Glutamate Excitotoxicity in Brain Metastases From Lung, Breast and Melanoma Treated With Stereotactic Radiosurgery

Brain Metastases, Adult Clinical Trial

Official title:

Glutamate Excitotoxicity in Brain Metastases From Lung, Breast and Melanoma Treated With Stereotactic Radiosurgery

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04785521
• Other study ID #: NCH04-2020
• Status: Recruiting
• Start date: July 1, 2020
• Est. completion date: December 31, 2025

Study information

• Verified date: January 2024
• Source: IRCCS San Raffaele
• Contact: Laura Sincinelli
• Phone: 00390226435568
• Email: sincinelli.laura[@]hsr.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Brain metastases (BM) represents a devastating clinical reality, carrying an estimated survival time of less than one year. Number of reasons, including complicated tumor biology and difficulties in modeling metastatic cancer in brain microenvironment, do hinder research on this topic. BM are indeed the most frequent neoplasm in the central nervous system (CNS) and is estimated that up to 14% of all newly diagnosed cancers will metastasize to the brain. A number of reasons, including complicated tumor biology and difficulties in modeling metastatic cancer in brain microenvironment, do hinder research on this topic. Present knowledge regarding alterations in Glutamate (Glu) homeostasis and BM is poor. This study aims at investigating Glu balance in BM patients and providing supporting evidence to the identification of new putative biomarkers to be used as potential therapeutic targets.

Description:

Experimental procedure: Serum levels of glutamic oxaloacetic transaminase (GOT1), glutamate Pyruvate Transaminase (GPT) and lactate dehydrogenase (LDH) levels and serum glutamate, aspartate and lactate levels of a total of 100 patients will be collected and divided in three different groups: - A: BM group (n=50), patients affected by BM from lung, breast and melanoma, candidates to SRS - B: Control group 1 (n=25), patients with the same primary controlled tumors without nor brain nor extracranial metastases - C: Control group 2 (n=25), patients with benign intracranial lesions candidates to SRS treatment. In A) and C) serum GOT1, GPT and LDH levels and serum glutamate, aspartate, lactate levels will be evaluated before and after SRS treatment (at 3, 6 and 9 months follow-up). In B) serum biomarkers levels will be only collected at baseline. • Oncological and imaging data will be collected during follow-up in patients enrolled in the present studies. MRI imaging will be performed at definite timepoints (baseline and 3, 6 and 9 months follow-up). Serum levels of markers will be analyzed in each group and results will be compared between them. Moreover, MRI changes and oncological relevant outcomes will be investigated.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 31, 2025
• Est. primary completion date: July 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria (Target group)

• Adult patients carrying melanoma, breast or lung cancer BM of new diagnosis
• Patients eligible to SRS-GK treatment Inclusion Criteria (Control group 1)
• Adult patients carrying melanoma, breast or lung cancer without BM Inclusion Criteria (Control group 2)
• Adult patients carrying intracranial extra-axial benign tumor
• Patients eligible to SRS-GK treatment

Exclusion Criteria:

• Acute or chronic liver disease
• Severe anemia (Hb <8g/dl)
• Pregnant or breastfeeding patient
• Pediatric patients
• Patients not able to express informed consent

Related Conditions & MeSH terms

• Brain Metastases, Adult
• Brain Neoplasms
• Neoplasm Metastasis

Intervention

Radiation:
• Stereotactic radiosurgery
Gamma Knife stereotactic radiosurgery (SRS-GK)

Diagnostic Test:
• Blood samples
Serum Glu levels and Glu-regulation markers assessed prior to and following SRS-GK in BM or benign lesions or at baseline in non-BM patients.

Locations

Country	Name	City	State
Italy	IRCCS San Raffaele Scientific Institute	Milan

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS San Raffaele

Country where clinical trial is conducted

Italy, 

References & Publications (7)

Franzin A, Snider S, Picozzi P, Bolognesi A, Serra C, Vimercati A, Passarin O, Mortini P. Evaluation of different score index for predicting prognosis in gamma knife radiosurgical treatment for brain metastasis. Int J Radiat Oncol Biol Phys. 2009 Jul 1;74(3):707-13. doi: 10.1016/j.ijrobp.2008.08.062. Epub 2008 Dec 25. — View Citation

Lowery FJ, Yu D. Brain metastasis: Unique challenges and open opportunities. Biochim Biophys Acta Rev Cancer. 2017 Jan;1867(1):49-57. doi: 10.1016/j.bbcan.2016.12.001. Epub 2016 Dec 6. — View Citation

Miladinovic T, Nashed MG, Singh G. Overview of Glutamatergic Dysregulation in Central Pathologies. Biomolecules. 2015 Nov 11;5(4):3112-41. doi: 10.3390/biom5043112. — View Citation

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. — View Citation

Sharma MK, Seidlitz EP, Singh G. Cancer cells release glutamate via the cystine/glutamate antiporter. Biochem Biophys Res Commun. 2010 Jan 1;391(1):91-5. doi: 10.1016/j.bbrc.2009.10.168. Epub 2009 Nov 5. — View Citation

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. — View Citation

Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, McCabe BD, Galvan JA, Robinson HPC, Zlobec I, Ciriello G, Hanahan D. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019 Sep;573(7775):526-531. doi: 10.1038/s41586-019-1576-6. Epub 2019 Sep 18. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum markers determination in newly diagnosed BM (lung, breast and melanoma) patients, before SRS treatment.	GOT1, GPT and LDH levels and serum glutamate, aspartate and lactate levels. All measures in mg/dl.	Baseline (pre-SRS);
Primary	Serum markers determination in newly diagnosed BM (lung, breast and melanoma) patients, after SRS treatment.	GOT1, GPT and LDH levels and serum glutamate, aspartate and lactate levels. All measures in mg/dl.	Baseline (pre-SRS) and at 3, 6 and 9 months
Primary	Serum markers determination in melanoma, lung or breast cancer patients without BM.	Comparison of serum GOT1, GPT and LDH levels and serum glutamate, aspartate and lactate levels between BM and non-BM patients. All measures in mg/dl.	Baseline
Primary	Serum markers determination in patients carrying benign intracranial lesions before and after SRS treatment.	Comparison of serum GOT1, GPT and LDH levels and serum glutamate, aspartate and lactate levels between BM and benign lesion patients. All measures in mg/dl.	Baseline (pre-SRS) and at 3, 6 and 9 months
Secondary	Studying correlation of serum markers levels with MRI changes following SRS-GK	Correlation between trends of markers and incidence of MRI changes.	3, 6 and 9 months