CE17 - Recherche translationnelle en santé

Magnetic resonance spectroscopic imaging markers of glioma genomics – GLIOMRS

Submission summary

In France, about 5000 new people with a primary malignant brain tumor are diagnosed each year. The most common primary tumors are gliomas, originating from glial cells (astrocytomas and oligodendrogliomas). Low-grade gliomas are mildly aggressive, but they often evolve into a more malignant form.
Mutations in the genes encoding isocitrate dehydrogenase (IDH) are found in about 80% of low-grade gliomas and secondary glioblastomas and are associated with a favorable prognosis. Remarkably, IDH-mutated gliomas are characterized by a specific cellular metabolism causing the accumulation of D-2-hydroxyglutarate (2HG) in tumor cells. 2HG can be detected in vivo using 1H magnetic resonance spectroscopy (MRS) and is recognized as a unique, noninvasive biomarker of IDH-mutated gliomas. Noninvasive detection of IDH mutations via 2HG MRS represents a crucial step for decision-making and patient care. Despite its clinical utility, however, 2HG detection is still not part of the clinical routine due to technical challenges and the fact that advanced MRS techniques for 2HG quantification are available only in a few research centres worldwide.
A subset of IDH-mutated tumors also presents a complete deletion of 1p and 19q chromosome arms (1p/19q codeletion). The 1p/19q codeletion is specifically linked to the oligodendroglial histologic subtype and it has been associated with a better patient outcome. However, the biological effects of this genetic alteration are still unclear and in vivo markers are lacking. Recently, we reported the first in vivo detection of the cystathionine molecule in human brain gliomas using MRS and explored the association between cystathionine accumulation and 1p/19q codeletion in gliomas. We hypothesized that cystathionine overproduction is linked to a partial deletion of chromosome 1p, yielding specific effects on cancer cell metabolism, and that cystathionine could be a marker of the compensatory anti-oxidant activity of cancer cells.
In this project, we will combine cutting edge MRI and MRS techniques for metabolic and microstructural characterization of brain tumors with the aim of providing novel reliable noninvasive biomarkers of tumor genetic subtypes. These methods will allow us to identify noninvasively IDH-mutated gliomas and, potentially, 1p/19q codeleted gliomas. In addition, we will investigate the utility of 2HG, cystathionine and MRI microstructural markers to monitor tumor response to anti-cancer treatments and tumor progression.
The outputs of this project, altogether, may open new avenues to a better understanding of the pathophysiological mechanisms of oncogenesis and the design of new treatments for gliomas. Advanced MRI/MRS methods will be translated into a clinical setting and will be shortly exploitable for diagnosis, prognosis, and planning of personalized therapies in the clinic.

Project coordination

Francesca Branzoli (Institut du cerveau et de la moelle epiniere)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

ICM Institut du cerveau et de la moelle epiniere

Help of the ANR 325,593 euros
Beginning and duration of the scientific project: February 2021 - 48 Months

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