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Foci of Tumor Heterogeneity in Diffuse Low-Grade Gliomas

NCT04423094 · Status: COMPLETED · Type: OBSERVATIONAL · Enrollment: 8

Last updated 2020-06-09

No results posted yet for this study

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

Sponsors & Collaborators

  • University Hospital, Montpellier

    lead OTHER

Principal Investigators

  • VALERIE RIGAUX, MD, PhD · University Hospital, Montpellier

Eligibility

Min Age
18 Years
Max Age
70 Years
Sex
FEMALE
Healthy Volunteers
No

Timeline & Regulatory

Start
2016-11-01
Primary Completion
2019-03-01
Completion
2019-03-30

Countries

  • France

Study Locations

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Entities

Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT04423094 on ClinicalTrials.gov