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Cell Death & Disease Sep 2023Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic...
Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas. The small molecule SETD8 inhibitor UNC0379, as well as siRNA-mediated inhibition of SETD8, blocked glioblastoma cell proliferation, by inducing DNA damage and activating cell cycle checkpoints. Specifically, in p53-proficient glioblastoma cells, SETD8 inhibition and DNA damage induced p21 accumulation and G1/S arrest whereas, in p53-deficient glioblastoma cells, DNA damage induced by SETD8 inhibition resulted in G2/M arrest mediated by Chk1 activation. Checkpoint abrogation, by the Wee1 kinase inhibitor adavosertib, induced glioblastoma cell lines and primary cells, DNA-damaged by UNC0379, to progress to mitosis where they died by mitotic catastrophe. Finally, UNC0379 and adavosertib synergized in restraining glioblastoma growth in a murine xenograft model, providing a strong rationale to further explore this novel pharmacological approach for adjuvant glioblastoma treatment.
Topics: Humans; Animals; Mice; Infant, Newborn; Glioblastoma; Apoptosis; Tumor Suppressor Protein p53; Cell Line, Tumor; G2 Phase Cell Cycle Checkpoints; Infant, Newborn, Diseases
PubMed: 37758718
DOI: 10.1038/s41419-023-06167-3 -
EBioMedicine Sep 2023Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying...
BACKGROUND
Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying synergistic treatments represents a major challenge.
METHODS
High-throughput screening was combined with target deconvolution and functional genomics to reveal targetable vulnerabilities in glioblastoma. The role of the top gene hit was investigated by RNA interference, transcriptomics and immunohistochemistry in glioblastoma patient samples. Drug combination screen using a custom-made library of 88 compounds in association with six inhibitors of the identified glioblastoma vulnerabilities was performed to unveil pharmacological synergisms. Glioblastoma 3D spheroid, organotypic ex vivo and syngeneic orthotopic mouse models were used to validate synergistic treatments.
FINDINGS
Nine targetable vulnerabilities were identified in glioblastoma and the top gene hit RRM1 was validated as an independent prognostic factor. The associations of CHK1/MEK and AURKA/BET inhibitors were identified as the most potent amongst 528 tested pairwise drug combinations and their efficacy was validated in 3D spheroid models. The high synergism of AURKA/BET dual inhibition was confirmed in ex vivo and in vivo glioblastoma models, without detectable toxicity.
INTERPRETATION
Our work provides strong pre-clinical evidence of the efficacy of AURKA/BET inhibitor combination in glioblastoma and opens new therapeutic avenues for this unmet medical need. Besides, we established the proof-of-concept of a stepwise approach aiming at exploiting drug poly-pharmacology to unveil druggable cancer vulnerabilities and to fast-track the identification of synergistic combinations against refractory cancers.
FUNDING
This study was funded by institutional grants and charities.
Topics: Animals; Mice; Glioblastoma; Aurora Kinase A; Drug Synergism; Cell Line, Tumor; Antineoplastic Agents; Drug Combinations
PubMed: 37572644
DOI: 10.1016/j.ebiom.2023.104752 -
Small (Weinheim An Der Bergstrasse,... Nov 2023Glioblastoma is one of the most aggressive central nervous system malignancies with high morbidity and mortality. Current clinical approaches, including surgical... (Review)
Review
Glioblastoma is one of the most aggressive central nervous system malignancies with high morbidity and mortality. Current clinical approaches, including surgical resection, radiotherapy, and chemotherapy, are limited by the difficulty of targeting brain lesions accurately, leading to disease recurrence and fatal outcomes. The lack of effective treatments has prompted researchers to continuously explore novel therapeutic strategies. In recent years, nanomedicine has made remarkable progress and expanded its application in brain drug delivery, providing a new treatment for brain tumors. Against this background, this article reviews the application and progress of nanomedicine delivery systems in brain tumors. In this paper, the mechanism of nanomaterials crossing the blood-brain barrier is summarized. Furthermore, the specific application of nanotechnology in glioblastoma is discussed in depth.
Topics: Humans; Blood-Brain Barrier; Glioblastoma; Brain; Drug Delivery Systems; Nanoparticles; Brain Neoplasms
PubMed: 37415556
DOI: 10.1002/smll.202302613 -
Cancer Medicine Sep 2023The latest fifth edition of the World Health Organization (WHO) classification of the central nervous system (CNS) tumors (WHO CNS 5 classification) released in 2021...
BACKGROUND
The latest fifth edition of the World Health Organization (WHO) classification of the central nervous system (CNS) tumors (WHO CNS 5 classification) released in 2021 defined astrocytoma, IDH-mutant, Grade 4. However, the understanding of this subtype is still limited. We conducted this study to describe the features of astrocytoma, IDH-mutant, Grade 4 and explored the similarities and differences between histological and molecular subtypes.
