Glutamate Excitotoxicity and Its Role in Glioblastoma Biology

Role of Glutamate-mediate Excitotoxicity in Invasion and Progression Processes of Glioblastoma Multiforme

Gliomas are the most frequent type of primary brain tumors in adults; among them glioblastoma multiforme (GBM) is the most malignant, being associated with the worst prognosis. Glutamate (Glu) is an aminoacid, responsible for essential functions in the Central Nervous System (CNS), acting both as metabolite and neurotransmitter. It is essential for regulating cellular metabolism and developmental synaptogenesis, cellular migration, differentiation and death. Recent scientific evidences have demonstrated alteration in Glu synthesis and signaling being directly involved in GBM growth and invasion

Study Overview

• Status: Recruiting
• Conditions: Brain Tumor, Primary
• Intervention / Treatment: Diagnostic test: Blood, CSF and tumor samples

Detailed Description

Glu and its scavenger's levels are measurable both in serum and in the cerebral-spinal fluid (CSF), thus making them ideal markers for tumor aggressiveness and disease activity as well as a potential target for new therapeutic approaches.

Serum and CSF levels of glutamic oxaloacetic transaminase (GOT1), Glutamate Pyruvate Transaminase (GPT) and glutamate and aspartate levels of a total of 40 patients will be collected.

Molecular biology analyses will be conducted and oncological and imaging data will be collected during follow-up in patients enrolled in the present studies. MRI imaging as well as blood sampling will be performed at definite timepoints (baseline and 3, 6 and 9 months follow-up).

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Sincinelli Laura; Phone Number: 0039 0226436658; Email: sincinelli.laura@hsr.it

Study Locations

• Italy
  • Milan, Italy, 20132
    • Recruiting
    • IRCCS San Raffaele Scientific Institute
    • Contact: Laura Sincinelli; Phone Number: 003926435568; Email: sincinelli.laura@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients with a brain lesion suspected for GBM, candidate to gross total tumor resection (GTR), followed by radiotherapy and chemotherapy (concomitant and adjuvant).

Description

Inclusion Criteria:

• Adult patients with a brain lesion suspected for GBM, candidate to gross total tumor resection (GTR), followed by radiotherapy and chemotherapy (concomitant and adjuvant).
• Patient able to provide informed consent.

Exclusion Criteria:

• Age < 18 years
• Liver disease
• Severe anemia (Hb <8mg/dl)
• Pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adult neurosurgical patients; Adult neurosurgical patients with a brain lesion suspected for GBM, candidate to gross total tumor resection (GTR), followed by radiotherapy and chemotherapy (concomitant and adjuvant).	Diagnostic test: Blood, CSF and tumor samples; Blood, CSF and brain tissue sampling of Glu and Glu regulatory proteins.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline characterization of Glutamate scavengers (Glu-sca) levels in serum	Serum GOT1 (UI/ml), GPT (UI/ml)	Baseline (before surgery)
Baseline characterization of Glutamate (Glu) levels in serum	Serum Glutamate (μM/L)	Baseline (before surgery)
Time changes in Glutamate scavengers (Glu-sca) levels in serum	Serum GOT1 (UI/ml), GPT (UI/ml)	At 3, 6, 9 months following surgery
Time changes in Glutamate (Glu) levels in serum	Serum Glutamate (μM/L)	At 3, 6, 9 months following surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterization of Glutamate scavengers (Glu-sca) levels in cerebrospinal fluid (CSF)	CSF levels GOT1 (UI/ml), GPT (UI/ml)	Baseline (before surgery)
Characterization of Glutamate (Glu) levels in cerebrospinal fluid (CSF)	CSF levels Glutamate (μM/L)	Baseline (before surgery)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between Glutamate metabolism and Glioblastoma molecular signature	Association between Glu and Glu-scavengers' levels and molecular patterns of Glioblastoma as described by 2021 WHO classification	Baseline levels of markers

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Investigators: Study Director: Pietro Mortini, MD, Prof., IRCCS San Raffaele

