2-Hydoxyglutarate: D/Riving Pathology in gLiomaS

Area of Science:

• Biochemistry
• Oncology
• Metabolomics

Background:

• Shared pathways exist between cancers and inborn errors of metabolism.
• 2-Hydroxyglutarate (2-HG) acidurias and isocitrate dehydrogenase (IDH) 1/2 mutant tumors exemplify this overlap.
• 2-HG exists as D(R)-2-HG and L(S)-2-HG enantiomers, elevated in respective acidurias.

Purpose of the Study:

• To explore the role of 2-HG enantiomers in cancer and metabolism.
• To understand the mechanism of 2-HG's impact on cellular processes and oncogenesis.
• To evaluate the potential of targeting 2-HG production for cancer therapy.

Main Methods:

• Review of recent studies on 2-HG synthesis and function.
• Analysis of 2-HG's structural similarity to α-ketoglutarate (α-KG).
• Investigation of 2-HG's inhibitory effects on α-KG-dependent enzymes.
• Discussion of in vivo detection methods for D-2-HG in gliomas.
• Evaluation of pharmacologic inhibitors of mutant IDH 1/2.

Main Results:

• D-2-HG is synthesized in IDH 1/2 mutant tumors, including gliomas and glioblastomas (GBM).
• L-2-HG is generated in hypoxia in IDH wild-type tumors.
• Both 2-HG enantiomers competitively inhibit α-KG-dependent enzymes, affecting DNA/histone methylation and oncogenesis.
• D-2-HG is detectable in vivo in glioma patients and models.
• IDH 1/2 inhibitors reduce D-2-HG production.

Conclusions:

• 2-HG enantiomers are crucial metabolites linking cancer and metabolic disorders.
• Inhibition of α-KG-dependent enzymes by 2-HG impacts oncogenesis.
• Targeting mutant IDH 1/2 offers a promising therapeutic strategy for D-2-HG-producing tumors.