METHODS
Patients who underwent surgery from January 2011 to January 2022, classified as astrocytoma, IDH-mutant, Grade 4 were included in this study. Clinical, radiological, histopathological, molecular pathological, and survival data were collected for analysis.
RESULTS
Altogether 33 patients with astrocytoma, IDH-mutant, Grade 4 were selected, including 20 with histological and 13 with molecular WHO Grade 4 astrocytoma. Tumor enhancement, intratumoral-necrosis like presentation, larger peritumoral edema, and more explicit tumor margins were frequently observed in histological WHO Grade 4 astrocytoma. Additionally, molecular WHO Grade 4 astrocytoma showed a tendency for relatively longer overall survival, while a statistical significance was not reached (47 vs. 25 months, p = 0.22). TP53, CDK6, and PIK3CA alteration was commonly observed, while PIK3R1 (p = 0.033), Notch1 (p = 0.027), and Mycn (p = 0.027) alterations may affect the overall survival of molecular WHO Grade 4 astrocytomas.
CONCLUSIONS
Our study scrutinized IDH-mutant, Grade 4 astrocytoma. Therefore, further classification should be considered as the prognosis varied between histological and molecular WHO Grade 4 astrocytomas. Notably, therapies aiming at PIK3R1, Notch 1, and Mycn may be beneficial.
Topics: Humans; N-Myc Proto-Oncogene Protein; Brain Neoplasms; Isocitrate Dehydrogenase; Mutation; Astrocytoma; Central Nervous System Neoplasms; Glioblastoma; World Health Organization
PubMed: 37667984
DOI: 10.1002/cam4.6476 -
No Shinkei Geka. Neurological Surgery Sep 2023The Central Nervous System Tumours: WHO Classification of Tumours, 5 ed.(WHO CNS5)incorporates molecular pathogenesis with histopathology to classify brain tumors into...
The Central Nervous System Tumours: WHO Classification of Tumours, 5 ed.(WHO CNS5)incorporates molecular pathogenesis with histopathology to classify brain tumors into more biologically and narrowly defined entities. According to this approach, adult-type diffuse gliomas are classified into three tumor types: astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and glioblastoma, IDH-wildtype. Astrocytoma and oligodendroglioma are clearly defined as IDH-mutant tumors, and glioblastoma as an IDH-wildtype tumor. WHO CNS5 provides clear diagnostic criteria framed as "essential and desirable diagnostic criteria," including histopathological and molecular features. In this article, we summarized the diagnostic and grading criteria of adult-type diffuse gliomas, which include histopathological and molecular features. Further, we presented a clinical diagnostic workflow based on the immunohistopathological studies, molecular tests and their surrogate assays, and histopathological features to establish the diagnosis of adult-type diffuse gliomas. We also discussed the limitations of the clinical diagnostic workflow; for instance, some tumors may not fit within this classification provided by this diagnostic flow. Despite these limitations, we are required to utilize the diagnostic criteria and determine optimal treatment in the clinical setting.
Topics: Adult; Humans; Glioblastoma; Oligodendroglioma; Glioma; Astrocytoma; Brain Neoplasms
PubMed: 37743327
DOI: 10.11477/mf.1436204816 -
Establishment and characterization of two novel patient-derived lines from canine high-grade glioma.Veterinary and Comparative Oncology Sep 2023High-grade glioma is an aggressive cancer that occurs naturally in pet dogs. Canine high-grade glioma (cHGG) is treated with radiation, chemotherapy or surgery, but has...
High-grade glioma is an aggressive cancer that occurs naturally in pet dogs. Canine high-grade glioma (cHGG) is treated with radiation, chemotherapy or surgery, but has no curative treatment. Within the past eight years, there have been advances in our imaging and histopathology standards as well as genetic charactereization of cHGG. However, there are only three cHGG cell lines publicly available, all of which were derived from astrocytoma and established using methods involving expansion of tumour cells in vitro on plastic dishes. In order to provide more clinically relevant cell lines for studying cHGG in vitro, the goal of this study was to establish cHGG patient-derived lines, whereby cancer cells are expanded in vivo by injecting cells into immunocompromized laboratory mice. The cells are then harvested from mice and used for in vitro studies. This method is the standard in the human field and has been shown to minimize the acquisition of genetic alterations and gene expression changes from the original tumour. Through a multi-institutional collaboration, we describe our methods for establishing two novel cHGG patient-derived lines, Boo-HA and Mo-HO, from a high-grade astrocytoma and a high-grade oligodendroglioma, respectively. We compare our novel lines to G06-A, J3T-Bg, and SDT-3G (traditional cHGG cell lines) in terms of proliferation and sensitivity to radiation. We also perform whole genome sequencing and identify an NF1 truncating mutation in Mo-HO. We report the characterization and availability of these novel patient-derived lines for use by the veterinary community.
