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CORDIS

Oncometabolitic control of tumor growth and epileptogenesis in IDH mutated gliomas: D2HG signaling mechanism.

Project description

Metabolic control of tumour growth and epileptogenesis: the case of gliomas

Gliomas may present with mutations in the isocitrate dehydrogenase (IDH) gene, which lead to the overproduction of the oncometabolite D-2-hydroxyglutarate (D2HG). D2HG is thought to participate in both epileptogenic and oncologic processes, modulating the excitatory neurotransmitter glutamate. The scope of the EU-funded GliomaSignals project is to investigate the role of D2HG in the neurobiology of gliomas and elucidate the mechanism by which it modulates, via its effects on glutamatergic signalling, tumour growth and epilepsy processes. The project's results are expected to shed light on the high epileptic activity associated with glioma tumour invasion and unveil novel targets for therapy.

Objective

Dysregulated growth processes of gliomas interact with pro-epileptic plasticity of brain circuits in such a way that the excitatory transmitter glutamate promotes autocrine tumor invasion as well as epileptic synchrony in surrounding cortical regions. Most low-grade gliomas are associated with mutations of Isocitrate DesHydrogenase (IDH) genes which lead to an excess of the oncometabolite D-2-Hydroxyglutarate (D2HG). With a structure mimicking glutamate, D2HG is thought to participate in both epileptogenic and oncologic processes. Importantly, while epileptic activity is accentuated, tumor prognosis is improved in affected people. My preliminary data now suggest a dual function for D2HG, acting as a glutamatergic agonist at high levels, but as an antagonist in the presence of glutamate. Solving this paradox will be a step forward in glioma science. The GliomasSignals project will examine the role of D2HG in the neurobiology of gliomas bringing electrophysiology concepts and tools to neuro-oncology, seeking to transform our understanding. It seeks to better understand how D2HG modulates glutamatergic signaling, affects neuronal excitability and tumor growth, and to detect the extent to which tumor infiltration colocalizes with epileptic remodeling. In vivo and in vitro work mostly on human tissue will aim at: 1- Map biomarkers of epileptic activity / tumor infiltration by cortical recordings during surgery using unique next generation Neurogrid electrodes. 2- Correlate D2HG levels, glutamate concentrations and tumor infiltration with recordings in peritumoral cortex at an unprecedented resolution. 3- Identify D2HG effects on glutamate signaling in human tissue slices producing epileptic activities and in a rodent model. 4- Explore D2HG long-term effects on epileptic activity and tumor growth / infiltration in co-cultures of tumors with surrounding peritumoral cortex by exploiting our unique capabilities for long-term human cortex organotypic cultures.

Host institution

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Net EU contribution
€ 1 875 135,00
Address
RUE DE TOLBIAC 101
75654 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Total cost
€ 1 875 135,00

Beneficiaries (1)