Trial Title:
Using the Epitranscriptome to Diagnose and Treat Gliomas
NCT ID:
NCT06575452
Condition:
Glioma
Conditions: Official terms:
Glioma
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Diagnostic
Masking:
None (Open Label)
Intervention:
Intervention type:
Diagnostic Test
Intervention name:
Blood, urine and tumoral tissue samples
Description:
Blood, urine and tumoral tissue samples
Arm group label:
Cohort 1
Intervention type:
Diagnostic Test
Intervention name:
Tumoral tissue samples
Description:
tumoral tissue samples
Arm group label:
Cohort 2
Arm group label:
Cohort 3
Summary:
Diffuse gliomas are among the most common tumors of the central nervous system, with high
morbidity and mortality and very limited therapeutic possibilities. The diffuse glioma
are characterized by significant variability in terms of age at diagnosis, histological
and molecular features, classification, ability to transform to a higher grade and/or to
disseminate in the brain, response to treatment and patient outcome.
One of the main challenges in the management of diffuse gliomas is related to tumor
heterogeneity within the same subgroup. Establishing an accurate tumor classification is
of paramount importance for selecting personalized therapy or avoiding unnecessary
treatment.
At present, the main diagnostic methods for detecting gliomas are based on
histopathological features and mutation detection. Yet difficulties remain, due to tumor
heterogeneity and sampling bias for tumors obtained from small biopsies. In particular,
grade 2 (low-grade) and grade 3 (high-grade) gliomas cannot be easily distinguished, as
intra-tumoral tumor grade heterogeneity is not uncommon in patients treated with
extensive surgical resection. Another challenge in the field of gliomas is longitudinal
monitoring of disease progression, which is currently mainly based on repeated brain
Magnetic Resonance Imaging (MRI). New tools to detect tumor changes before the onset of
imaging changes would be useful.
Several genetic, epigenetic, metabolic and immunological profiles have been established
for gliomas. Recently, the world of RiboNucleic Acid (RNA) has emerged as a promising
area to explore for cancer therapy, especially since the (re)discovery of RNA chemical
modifications. To date, more than 150 types of post-transcriptional modifications have
been reported on various RNA molecules. This complex landscape of chemical marks embodies
a new, invisible code that governs the post-transcriptional fate of RNA: stability,
splicing, storage, translation.
Detailed description:
Diffuse gliomas are among the most common tumors of the central nervous system, with high
morbidity and mortality and very limited therapeutic possibilities. Diffuse gliomas are
characterized by great variability in terms of age at diagnosis, histological and
molecular features, classification, ability to progress to a higher grade and/or to
disseminate in the brain, response to treatment and patient outcome. One of the major
challenges in the management of diffuse gliomas is related to the heterogeneity of tumor
behavior within the same tumor subgroup. Although efforts have been made in recent
decades to improve tumor characterization and classification, with the integration of
molecular markers (e.g. Isocitrate DeHydrogenase (IDH) mutation), it remains difficult to
predict treatment response and patient outcome at the individual level. Yet accurate
tumor classification is of paramount importance in choosing personalized therapy or
avoiding unnecessary treatments. At present, the main diagnostic methods for detecting
gliomas are based on histopathological features, mutation detection or chromosome copy
number variation.
However, difficulties remain, particularly with tumor classification, due to tumor
heterogeneity and sampling bias for tumors obtained from small biopsies. In particular,
grade 2 ("low-grade") and grade 3 ("high-grade") gliomas cannot be easily distinguished,
as intratumoral tumor grade heterogeneity is not uncommon in patients treated with
extensive surgical resection. Another challenge posed by gliomas is longitudinal
monitoring of disease progression, which currently relies mainly on repeated brain MRI
scans, with no return to the tumor itself due to the difficulty of obtaining new tumor
samples in this setting. New tools to detect tumor changes in plasma, before imaging
changes occur, would be useful. However, circulating markers present a real challenge, as
the detection of markers readily used in other cancer types (e.g. circulating free DNA
and circulating tumor cells) is hampered by a lack of sensitivity in gliomas.
Several genetic, epigenetic, metabolic and immunological profiles have been established
in gliomas, considerably expanding the knowledge of the biological characteristics of
these tumors and helping to identify potential treatments. Recently, the world of RNA has
emerged as a promising area to explore for cancer therapy, particularly since the
(re)discovery of chemical modifications of RNA (epitranscriptomics). To date, over 150
types of post-transcriptional modification have been reported on various RNA molecules.
This landscape complex of chemical marks embodies a new, invisible code that governs the
post-transcriptional fate of RNA: stability, splicing, storage, translation. Importantly,
RNA epigenetics has emerged as a new layer of gene expression regulation in healthy
tissues as well as in other pathologies such as cancer.
