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Current Treatment Options in Oncology Jul 2020Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a... (Review)
Review
Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.
Topics: Algorithms; Brain Neoplasms; Clinical Decision-Making; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Factor Analysis, Statistical; Glioblastoma; Glioma; Humans; Radiofrequency Ablation; Treatment Outcome
PubMed: 32734509
DOI: 10.1007/s11864-020-00773-5 -
Nature Aug 2019Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of... (Comparative Study)
Comparative Study
Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.
Topics: Animals; Cerebellar Neoplasms; Cerebellum; Child; Evolution, Molecular; Female; Fetus; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Glioma; Humans; Medulloblastoma; Mice; Sequence Analysis, RNA; Single-Cell Analysis; Time Factors; Transcription, Genetic; Transcriptome
PubMed: 31043743
DOI: 10.1038/s41586-019-1158-7 -
Targeting NQO1/GPX4-mediated ferroptosis by plumbagin suppresses in vitro and in vivo glioma growth.British Journal of Cancer Jul 2022Ferroptosis has attracted increasing interest in cancer therapy. Emerging evidences suggest that naturally occurring naphthoquinones exhibit potent anti-glioma effects...
BACKGROUND
Ferroptosis has attracted increasing interest in cancer therapy. Emerging evidences suggest that naturally occurring naphthoquinones exhibit potent anti-glioma effects via various mechanisms.
METHODS
The anti-glioma effects of plumbagin were evaluated by in vitro and in vivo experiments. Anti-glioma mechanism of plumbagin was studied by proteomics, flow cytometry, MDA assay, western blot, and RT-PCR. Gene knockdown/overexpression, molecular docking, PharmMappper database, and coimmunoprecipitation were used to study the targets of plumbagin.
RESULTS
Plumbagin showed higher blood-brain barrier penetration ability than that of lapachol and shikonin and elicited significant growth inhibitory effects in vitro and in vivo. Ferroptosis was the main mechanism of plumbagin-induced cell death. Mechanistically, plumbagin significantly downregulated the protein and mRNA levels of xCT and decreased GPX4 protein levels. NAD(P)H quinone dehydrogenase 1 (NQO1) was revealed as a plumbagin predictive target using PharmMappper database and molecular docking. Plumbagin enhanced NQO1 activity and decreased xCT expression, resulting in NQO1-dependent cell death. It also induced GPX4 degradation via the lysosome pathway and caused GPX4-dependent cell death.
CONCLUSIONS
Plumbagin inhibited in vitro and in vivo glioma growth via targeting NQO1/GPX4-mediated ferroptosis, which might be developed as a novel ferroptosis inducer or anti-glioma candidate.
Topics: Cell Line, Tumor; Ferroptosis; Glioma; Humans; Molecular Docking Simulation; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 35396498
DOI: 10.1038/s41416-022-01800-y -
Theranostics 2022Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) involved in the regulation of the immune system and displayed a cell-type-specific pattern in...
Machine learning-based identification of tumor-infiltrating immune cell-associated lncRNAs for improving outcomes and immunotherapy responses in patients with low-grade glioma.
Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) involved in the regulation of the immune system and displayed a cell-type-specific pattern in immune cell subsets. Given the vital role of tumor-infiltrating lymphocytes in effective immunotherapy, we explored the tumor-infiltrating immune cell-associated lncRNA (TIIClncRNA) in low-grade glioma (LGG), which has never been uncovered yet. This study utilized a novel computational framework and 10 machine learning algorithms (101 combinations) to screen out TIIClncRNAs by integratively analyzing the sequencing data of purified immune cells, LGG cell lines, and bulk LGG tissues. The established TIIClnc signature based on the 16 most potent TIIClncRNAs could predict outcomes in public datasets and the Xiangya in-house dataset with decent efficiency and showed better performance when compared with 95 published signatures. The TIIClnc signature was strongly correlated to immune characteristics, including microsatellite instability, tumor mutation burden, and interferon γ, and exhibited a more active immunologic process. Furthermore, the TIIClnc signature predicted superior immunotherapy response in multiple datasets across cancer types. Notably, the positive correlation between the TIIClnc signature and CD8, PD-1, and PD-L1 was verified in the Xiangya in-house dataset. The TIIClnc signature enabled a more precise selection of the LGG population who were potential beneficiaries of immunotherapy.
