Glutamate Excitotoxicity and Its Role in Glioblastoma Biology
Study Details
Study Description
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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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 Design
Arms and Interventions
| Arm | 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.
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Outcome Measures
Primary Outcome Measures
- Baseline characterization of Glutamate scavengers (Glu-sca) levels in serum [Baseline (before surgery)]
Serum GOT1 (UI/ml), GPT (UI/ml)
- Baseline characterization of Glutamate (Glu) levels in serum [Baseline (before surgery)]
Serum Glutamate (μM/L)
- Time changes in Glutamate scavengers (Glu-sca) levels in serum [At 3, 6, 9 months following surgery]
Serum GOT1 (UI/ml), GPT (UI/ml)
- Time changes in Glutamate (Glu) levels in serum [At 3, 6, 9 months following surgery]
Serum Glutamate (μM/L)
Secondary Outcome Measures
- Characterization of Glutamate scavengers (Glu-sca) levels in cerebrospinal fluid (CSF) [Baseline (before surgery)]
CSF levels GOT1 (UI/ml), GPT (UI/ml)
- Characterization of Glutamate (Glu) levels in cerebrospinal fluid (CSF) [Baseline (before surgery)]
CSF levels Glutamate (μM/L)
Other Outcome Measures
- Association between Glutamate metabolism and Glioblastoma molecular signature [Baseline levels of markers]
Association between Glu and Glu-scavengers' levels and molecular patterns of Glioblastoma as described by 2021 WHO classification
Eligibility Criteria
Criteria
Inclusion Criteria:
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Adult patients with a brain lesion suspected for GBM, candidate to gross total tumor resection (GTR), followed by radiotherapy and chemotherapy (concomitant and adjuvant).
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Patient able to provide informed consent.
Exclusion Criteria:
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Age < 18 years
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Liver disease
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Severe anemia (Hb <8mg/dl)
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Pregnancy
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | IRCCS San Raffaele Scientific Institute | Milan | Italy | 20132 |
Sponsors and Collaborators
- IRCCS San Raffaele
Investigators
- Study Director: Pietro Mortini, MD, Prof., IRCCS San Raffaele
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- NCH02-2020