radiation 
NCT01534845 Unknown status Anaplastic glioma of brain|loss of chromosomes 1p/19q Temozolomide (temodal) Phase II Chemotherapy 
NCT03180502 Recruiting WHO grade II/III glioma with IDH mutation Intensity-modulated radiotherapy; proton beam radiotherapy; temozolomide Phase II Radiation 
NCT02381886 Active, not recruiting Advanced malignancies with IDH1-R132 mutations IDH305 Phase I IDHmut inhibition 
NCT NumberStatusConditionsInterventionsPhasesStrategy
NCT03666559 Not yet recruiting Recurrent IDH1/2-mutated glioma Azacitidine Phase II Chemotherapya 
NCT03030066 Active, not recruiting Glioma with IDH1-R132 mutation DS-1001b Not applicable IDHmut inhibition 
NCT02481154 Active, not recruiting Solid tumor with IDH1 or IDH2 mutation AG881 Phase I IDHmut inhibition 
NCT02073994 Active, not recruiting Cholangiocarcinoma, chondrosarcoma, glioma, other advanced solid tumors AG-120 Phase I IDHmut inhibition 
NCT03914742 Not yet recruiting Recurrent glioma and glioblastoma with IDH1/2 mutations PARP inhibitor BGB-290; temozolomide; conventional surgery Phase I/phase II Synthetic lethal/sick 
NCT02333513 Unknown status Recurrent high-grade glioma Lomustine/vincristine/procarbazine Not applicable Chemotherapy 
NCT03684811 Recruiting Glioma/glioblastoma; hepatobiliary tumors; chondrosarcoma; intrahepatic cholangiocarcinoma; other solid tumors with IDH1 mutations FT-2102; azacitidine; nivolumab; gemcitabine; and cisplatin Phase I|phase II IDHmut inhibition 
NCT03749187 Recruiting Newly diagnosed or recurrent grade I–IV gliomas with IDH1/2 mutations in adolescents and young adults (ages 13–25) Drug: PARP inhibitor BGB-290|drug: temozolomide Phase I Synthetic lethal/sick 
NCT03343197 Active, not recruiting Glioma AG-120; AG881 Phase I  
NCT04056910 Not yet recruiting Advanced solid tumor; contrast-enhancing IDH-mutant glioma Ivosidenib; nivolumab Phase II IDHmut inhibition; Immunotherapy 
NCT02496741 Unknown status Glioma, cholangiocarcinoma, chondrosarcoma Metformin and chloroquine combination Phase I|phase II Synthetic lethal/sick 
NCT03718767 Recruiting Recurrent glioma with IDH mutation Nivolumab Phase II Immunotherapy 
NCT02746081 Active, not recruiting Solid tumors BAY1436032 Phase I IDHmut inhibition 
NCT01358058 Active, not recruiting Low-grade glioma, WHO grade 3 glioma IDH1/2 mutation and/or 1p/19q codeletion Proton radiation Not applicable Radiation 
NCT01534845 Unknown status Anaplastic glioma of brain|loss of chromosomes 1p/19q Temozolomide (temodal) Phase II Chemotherapy 
NCT03180502 Recruiting WHO grade II/III glioma with IDH mutation Intensity-modulated radiotherapy; proton beam radiotherapy; temozolomide Phase II Radiation 
NCT02381886 Active, not recruiting Advanced malignancies with IDH1-R132 mutations IDH305 Phase I IDHmut inhibition 

Note: A number of clinical trials investigating therapies for the treatment of IDHmut gliomas are focused on testing the direct inhibition of IDHmut enzymes via small molecule inhibition. In contrast, several trials, including the use of PARP inhibitors, are being investigated to evaluate the potential for synthetic lethal/sick strategies that allow IDHmut activity to continue while targeting a downstream vulnerability created by elevated levels of D-2HG or compensatory adaptations to IDHmut activity.

aAzacitidine is a hypomethylation chemotherapeutic agent that is used to target (and potentially reverse) the downstream DNA hypermethylation caused by D-2HG–mediated inhibition of TET hydroxylases.