Topics: Glioma; Humans; Immunologic Factors; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Machine Learning; RNA, Long Noncoding
PubMed: 35966587
DOI: 10.7150/thno.74281 -
Frontiers in Immunology 2022Lower-grade glioma (LGG) is a common malignant primary tumour in the central nervous system, and most patients eventually develop highly aggressive gliomas despite...
Lower-grade glioma (LGG) is a common malignant primary tumour in the central nervous system, and most patients eventually develop highly aggressive gliomas despite comprehensive traditional treatment. Tumour molecular subtypes and prognostic biomarkers play a crucial role in LGG diagnosis and treatment. Therefore, the identification of novel biomarkers in LGG patients is crucial for predicting the prognosis of glioma. Immunogenic cell death (ICD) is defined as regulated cell death that is sufficient to activate the adaptive immune response of immunocompetent hosts. The combination of ICD and immunotherapy might exert a greater and more persistent antitumour effect in gliomas. In our study, we explored the expression, function, and genetic alterations of 34 ICD-related genes. Using 12 ICD-related genes, including IL17RA, IL1R1, EIF2AK3, CD4, PRF1, CXCR3, CD8A, BAX, PDIA3, CASP8, MYD88, and CASP1, we constructed and validated an ICD-related risk signature least absolute shrinkage and selection operator (LASSO) Cox regression analysis. All the information was obtained from public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and the Chinese Glioma Genome Atlas (CGGA) databases. Our results revealed that ICD-high risk groups have a poor prognosis and might be more sensitive to immune checkpoint blockade (ICB) immunotherapy. In addition, ICD-high risk groups were associated with 1p19q noncodeletion, higher WHO grade, wild type IDH, and an immunosuppressive tumour microenvironment. We verified the prognostic value of 12 ICD-related genes in TCGA and CGGA databases. Immunohistochemistry was performed to verify the expression of several ICD-related genes at the protein level. Our study provides a novel and comprehensive perspective to elucidate the underlying mechanisms of LGG prognosis and direction for future individualized cancer immunotherapy.
Topics: Humans; Brain Neoplasms; Tumor Microenvironment; Immunogenic Cell Death; Transcriptome; Glioma; Prognosis
PubMed: 36325335
DOI: 10.3389/fimmu.2022.1011757 -
Nature Communications Jul 2023Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed to...
Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed to identify patients likely to benefit from MAPKi therapy. Here, we identify MAPK-related genes enriched in MAPKi-sensitive cell lines using the GDSC dataset and apply them to calculate class-specific MAPKi sensitivity scores (MSSs) via single-sample gene set enrichment analysis. The MSSs discriminate MAPKi-sensitive and non-sensitive cells in the GDSC dataset and significantly correlate with response to MAPKi in an independent PDX dataset. The MSSs discern gliomas with varying MAPK alterations and are higher in pLGG compared to other pediatric CNS tumors. Heterogenous MSSs within pLGGs with the same MAPK alteration identify proportions of potentially sensitive patients. The MEKi MSS predicts treatment response in a small set of pLGG patients treated with trametinib. High MSSs correlate with a higher immune cell infiltration, with high expression in the microglia compartment in single-cell RNA sequencing data, while low MSSs correlate with low immune infiltration and increased neuronal score. The MSSs represent predictive tools for the stratification of pLGG patients and should be prospectively validated in clinical trials. Our data supports a role for microglia in the response to MAPKi.
Topics: Child; Humans; Glioma; Cell Line; Protein Kinase Inhibitors; Biomarkers
PubMed: 37500667
DOI: 10.1038/s41467-023-40235-8 -
Neuro-oncology Jan 2023Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study... (Clinical Trial)
Clinical Trial
BACKGROUND
Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation.
METHODS
This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II.
RESULTS
Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each).
CONCLUSIONS
Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.