Publications and helpful links

General Publications

• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
• Ruban A, Berkutzki T, Cooper I, Mohar B, Teichberg VI. Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Invest New Drugs. 2012 Dec;30(6):2226-35. doi: 10.1007/s10637-012-9799-5.
• Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY, Sontheimer H. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci. 2005 Aug 3;25(31):7101-10. doi: 10.1523/JNEUROSCI.5258-04.2005.
• Robert SM, Sontheimer H. Glutamate transporters in the biology of malignant gliomas. Cell Mol Life Sci. 2014 May;71(10):1839-54. doi: 10.1007/s00018-013-1521-z. Epub 2013 Nov 27.
• Willard SS, Koochekpour S. Glutamate signaling in benign and malignant disorders: current status, future perspectives, and therapeutic implications. Int J Biol Sci. 2013 Aug 9;9(7):728-42. doi: 10.7150/ijbs.6475. eCollection 2013.
• Olar A, Aldape KD. Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol. 2014 Jan;232(2):165-77. doi: 10.1002/path.4282.
• Wang W, Shi G, Ma B, Hao X, Dong X, Zhang B. Chemotherapy for Adults with Malignant Glioma: A Systematic Review and Network Meta-Analysis. Turk Neurosurg. 2017;27(2):174-181. doi: 10.5137/1019-5149.JTN.15462-15.0.
• de Groot J, Sontheimer H. Glutamate and the biology of gliomas. Glia. 2011 Aug;59(8):1181-9. doi: 10.1002/glia.21113. Epub 2010 Dec 29.
• O'Kane RL, Martinez-Lopez I, DeJoseph MR, Vina JR, Hawkins RA. Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. J Biol Chem. 1999 Nov 5;274(45):31891-5. doi: 10.1074/jbc.274.45.31891.
• Ruban A, Biton IE, Markovich A, Mirelman D. MRS of brain metabolite levels demonstrates the ability of scavenging of excess brain glutamate to protect against nerve agent induced seizures. Int J Mol Sci. 2015 Feb 2;16(2):3226-36. doi: 10.3390/ijms16023226.
• Teichberg VI, Cohen-Kashi-Malina K, Cooper I, Zlotnik A. Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience. 2009 Jan 12;158(1):301-8. doi: 10.1016/j.neuroscience.2008.02.075. Epub 2008 Mar 18.
• Rijpkema M, Schuuring J, van der Meulen Y, van der Graaf M, Bernsen H, Boerman R, van der Kogel A, Heerschap A. Characterization of oligodendrogliomas using short echo time 1H MR spectroscopic imaging. NMR Biomed. 2003 Feb;16(1):12-8. doi: 10.1002/nbm.807.
• Roslin M, Henriksson R, Bergstrom P, Ungerstedt U, Bergenheim AT. Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis. J Neurooncol. 2003 Jan;61(2):151-60. doi: 10.1023/a:1022106910017.
• Takano T, Lin JH, Arcuino G, Gao Q, Yang J, Nedergaard M. Glutamate release promotes growth of malignant gliomas. Nat Med. 2001 Sep;7(9):1010-5. doi: 10.1038/nm0901-1010.
• Corsi L, Mescola A, Alessandrini A. Glutamate Receptors and Glioblastoma Multiforme: An Old "Route" for New Perspectives. Int J Mol Sci. 2019 Apr 11;20(7):1796. doi: 10.3390/ijms20071796.
• Campos F, Rodriguez-Yanez M, Castellanos M, Arias S, Perez-Mato M, Sobrino T, Blanco M, Serena J, Castillo J. Blood levels of glutamate oxaloacetate transaminase are more strongly associated with good outcome in acute ischaemic stroke than glutamate pyruvate transaminase levels. Clin Sci (Lond). 2011 Jul;121(1):11-7. doi: 10.1042/CS20100427.
• Campos F, Sobrino T, Ramos-Cabrer P, Castellanos M, Blanco M, Rodriguez-Yanez M, Serena J, Leira R, Castillo J. High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke. J Cereb Blood Flow Metab. 2011 Jun;31(6):1387-93. doi: 10.1038/jcbfm.2011.4. Epub 2011 Jan 26.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): September 30, 2029

Study Registration Dates

• First Submitted: March 2, 2021
• First Submitted That Met QC Criteria: March 16, 2023
• First Posted (Actual): March 20, 2023

Study Record Updates

• Last Update Posted (Actual): June 11, 2025
• Last Update Submitted That Met QC Criteria: June 6, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Brain tumor; Glutamate
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Glioblastoma; Brain Neoplasms
• Other Study ID Numbers: NCH02-2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No