Ignite Creation Date:
2024-10-26 @ 3:39 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06575452
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-08-23
Brief Title:
Using the Epitranscriptome to Diagnose and Treat Gliomas
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Using the Epitranscriptome to Diagnose and Treat Gliomas
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EPIGLIO
Brief 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 andor 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 rediscovery 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
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 rediscovery 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 andor 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 eg 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 eg 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 rediscovery 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 PCIF1CAPAM 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 eg n62-O-dimethyladenosine m6Am 1-methylguanosine m1G while others were down-regulated eg adenosine A 5-methoxycarbonylmethyl-2-thiouridine mcm5s2U Importantly not all the tagged RNAs detected were altered eg 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
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 eg 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 rediscovery 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 PCIF1CAPAM 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 eg n62-O-dimethyladenosine m6Am 1-methylguanosine m1G while others were down-regulated eg adenosine A 5-methoxycarbonylmethyl-2-thiouridine mcm5s2U Importantly not all the tagged RNAs detected were altered eg 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None