Topics: Humans; Pyridines; Quinolines; Glioma; Isocitrate Dehydrogenase
PubMed: 35639513
DOI: 10.1093/neuonc/noac139 -
Chinese Clinical Oncology Dec 2022Radiotherapy (RT) continues to be an important component of treatment of glioma, particularly high-grade glioma and glioblastoma multiforme (GBM). GBM is one of the most... (Review)
Review
Radiotherapy (RT) continues to be an important component of treatment of glioma, particularly high-grade glioma and glioblastoma multiforme (GBM). GBM is one of the most aggressive central nervous system (CNS) tumors, with high rates of recurrence and very low rates of long-term survival. However, outcomes in these patients are improving with modern genetic profiling and multimodal therapy, which leads to more consideration for the risk for toxicities associated with traditional photon-based RT. Proton therapy (PT) is an increasingly available method to reduce off-target irradiation in CNS tumors due to the intrinsic properties of heavy-particle irradiation. Here, we review currently available data examining the used of PT in glioma patients, including dose escalation for GBM, re-irradiation (reRT) of recurrent glioma, and the potential cognitive sparing effects of conventional dose PT. We discuss the incorporation of PT into the multimodal therapy of GBM patients, and how the aggressive nature of the disease poses a unique challenge to PT study design. We also describe how PT may provide the most feasible method for implementing high rate 'FLASH' RT and the implications for glioma patients. We conclude with a discussion of ongoing clinical trials, the necessity of continued research, and how we interpret and incorporate available data into our current practice.
Topics: Humans; Glioblastoma; Protons; Brain Neoplasms; Neoplasm Recurrence, Local; Glioma
PubMed: 36632979
DOI: 10.21037/cco-22-92 -
Current Neurology and Neuroscience... May 2023Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct type of primary brain tumors with unique characteristics, behavior, and disease outcomes. This article... (Review)
Review
PURPOSE OF REVIEW
Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct type of primary brain tumors with unique characteristics, behavior, and disease outcomes. This article provides a review of standard of care treatment options and innovative, therapeutic approaches that are currently under investigation for these tumors.
RECENT FINDINGS
Extensive pre-clinical data and a variety of clinical studies support targeting IDH mutations in glioma using different mechanisms, which include direct inhibition and immunotherapies that target metabolic and epigenomic vulnerabilities caused by these mutations. IDH mutations have been recognized as an oncogenic driver in gliomas for more than a decade and as a positive prognostic factor influencing the research for new therapeutic methods including IDH inhibitors, DNA repair inhibitors, and immunotherapy.
Topics: Humans; Isocitrate Dehydrogenase; Brain Neoplasms; Glioma; Mutation; Immunotherapy
PubMed: 37060388
DOI: 10.1007/s11910-023-01265-3 -
Magnetic Resonance in Medical Sciences... Mar 2022One of the major issues in the surgical treatment of gliomas is the concern about maximizing the extent of resection while minimizing neurological impairment. Thus,... (Review)
Review
One of the major issues in the surgical treatment of gliomas is the concern about maximizing the extent of resection while minimizing neurological impairment. Thus, surgical planning by carefully observing the relationship between the glioma infiltration area and eloquent area of the connecting fibers is crucial. Neurosurgeons usually detect an eloquent area by functional MRI and identify a connecting fiber by diffusion tensor imaging. However, during surgery, the accuracy of neuronavigation can be decreased due to brain shift, but the positional information may be updated by intraoperative MRI and the next steps can be planned accordingly. In addition, various intraoperative modalities may be used to guide surgery, including neurophysiological monitoring that provides real-time information (e.g., awake surgery, motor-evoked potentials, and sensory evoked potential); photodynamic diagnosis, which can identify high-grade glioma cells; and other imaging techniques that provide anatomical information during the surgery. In this review, we present the historical and current context of the intraoperative MRI and some related approaches for an audience active in the technical, clinical, and research areas of radiology, as well as mention important aspects regarding safety and types of devices.
Topics: Brain Neoplasms; Diffusion Tensor Imaging; Glioma; Humans; Magnetic Resonance Imaging; Wakefulness
PubMed: 34880193
DOI: 10.2463/mrms.rev.2021-0116