IDH-mutated gliomas promote epileptogenesis through d-2-hydroxyglutarate-dependent mTOR hyperactivation

Abstract

Background Uncontrolled seizures in patients with gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Here, we hypothesize that the active metabolite D-2-hydroxyglutarate (D-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures. Methods We use a complementary study of in vitro neuron-glial cultures and electrographically sorted human cortical tissue from patients with IDH-mutant gliomas to test this hypothesis. We utilize micro-electrode arrays for in vitro electrophysiological studies in combination with pharmacological manipulations and biochemical studies in order to better elucidate the impact of D-2-HG on cortical metabolism and neuronal spiking activity. Results We demonstrate that D-2-HG leads to increased neuronal spiking activity and promotes a distinct metabolic profile in surrounding neurons, evidenced by distinct metabolomic shifts and increased LDHA expression, as well as upregulation of mTOR signaling. The increases in neuronal activity are induced by mTOR activation and reversed with mTOR inhibition. Conclusion Together, our data suggest that metabolic disruptions in the surrounding cortex due to D-2-HG may be a driving event for epileptogenesis in patients with IDH-mutant gliomas.

Mutant IDH in Gliomas: Role in Cancer and Treatment Options

“…Mice bearing mutant IDH1 tumours showed a significant increase in their survival following treatment with D2-HGDH-OE CAR-T cells. It was later shown that the mechanism behind this was down to the reduction in D2-HG, and therefore the removal of immune suppression, allowing for an increase in memory cell differentiation and cytokine production [77].…”

“…Indeed, it has been demonstrated that activation of NMDA receptors, whether by glutamate or D2-HG, leads to an increase in membrane excitation and thus, epilepsy [93] [94]. The epileptogenic activity elicit by IDH mutation on the neighboring neurons has been recently demonstrated to be triggered by the mTOR pathway and it can be blocked by the addition of rapamycin [77]. However, the concentrations of extracellular D2-HG produced by mutant IDH can reach the mM range [95], whilst the normal extracellular concentration of glutamate is estimated to be between the nM and µM range [96].…”

Management of epilepsy in brain tumor patients

“…Several important clinically relevant factors contributing to epileptogenesis (i.e. the development and extension of brain tissue capable of generating spontaneous recurrent seizures) in brain tumors have been identified, including IDH-mutation and its active metabolite d -2-hydroxyglutarate [ 8 , 9 ], and BRAF V600E mutation (especially in gangliogliomas) [ 10 ▪ , 11 ▪▪ ].…”

Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors

“…These mutations, however, are not decisive for the development of epilepsy, as IDH1 and IDH2 mutations do increase the risk of developing seizures in gliomas [ 51 , 52 , 53 , 54 ], while LEATs typically lack IDH1 or IDH2 mutations and 1p/19q co-deletions [ 11 , 40 , 41 , 42 ]. Moreover, recent data suggest that the mTOR pathway hyperactivation by d-2-HG is a potential mechanism of epileptogenesis in patients with IDH-mutated gliomas [ 3 , 55 , 56 ].…”