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Cancer Cell May 2024A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we...
A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
Topics: Oligodendroglioma; Isocitrate Dehydrogenase; Humans; Cell Differentiation; Mutation; Brain Neoplasms; Cell Lineage; Receptor, Notch1; Cell Proliferation; Animals; Astrocytes; Mice; Single-Cell Analysis
PubMed: 38579724
DOI: 10.1016/j.ccell.2024.03.008 -
Neuro-oncology Mar 2021We report the analysis involving patients treated on the initial CODEL design. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We report the analysis involving patients treated on the initial CODEL design.
METHODS
Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm.
RESULTS
Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months.
CONCLUSIONS
TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.
Topics: Adult; Brain Neoplasms; Humans; Isocitrate Dehydrogenase; Oligodendroglioma; Progression-Free Survival; Temozolomide
PubMed: 32678879
DOI: 10.1093/neuonc/noaa168 -
Neurologic Clinics May 2022Gliomas are the most common intrinsic brain tumor in adults. Although maximal tumor resection improves survival, this must be balanced with preservation of neurologic... (Review)
Review
Gliomas are the most common intrinsic brain tumor in adults. Although maximal tumor resection improves survival, this must be balanced with preservation of neurologic function. Technological advancements have greatly expanded our ability to safely maximize tumor resection and design innovative therapeutic trials that take advantage of intracavitary delivery of therapeutic agents after resection. In this article, we review the role of surgical intervention for both low-grade and high-grade gliomas and the innovations that are driving and expanding the role of surgery in this therapeutically challenging group of malignancies.
Topics: Adult; Brain Neoplasms; Glioma; Humans
PubMed: 35465885
DOI: 10.1016/j.ncl.2021.11.003 -
Acta Neuropathologica Communications Aug 2022Chromosomal instability (CIN) is a fundamental property of cancer and a key underlying mechanism of tumorigenesis and malignant progression, and has been documented in a... (Review)
Review
Chromosomal instability (CIN) is a fundamental property of cancer and a key underlying mechanism of tumorigenesis and malignant progression, and has been documented in a wide variety of cancers, including colorectal carcinoma with mutations in genes such as APC. Recent reports have demonstrated that CIN, driven in part by mutations in genes maintaining overall genomic stability, is found in subsets of adult-type diffusely infiltrating gliomas of all histologic and molecular grades, with resulting elevated overall copy number burden, chromothripsis, and poor clinical outcome. Still, relatively few studies have examined the effect of this process, due in part to the difficulty of routinely measuring CIN clinically. Herein, we review the underlying mechanisms of CIN, the relationship between chromosomal instability and malignancy, the prognostic significance and treatment potential in various cancers, systemic disease, and more specifically, in diffusely infiltrating glioma subtypes. While still in the early stages of discovery compared to other solid tumor types in which CIN is a known driver of malignancy, the presence of CIN as an early factor in gliomas may in part explain the ability of these tumors to develop resistance to standard therapy, while also providing a potential molecular target for future therapies.
Topics: Adult; Chromosomal Instability; Chromothripsis; Glioma; Humans; Mutation; Prognosis
PubMed: 35978439
DOI: 10.1186/s40478-022-01420-w -
Hematology/oncology Clinics of North... Feb 2022Isocitrate dehydrogenase (IDH) 1 and 2 mutations represent essential components for the diagnosis of diffuse astrocytic tumors and oligodendroglioma. IDH wild-type glial... (Review)
Review
Isocitrate dehydrogenase (IDH) 1 and 2 mutations represent essential components for the diagnosis of diffuse astrocytic tumors and oligodendroglioma. IDH wild-type glial tumors include a wide spectrum of tumors with differences in prognosis and recommended therapeutic approaches. Tumors characterized as molecular glioblastoma in the World Health Organization 2021 classification should be treated according to the glioblastoma therapeutic principles and included in glioblastoma trials. Improving on existing treatments options including targeted and immunotherapy approaches is imperative for most patients with IDH wild-type glial tumors, and enrollment in clinical trials is encouraged.
Topics: Brain Neoplasms; Glioblastoma; Glioma; Humans; Isocitrate Dehydrogenase; Oligodendroglioma
PubMed: 34756799
DOI: 10.1016/j.hoc.2021.08.007 -
Brain : a Journal of Neurology Nov 2023Tumour heterogeneity is increasingly recognized as a major obstacle to therapeutic success across neuro-oncology. Gliomas are characterized by distinct combinations of...