Chemical markers are associated with cancer evolution and adaptation, as well as with
response to conventional therapies. Based on these observations, it is envisaged that:
(1) the RNA epigenetic landscape evolves with cancer progression, establishing a
"chemical signature" that could be exploited for diagnostic, prognostic and treatment
response prediction purposes; (2) several chemical marks are not mere "transient"
alterations but rather "driving" alterations of the tumorigenic process; (3) unlike
unmodified nucleosides, modified nucleosides are preferentially excreted as metabolic end
products in urine after circulating in the blood. Consequently, altered RNA markers in
cancerous tissues can be detected in urine and blood and exploited for diagnostic
purposes. An original approach recently published combines multiplex analysis of RNA
marks by mass spectrometry with bioinformatics and machine learning. Using total RNA
samples extracted from an existing cohort of patients (59 grade 2, 3 and 4 gliomas; 19
non-cancerous control samples), a first "chemical signature" capable of predicting glioma
grade with remarkable efficiency and accuracy has been established.
N6, 2'-O-dimethyladenosine (m6Am), the most up-regulated marker in glioblastoma (GBM), is
a driver of colorectal cancer aggressiveness. Located at the 5' end of messenger
RiboNucleic Acid (mRNA), m6Am can influence mRNA stability and translation efficiency.
This chemical tag is deposited by the Phosphorylated Carboxyl terminal domain Interacting
Factor 1 (PCIF1), also known as CAPAM (PCIF1/CAPAM) methyltransferase (writer) and
removed by the Fat mass and Obesity-associated protein (FTO) demethylase (eraser). FTO is
down-regulated in colorectal cancer stem cells (CSCs), consistent with m6Am accumulation.
High levels of m6Am significantly enhance CSC properties such as in vivo tumor initiation
and chemoresistance, without significant changes to the transcriptome. This aggressive
phenotype can be reversed by inhibition of PCIF1, demonstrating the potential of
targeting epigenetic RNA effectors. The preliminary data on patient-derived glioma cell
lines suggest a similar mechanism in glioma, where down-regulation of FTO promotes
sphere-forming capacity in suspension culture of GBM stem cells.
(3) A method has been established to detect RNA markers in plasma samples that yielded
favorable results after analysis of plasma samples from a colorectal cancer cohort. The
same process was used to obtain preliminary data by analyzing plasma samples from grade 2
glioma patients vs. healthy donors. This experiment confirmed the possibility of
detecting and quantifying 20 circulating nucleosides in blood. Significant changes were
demonstrated between healthy donors and glioma patient samples for some of the
circulating nucleosides. Some were up-regulated (e.g. n6,2'-O-dimethyladenosine (m6Am),
1-methylguanosine (m1G)) while others were down-regulated (e.g. adenosine (A),
5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U)). Importantly, not all the tagged RNAs
detected were altered (e.g. N1-methyladenosine (m1A); 5-methylcytosine (m5C)). If
confirmed by a larger cohort, these changes could constitute an epitranscriptomics-based
circulating signature for early disease detection. This preliminary experience reinforces
the interest in m6Am.
Finally, changes were also observed in the serum of the same patients compared to healthy
donor subjects, but from other nucleosides. This underlines the importance of studying
circulating markers in blood for the diagnosis of gliomas.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Male / female over 18 years of age,
- Surgery (tumor resection) scheduled at Montpellier University Hospital for
suspected, diffuse glioma, confirmed on tissue sample: IDH mutated grade 2 glioma
(excluding tumors with a focus of grade 3 or 4 glioma), IDH mutated grade 3 glioma
or GBM, IDH wild-type,
- No history of treatment (surgery, radiotherapy or chemotherapy) for glioma,
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests and other study procedures,
- Patient has given express written informed consent prior to any study procedure,
- Patient affiliated to a French health insurance.
Exclusion Criteria:
- Patients whose regular follow-up is impossible for psychological, family, social or
geographical reasons,
- Patients under guardianship, curatorship or safeguard of justice,
- Pregnant and/or breast-feeding patient (information gathered from the medical file,
as part of the patient's standard medical care and follow-up),
- Histo-molecular diagnosis of grade 4 IDH-mutated astrocytoma,
- For grade 2 gliomas, presence within the tumor of one or more higher-grade sites (3
or 4).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
Insitut Régional du Cancer de Montpellier
Address:
City:
Montpellier
Zip:
34298
Country:
France
Contact:
Last name:
Amélie Darlix, MD
Phone:
4-67-61-25-57
Phone ext:
+33
Email:
amelie.darlix@icm.unicancer.fr
Investigator:
Last name:
Amélie Darlix, MD
Email:
Principal Investigator
Facility:
Name:
CHU Montpellier - Hôpital St Eloi
Address:
City:
Montpellier
Zip:
34090
Country:
France
Contact:
Last name:
Luc Bauchet, MD
Phone:
4 67 33 66 12
Phone ext:
+33
Email:
l-bauchet@chu-montpellier.fr
Start date:
November 2024
Completion date:
April 2028
Lead sponsor:
Agency:
Institut du Cancer de Montpellier - Val d'Aurelle
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute, France
Agency class:
Other
Source:
Institut du Cancer de Montpellier - Val d'Aurelle
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06575452
