Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid of High-Grade Glioma Patients

This work compares the metabolic profiles of plasma and the cerebrospinal fluid (CSF) of the patients with high-grade (III and IV) gliomas and the conditionally healthy controls using the wide-range targeted screening of low molecular metabolites by HPLC-MS/MS. The obtained data were analyzed using robust linear regression with Huber’s M-estimates, and a number of metabolites with correlated content in plasma and CSF was identified. The statistical analysis shows a significant correlation of metabolite content in plasma and CSF samples for the majority of metabolites. Several metabolites were shown to have high correlation in the control samples, but not in the glioma patients. This can be due to the specific metabolic processes in the glioma patients or to the damaged integrity of blood-brain barrier. The results of our study may be useful for the understanding of molecular mechanisms underlying the development of gliomas, as well as for the search of potential biomarkers for the minimally invasive diagnostic procedures of gliomas.

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Single-Cell Transcriptomic Analysis Revealed a Critical Role of SPP1/CD44-Mediated Crosstalk Between Macrophages and Cancer Cells in Glioma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.779319 ◽

2021 ◽

Vol 9 ◽

Author(s):

Cong He ◽

Luoyan Sheng ◽

Deshen Pan ◽

Shuai Jiang ◽

Li Ding ◽

...

Keyword(s):

Single Cell ◽

Tumor Heterogeneity ◽

Molecular Mechanisms ◽

Critical Role ◽

Cell Communication ◽

High Grade Glioma ◽

Sequencing Analysis ◽

High Grade ◽

Cellular Components

High-grade glioma is one of the most lethal human cancers characterized by extensive tumor heterogeneity. In order to identify cellular and molecular mechanisms that drive tumor heterogeneity of this lethal disease, we performed single-cell RNA sequencing analysis of one high-grade glioma. Accordingly, we analyzed the individual cellular components in the ecosystem of this tumor. We found that tumor-associated macrophages are predominant in the immune microenvironment. Furthermore, we identified five distinct subpopulations of tumor cells, including one cycling, two OPC/NPC-like and two MES-like cell subpopulations. Moreover, we revealed the evolutionary transition from the cycling to OPC/NPC-like and MES-like cells by trajectory analysis. Importantly, we found that SPP1/CD44 interaction plays a critical role in macrophage-mediated activation of MES-like cells by exploring the cell-cell communication among all cellular components in the tumor ecosystem. Finally, we showed that high expression levels of both SPP1 and CD44 correlate with an increased infiltration of macrophages and poor prognosis of glioma patients. Taken together, this study provided a single-cell atlas of one high-grade glioma and revealed a critical role of macrophage-mediated SPP1/CD44 signaling in glioma progression, indicating that the SPP1/CD44 axis is a potential target for glioma treatment.

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Elimination of Cancer Stem–Like Side Population in Human Glioblastoma Cells Accompanied With Stemness Gene Suppression by Korean Herbal Recipe MSC500

Integrative Cancer Therapies ◽

10.1177/1534735414549623 ◽

2014 ◽

Vol 13 (6) ◽

pp. 541-554 ◽

Cited By ~ 5

Author(s):

Chih-Jung Yao ◽

Tae-Young Han ◽

Ping-Hsiao Shih ◽

Tsu-Yi Yi ◽

I-Chun Lai ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Molecular Mechanisms ◽

Side Population ◽

High Grade Glioma ◽

Therapeutic Effects ◽

Mrna Levels ◽

High Grade ◽

Human Glioblastoma ◽

High Grade Gliomas ◽

E Cadherin

Background: High-grade gliomas are the most common and invasive malignant brain tumors in adults, and they are almost universally fatal because of drug resistance and recurrence. In spite of the progress in adjuvant therapy (like temozolomide) and irradiation after surgery, no effective salvage therapy is currently available for relapsed patients. A Korean herbal recipe MSC500 has been reported to have beneficial therapeutic effects in patients with high-grade gliomas who are relapsed or refractory to conventional treatments. But the underlying molecular mechanisms remain unclear. Methods: As Cancer stem cell (CSC) plays a pivotal role in the resistance to conventional cancer therapy, we explored the effects of MSC500 on the CSC-like side population (SP) in GBM8401 human glioblastoma multiforme cells. Results: Compared with the parental cells, the SP cells were more resistant to temozolomide but sensitive to MSC500. The mRNA levels of stemness genes such as Nanog, CD133, and ABCG2 were much higher in the SP cells, and so was E-cadherin, which was reported to correlate with the aggressiveness of glioblastoma multiforme. Treatment with MSC500 decreased the proportion of SP cells and high ALDH activity cells from 1.6% to 0.3% and from 0.9% to 0.1%, respectively, accompanied with suppression of the aforementioned stemness genes and E-cadherin, as well as other CSC markers such as ABCB5, Oct-4, Sox-2, β-catenin, Gli-1, and Notch-1. Conclusion: Our results suggest the potential role of MSC500 as an integrative and complementary therapeutic for advanced or refractory high-grade glioma patients.

