Glutamate Excitotoxicity and Its Role in Glioblastoma Biology

NCT05775458 | Recruiting

• 1 other identifier: NCH02-2020
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Brain Tumor, Primary

Keywords

Brain tumor; Glutamate

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (2)

• Characterization of Glutamate scavengers (Glu-sca) levels in cerebrospinal fluid (CSF)

  Baseline (before surgery)

• Characterization of Glutamate (Glu) levels in cerebrospinal fluid (CSF)

  Baseline (before surgery)

Other Outcomes (1)

• Association between Glutamate metabolism and Glioblastoma molecular signature

  Baseline levels of markers

Study Arms (1)

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

Interventions

Blood, CSF and tumor samples DIAGNOSTIC_TEST

Blood, CSF and brain tissue sampling of Glu and Glu regulatory proteins.

Adult neurosurgical patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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).

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (1)

IRCCS San Raffaele Scientific Institute

Milan, Milan, 20132, Italy

RECRUITING

Related Publications (17)

• 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.

  PMID: 24114756 BACKGROUND

• 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.

  PMID: 15758009 BACKGROUND

• 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.

  PMID: 27337236 BACKGROUND

• 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.

  PMID: 24281762 BACKGROUND

• 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.

  PMID: 21192095 BACKGROUND

• 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.

  PMID: 10542215 BACKGROUND

• 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.

  PMID: 25648322 BACKGROUND

• 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.

  PMID: 18423998 BACKGROUND

• 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.

  PMID: 12577293 BACKGROUND

• 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.

  PMID: 12622454 BACKGROUND

• 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.

  PMID: 23983606 BACKGROUND

• 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.

  PMID: 16079392 BACKGROUND

• 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.

  PMID: 22392507 BACKGROUND

• 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.

  PMID: 11533703 BACKGROUND

• 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.

  PMID: 30978987 BACKGROUND

• 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.

  PMID: 21265738 BACKGROUND

• 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.

  PMID: 21266984 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood and CSF samples.

MeSH Terms

Conditions

Brain Neoplasms

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Pietro Mortini, MD, Prof.

  IRCCS San Raffaele

  STUDY DIRECTOR

Central Study Contacts

Sincinelli Laura

CONTACT

0226436658; sincinelli.laura@hsr.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of department

Study Record Dates

• First Submitted: March 2, 2021
• First Posted: March 20, 2023
• Study Start: June 1, 2020
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): September 30, 2029
• Last Updated: June 11, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)