Tumour heterogeneity is increasingly recognized as a major obstacle to therapeutic success across neuro-oncology. Gliomas are characterized by distinct combinations of genetic and epigenetic alterations, resulting in complex interactions across multiple molecular pathways. Predicting disease evolution and prescribing individually optimal treatment requires statistical models complex enough to capture the intricate (epi)genetic structure underpinning oncogenesis. Here, we formalize this task as the inference of distinct patterns of connectivity within hierarchical latent representations of genetic networks. Evaluating multi-institutional clinical, genetic and outcome data from 4023 glioma patients over 14 years, across 12 countries, we employ Bayesian generative stochastic block modelling to reveal a hierarchical network structure of tumour genetics spanning molecularly confirmed glioblastoma, IDH-wildtype; oligodendroglioma, IDH-mutant and 1p/19q codeleted; and astrocytoma, IDH-mutant. Our findings illuminate the complex dependence between features across the genetic landscape of brain tumours and show that generative network models reveal distinct signatures of survival with better prognostic fidelity than current gold standard diagnostic categories.
Topics: Humans; Bayes Theorem; Gene Regulatory Networks; Mutation; Isocitrate Dehydrogenase; Brain Neoplasms; Glioma
PubMed: 37665980
DOI: 10.1093/brain/awad199 -
Cureus Jun 2022This study describes a retrospective case series of patients with glioma who received ketogenic metabolic therapy through dietary adherence and intermittent fasting.
PURPOSE
This study describes a retrospective case series of patients with glioma who received ketogenic metabolic therapy through dietary adherence and intermittent fasting.
METHODS
A retrospective chart review of a single surgeon's clinic records was performed to identify patients who maintained nutritional ketosis for at least four months between January 2015 and October 2020.
RESULTS
Sixteen patients who met the inclusion criteria constituted a heterogeneous population of patients with diagnoses including eight World Health Organization (WHO) grade IV gliomas (seven glioblastoma, one gliosarcoma), seven WHO grade III gliomas (three oligodendroglioma, four astrocytoma), and one WHO grade II oligodendroglioma. mutation status was present for 12 patients, and methylation status was present for eight patients. The mean (standard deviation [SD]) duration of ketogenic metabolic therapy was 20.6 (13.8) months. The Response Assessment in Neuro-oncology Criteria was applied during the ketogenic metabolic therapy interval, indicating a complete response in eight patients and partial response in eight patients. The mean (SD) progression-free survival while patients maintained ketogenic metabolic therapy was 20.0 (14.4) months.
CONCLUSION
Ketogenic metabolic therapy appears to convey a survival advantage within this patient series, which highlights the possibility that this therapy, when strictly applied, can augment the standard of care. Further exploration of this modality in a prospective series is warranted to formally explore this therapy.
PubMed: 35923675
DOI: 10.7759/cureus.26457 -
International Journal of Molecular... Oct 2020Hepatocyte growth factor (HGF) ligand and its receptor tyrosine kinase (RTK) mesenchymal-epithelial transition factor (MET) are important regulators of cellular... (Review)
Review
Hepatocyte growth factor (HGF) ligand and its receptor tyrosine kinase (RTK) mesenchymal-epithelial transition factor (MET) are important regulators of cellular processes such as proliferation, motility, angiogenesis, and tissue regeneration. In healthy adult somatic cells, this ligand and receptor pair is expressed at low levels and has little activity except when tissue injuries arise. In cancer cells, HGF/MET are often overexpressed, and this overexpression is found to correlate with tumorigenesis, metastasis, and poorer overall prognosis. This review focuses on the signaling of these molecules in the context of malignant brain tumors. RTK signaling pathways are among the most common and universally dysregulated pathways in gliomas. We focus on the role of HGF/MET in the following primary malignant brain tumors: astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, and embryonal central nervous system tumors (including medulloblastomas and others). Brain metastasis, as well as current advances in targeted therapies, are also discussed.
Topics: Animals; Brain Neoplasms; Glioma; Hepatocyte Growth Factor; Humans; Neoplasm Metastasis; Proto-Oncogene Proteins c-met; Signal Transduction
PubMed: 33066121
DOI: 10.3390/ijms21207546