The studies described above serve to highlight the emerging strategies in which the activity of IDH1mut is intentionally maintained to exploit and target downstream synthetic lethal/sick sensitivities for glioma therapy. In light of these findings, how should the role of IDH1 mutations in glioma be considered? Given the genetic evidence of IDH1 mutations as early, truncal mutations in gliomas, coupled with the epigenetic impact of D-2HG and inhibition of differentiation, it is relatively clear that D-2HG plays a central role in driving gliomagenesis in grade II/III gliomas (3, 4, 6, 15, 61). Given this conclusion, coupled with evidence from AML clinical trials showing mutant IDH inhibition induces therapeutic responses, it seems clear that these mutations function as early oncogenic drivers of grade II/III gliomas. However, as discussed above, emerging evidence also indicates that D-2HG produced by mutant IDH enzymes becomes nonessential for at least a subset of gliomas as they progress to higher-grade tumors, and this transition likely coincides with acquisition of tertiary driver alterations (29, 41, 45, 46, 62). Therefore, the role of IDH1/2 mutations in gliomas appears to involve early essentiality followed by a transition to a passenger function during disease progression. Although the mechanism for such a transition requires further investigation, studies of spontaneous loss of D-2HG production or specific CRISPR/Cas9-mediated deletion of the IDH1R132H allele in patient-derived cells demonstrate that hypomethylation occurs predominantly at CGI shores/shelves (45, 46). An intriguing hypothesis stemming from this observation is that once D-2HG–mediated hypermethylation is established via TET hydroxylase inhibition, glioma cells are capable of maintaining G-CIMP independent of D-2HG through the actions of DNA methyltransferases (e.g., DNMT1).This may be consistent with loss of methylation at CGI shores/shelves, which are susceptible to passive demethylation and more rapid turnover of methylation during cell division (63, 64).

A better understanding of the role of IDH1R132H in gliomas, including the evolution of IDH1R132H function over the course of disease progression, is critically important given that emerging evidence from the field is beginning to inform divergent strategies for the treatment of IDHmut gliomas (Table 1). On one hand, at least two clinical trials are underway to investigate the role of PARP inhibitors in combination with TMZ for the treatment of IDHmut gliomas (NCT03914742, NCT03749187) and both of these trials list prior use of small-molecule mutant IDH1/2 inhibitors as an exclusion criterion. In contrast, numerous clinical trials investigating the efficacy of mutant IDH1/2 inhibitors in lower-grade gliomas (and other cancers) are ongoing (Table 1). Notably, the available clinical evidence to date comes from a previous phase I/II clinical trial that tested the combination of TMZ and veliparib in bevacizumab-naïve and bevacizumab-refractory cohorts. In this trial, there was no observed benefit in overall or progression-free survival with veliparib plus TMZ therapy, although IDHmut status was not reported previously (65). To prioritize preclinical research for the benefit of glioma patients, an emphasis should be placed on investigating the robustness of PARP inhibitor sensitivity across various patient-derived cell lines and preclinical model systems. This should include testing of IDH1R132H inhibitors for inducing radiosensitivity or radioresistance, as well as testing HR-mediated DNA damage repair in patient-derived glioma models in the presence or absence of IDHmut inhibitors. This approach will help to better understand the relationship between IDHmut status, PARP inhibitor sensitivity, and the role that each of these plays in response to standard-of-care therapies. Finally, special attention should be paid to the glioma subtypes in these studies to identify whether underlying genetic factors may play a role in IDHmut inhibitor or PARP inhibitor response.

H. Yan reports personal fees and other from Genetron Holdings (owner interest), personal fees from Agios, and personal fees from PGDX outside the submitted work; in addition, H. Yan has a patent for Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma issued, licensed, and with royalties paid from Agios, a patent for Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma issued, licensed, and with royalties paid from PGDX, a patent for Methods for rapid and sensitive detection of hotspot mutations issued, licensed, and with royalties paid from Gentron Holdings, a patent for Homozygous and heterozygous IDH1 gene-defective human astrocytoma cell lines pending, and a patent for homozygous and heterozygous IDH1 gene-defective cell lines derived from human colorectal cells pending. No disclosures were reported by the other author.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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