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SDIRSACR Oncology Insights

L16

Exploring the Metabolic Landscape of IDH-Mutant Gliomas for Therapeutic Intervention

Anushka Srivastava , Archismita Chatterjee , Ellora Sen 1
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1
1 National Brain Research Centre (BRIC-NBRC), NH8, Manesar, Gurugram 122052,Haryana, India
Keywords: glioma, metabolism, inflammation, methylation

Background: Glioblastoma multiforme (GBM) – the most malignant of brain cancers, characterized by an aberrant
metabolic profile, is largely refractory to current therapeutic regimens. Mutations in isocitrate dehydrogenase (IDH), –
a rate-limiting enzyme in TCA cycle that catalyses the conversion of isocitrate to α-ketoglutarate (α-KG), are prominent
in lower-grade gliomas and secondary glioblastomas. Mutations in the IDH1 gene are associated with a better clinical
outcome when compared to patients harboring gliomas with the wild-type IDH1 gene. The common point mutation
R132H in IDH1 (IDH1-R132H) is associated with a gain-of-function activity that converts α-KG to d-2-hydroxyglutarate
(d-2HG), which accumulates in IDH1 mutant gliomas [1]. IDH1 mutation establishes CIMP (CpG island methylator
phenotype) by remodeling the methylome and transcriptome, resulting in distinct methylation and transcription
patterns in mutants as compared to IDH1WT [2]. We have previously reported that IDH1 mutation in gliomas alters
redox balance [3, 4], chemotherapeutic resistance [5], and immune evasion pathways [6]. 2-HG, produced in IDH1-MT,
functionally alters the metabolism of glioma cells. As the rewiring of metabolic reprogramming with the epigenetic
landscape in gliomas can differentially influence chemoresistance, we investigated whether the altered metabolic
profile of tumours harboring IDH1 mutation contributes to the differential methylation status of genes associated with
survival responses and chemoresistance in these tumours.
Materials and Methods: Genome-wide methylation on tumors derived from IDH1 wild-type and mutant glioma patients
was performed using Infinium Methylation EPIC v2.0. Immunohistochemistry, quantitative real-time PCR (qRT-PCR),
Western blot analysis, were performed on patient derived tumor samples harboring IDH-MT or WT counterparts. In
vitro genetic and pharmacological manipulations, together with biochemical assays, were conducted on commercially
available glioma cell lines, treated with 2HG to mimic IDH1MT conditions or stably or transiently transfected with IDH1-
WT and IDH1-R132H constructs as described previously [6].
Results: Methylation profiling data from IDH wild-type and mutant glioma patients indicated hypermethylation of
several significant regulators of inflammation, including the suppressor of cytokine signaling 3 (SOCS3) in IDH1MT. This
finding in clinical samples was recapitulated in cells harboring IDH1 mutation. In vitro genetic and pharmacological
studies indicated SOCS3 as a molecular target of glycolysis, as inhibition of glycolysis affected SOCS3 expression through
altered methylation at its promoter. Given the substantial prognostic relevance of SOCS3 and its potential as a target
for immunotherapy, we identified drugs from Genomics of Drug Sensitivity in Cancer (GDSC) [7], directed at clinically
impactful genes related to the glycolysis-SOCS3 axis. The identified drug, which is a known anti-cancer chemotherapy
target, induced death in both IDH1-MT and IDH1-WT cells. This heightened sensitivity to drug targeting the glycolysis-
SOCS3 axis was SOCS3-dependent, as SOCS3 over-expression in IDH1MT cells rescued the cytotoxic effect.
Conclusions: Our findings suggest that the distinct genetic landscape rewires energy metabolism and survival responses
in the context of distinct molecular signatures associated with predictive and prognostic values in glioma patients. By
understanding the less aggressive phenotypes of IDH1 mutant gliomas and exploring various cell survival and death
pathways, we can gain novel insights into exploiting these signaling molecules for their therapeutic significance.

Acknowledgments and funding: Indian Council of Medical Research (ICMR) – Centre for Advanced Research (CAR),
BRIC-NBRC (Biotechnology Research and Innovation Council – National Brain Research Centre, Dept. of Biotechnology,
Govt. of India).

References

1. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce
2-hydroxyglutarate. Nature 2009; 462: 739-744.
2. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al. IDH1 mutation is sufficient to establish the glioma
hypermethylator phenotype. Nature 2012; 483: 479-483.
3. Patrick S, Gowda P, Lathoria K, Suri V, Sen E. YAP1-mediated regulation of mitochondrial dynamics in IDH1 mutant
gliomas. J Cell Sci 2021; 134.
4. Lathoria K, Gowda P, Umdor SB, Patrick S, Suri V, Sen E. PRMT1 driven PTX3 regulates ferritinophagy in glioma.

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