Foci of Tumor Heterogeneity in Diffuse Low-Grade Gliomas

NCT04423094 | Completed

• 1 other identifier: RECHMPL19_0469
• Study Type: observational
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Diffuse low-grade gliomas (DLGG) are slow-growing primary-cancer of the brain and spinal cord. They represent up to 15% of the developing tumors in those organs with fatal outcome for the patients because of their evolution. The reasons for this transformation towards more malignant tumors still remain ill defined. Previously, the research team in neuro oncology at Montpellier University Hospital found foci of tumor heterogeneity within 20 to 30 % of the patients developing a DLGG and published their results. The investigators assumed that those foci represent the early beginning of the transformation from a diffuse low-grade glioma to a glioblastoma, tumor with highly malignant cells and a life expectancy of two years in average for the patient. Methods: The investigators selected adult patients with no prior surgery nor neuro oncology treatment when enrolled. They presented a specific mutation for an enzyme of the metabolism named IDH1, standing for Isocitrate Dehydrogenase 1, found in 70% of DLGG. Patients were also selected because they presented foci of tumor heterogeneity. After obtaining their consent, the investigators studied by immunohistochemistry the pathways deregulated between the DLGG and the foci. The investigators also extracted RNAs, molecules expressing the life and metabolism of tumor cells, and compared them to know what genes were differentially expressed between the DLGG and the foci. All RNAs were tested for quality control prior to be processed further. The investigators then studied 8 patients with compliance with ethics, authorizations and institutional guidelines. Genes of interest were studied in vitro to assess their functions. The investigators found a barely described enzyme of the catabolism of the phosphoethanolamines and discovered a new anti-proliferative tumor-role for it. •Discussion: The investigators first showed that foci have a higher percentage of p-STAT3+ cells which indicates STAT3 pathway activation in these cells. Phosphorylated STAT3 translocates to the cell nucleus to regulate many genes involved in proliferation, apoptosis and angiogenesis. As such, phosphorylation of STAT proteins, notably STAT3, is involved in the pathogenesis of many cancers, including GBM, by promoting cell cycle progression, stimulating angiogenesis, and impairing tumor immune surveillance. The investigators found that ETNPPL RNA and protein are reduced in foci cells and absent in glioblastomas. This is consistent with glioma database analyses showing that ETNPLL expression is inversely correlated to STAT3 and MKI67 whose expression are higher in foci and glioblastomas. In addition, Kaplan-Meier analysis shows that patients with low expression of ETNPPL have lower overall survival These observations suggested that this enzyme may oppose glioma cells proliferation. The investigators demonstrated this hypothesis by overexpressing ETNPPL in 3 glioblastoma cell cultures. Two were sensitive to ETNPPL overexpression which reduced their growth while no effect was detected in Gli4 cells. These glioblastoma-derived cultures have different types of mutations.

Conditions

Glioma

Outcome Measures

Primary Outcomes (1)

• statistically significant increase in the number of tumor cells

  statistically significant increase in the number of tumor cells

  1 day

Secondary Outcomes (1)

• determine predictive markers of this tumor development

  1 day

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

An individual must fulfill all of the following criteria in order to be eligible for study enrollment Aged between 18 and 70 years, Suffering from IDH1-mutated diffuse low-grade glioma, No pre operative nor oncology treatment prior to join the study.

You may qualify if:

• An individual must fulfill all of the following criteria in order to be eligible for study enrollment:
• Aged between 18 and 70 years.
• Suffering from IDH1-mutated diffuse low-grade glioma.
• No pre operative nor oncology treatment prior to join the study.
• Signed informed consent form.

You may not qualify if:

• Subject unable to read or/and write
• Grade 3 or 4 gliomas
• Tumor with IDH1-WT status

Sponsors & Collaborators

• University Hospital, Montpellier: lead

Study Sites (1)

Uh Montpellier

Montpellier, 34295, France

Location

MeSH Terms

Conditions

Glioma

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• VALERIE RIGAUX, MD, PhD

  University Hospital, Montpellier

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2019
• First Posted: June 9, 2020
• Study Start: November 1, 2016
• Primary Completion: March 1, 2019
• Study Completion: March 30, 2019
• Last Updated: June 9, 2020

Record last verified: 2019-11

Locations

FR (1)