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Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

Journal of Personalized Medicine ◽

10.3390/jpm10040290 ◽

2020 ◽

Vol 10 (4) ◽

pp. 290

Author(s):

Lisa Mayr ◽

Armin S. Guntner ◽

Sibylle Madlener ◽

Maria T. Schmook ◽

Andreas Peyrl ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Combination Therapy ◽

Clinical Experience ◽

Clinical Studies ◽

High Grade Glioma ◽

Treatment Modalities ◽

Intrathecal Therapy ◽

High Grade ◽

Promising Therapeutic Approach

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.

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Tumor-treating-fields therapy may influence the cerebrospinal fluid shunt valve settings in patients with high-grade glioma

Brain and Spine ◽

10.1016/j.bas.2021.100499 ◽

2021 ◽

Vol 1 ◽

pp. 100499

Author(s):

B. Sommer ◽

I. Konietzko ◽

M.N. Bonk ◽

B. Hackanson ◽

M. Trepel ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

High Grade Glioma ◽

High Grade ◽

Cerebrospinal Fluid Shunt ◽

Shunt Valve ◽

Tumor Treating Fields

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CBIO-04. G-QUADRUPLEX STABILIZATION ENHANCES REPLICATION STRESS AND DNA DAMAGE IN ATRX-DEFICIENT HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.105 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi27-vi28

Author(s):

Sharvari Dharmaiah ◽

Vasudev Tadimeti ◽

Prit Benny Malgulwar ◽

Christian Alvarez ◽

Ahsan Farooqi ◽

...

Keyword(s):

Dna Damage ◽

Molecular Mechanisms ◽

Standard Of Care ◽

High Grade Glioma ◽

Replication Stress ◽

High Grade ◽

Loss Of Function ◽

Enhanced Sensitivity ◽

Alternative Lengthening ◽

Dna Secondary Structures

Abstract Loss of function mutations in α-thalassaemia/mental retardation X-linked (ATRX) are a critical molecular hallmark for invariably fatal high-grade glioma (HGG). Mutational inactivation of histone chaperone ATRX leads to accumulations of abnormal DNA secondary structures known as G-quadruplexes (G4s), thereby inducing replication stress and DNA damage. As G4s arise at GC-rich regions (i.e., pericentromeric and telomeric regions), ATRX-deficiency alters genome-wide accessibility of chromatin, leads to transcriptional dysregulation, and induces alternative lengthening of telomeres (ALT). Our goal is to target ATRX deficiency through G4 stabilizers, which represent a class of novel small molecule compounds that selectively bind to and stabilize G4 structures. However, the genomic consequences and efficacy of this therapy for ATRX-deficient HGG are poorly understood. We therefore sought to evaluate the molecular mechanisms that drive selective lethality in patient-derived ATRX-deficient glioma stem cells (GSCs), following G4 stabilization. We found that ATRX-deficient GSCs demonstrate dose-dependent enhanced sensitivity to G4 stabilization, compared to ATRX-intact controls. Cell viability assays confirmed the specificity of our G4 stabilizer in comparison to other commonly used G4 stabilizers. Interestingly, G4 stabilization activated p53-independent apoptosis in ATRX-deficient GSCs. Furthermore, ATRX-deficient GSCs exhibit upregulated expression of both ATR and ATM pathways upon G4 stabilization, indicating enhanced replication stress and DNA damage via double-stranded breaks, respectively. Our preliminary findings suggest that ATR and ATM activation leads to the inhibition of transcription factor NF-κB, which in turn drives apoptosis. Lastly, our data indicate that G4 stabilization perturbs the ALT phenotype in ATRX-deficient GSCs, likely contributing to telomeric dysfunction. Taken together, these findings suggest that G4 stabilizers could synergize with ionizing radiation, the standard of care, as they are both DNA-damaging therapies. Our work defines mechanisms of action and efficacy of a novel therapeutic strategy for ATRX-deficient HGG, with strong implications for other ATRX-deficient cancers.

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371MO Usefulness of circulating tumour DNA detection from cerebrospinal fluid in recurrent high-grade glioma

Annals of Oncology ◽

10.1016/j.annonc.2020.08.480 ◽

2020 ◽

Vol 31 ◽

pp. S400

Author(s):

M. Fontanilles ◽

A. Deniel ◽

F. Marguet ◽

L. Beaussire ◽

N. Magne ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Dna Detection ◽

High Grade Glioma ◽

High Grade ◽

Circulating Tumour Dna

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Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms21197193 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7193 ◽

Cited By ~ 1

Author(s):

Maya S. Graham ◽

Ingo K. Mellinghoff

Keyword(s):

Targeted Therapies ◽

Molecular Mechanisms ◽

Malignant Gliomas ◽

High Grade Glioma ◽

High Grade ◽

Cancer Death ◽

Preclinical Models ◽

Molecular Alterations ◽

Potential Impact ◽

Pediatric High Grade Glioma

Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease.

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