Topics: Humans; Dogs; Animals; Mice; Dog Diseases; Glioma; Astrocytoma; Brain Neoplasms
PubMed: 37254642
DOI: 10.1111/vco.12912 -
Seminars in Cancer Biology Jun 2024Glioblastoma (GBM) is the most aggressive tumor among the gliomas and intracranial tumors and to date prognosis for GBM patients remains poor, with a median survival... (Review)
Review
Glioblastoma (GBM) is the most aggressive tumor among the gliomas and intracranial tumors and to date prognosis for GBM patients remains poor, with a median survival typically measured in months to a few years depending on various factors. Although standardized therapies are routinely employed, it is clear that these strategies are unable to cope with heterogeneity and invasiveness of GBM. Furthermore, diagnosis and monitoring of responses to therapies are directly dependent on tissue biopsies or magnetic resonance imaging (MRI) techniques. From this point of view, liquid biopsies are arising as key sources of a variety of biomarkers with the advantage of being easily accessible and monitorable. In this context, extracellular vesicles (EVs), physiologically shed into body fluids by virtually all cells, are gaining increasing interest both as natural carriers of biomarkers and as specific signatures even for GBM. What makes these vesicles particularly attractive is they are also emerging as therapeutical vehicles to treat GBM given their native ability to cross the blood-brain barrier (BBB). Here, we reviewed recent advances on the use of EVs as biomarker for liquid biopsy and nanocarriers for targeted delivery of anticancer drugs in glioblastoma.
Topics: Humans; Glioblastoma; Extracellular Vesicles; Biomarkers, Tumor; Brain Neoplasms; Animals; Liquid Biopsy; Blood-Brain Barrier; Antineoplastic Agents
PubMed: 38754752
DOI: 10.1016/j.semcancer.2024.04.003 -
Arquivos de Neuro-psiquiatria Dec 2023Long-term epilepsy-associated tumors (LEATs) include a series of neoplasms that commonly occur in children, adolescents, or young adults, have an astrocytic or...
Long-term epilepsy-associated tumors (LEATs) include a series of neoplasms that commonly occur in children, adolescents, or young adults, have an astrocytic or glioneuronal lineage, are histologically benign (WHO grade1) with a neocortical localization predominantly situated in the temporal lobes. Clinically, chronic refractory epilepsy is usually the unique symptom. Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNT) are the most common representative entities besides pilocytic astrocytomas (PA) and angiocentric gliomas (AG). Recent molecular studies have defined new clinicopathological entities, which are recognized by the WHO 2021 classification of brain tumors. Some of them such as diffuse astrocytoma or altered, polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and multilocular and vacuolating neuronal tumor (MVNT) are currently considered LEATs. The relationship between LEATs and epilepsy is still a matter of debate, and there is a general agreement about the beneficial effects of an early neurosurgical intervention on the clinical outcome.
Topics: Adolescent; Young Adult; Humans; Child; Epilepsy; Glioma; Brain Neoplasms; Ganglioglioma; Astrocytoma; Neoplasms, Neuroepithelial
PubMed: 38157880
DOI: 10.1055/s-0043-1777730 -
Neurobiology of Disease Nov 2023Epilepsy, a common complication of diffuse low-grade gliomas (DLGGs; diffuse oligodendroglioma and astrocytoma collectively), severely compromises the quality of life of...
Epilepsy, a common complication of diffuse low-grade gliomas (DLGGs; diffuse oligodendroglioma and astrocytoma collectively), severely compromises the quality of life of patients. DLGG epileptogenicity may primarily be generated by interactions between the tumor and the neocortex. Neuronal uptake of dysfunctional mitochondria from the extracellular environment can lead to abnormal neuronal discharge. Mitochondrial dysfunction is frequently observed in gliomas that can transmigrate across the plasma membranes. Here, we examined the role of the Rho GTPase-activating protein 44 (RICH2) in mitochondrial dynamics and DLGG-related epilepsy. We investigated the association between mitochondrial and RICH2 expression in human DLGG tissues using immunohistochemistry. We examined the association between RICH2 and epilepsy in nude mouse glioma models by electrophysiology. The effect of RICH2 on mitochondrial morphology and calcium motility were assessed by single cell fluorescence microscopy. Quantitative RT-PCR (qRT-PCR) and Western blot analysis were performed to characterize RICH2 induced expression changes in the genes related to mitochondrial dynamics, mitogenesis and mitochondrial function. We found that RICH2 expression was higher in oligodendroglioma than in astrocytoma and was correlated with better prognosis and higher epilepsy rate in patients. The expression of mitochondria may be associated with clinical DLGG-related epilepsy and reduced by RICH2 overexpression. And RICH2 could promote DLGG-related epilepsy in tumorigenic nude mice. RICH2 overexpression decreased calcium flow and the mitochondria released from glioma cells (SW1088 and U251) into the extracellular environment, potentially via downregulation of MFN-1/MFN-2 levels which suggests reduced mitochondrial fusion. In addition, we observed decreased mitochondrial trafficking into neurons (released from glioma cells and trafficked into neurons), which could explain the higher incidence of DLGG-related epilepsy due to reduced neuroprotection. Furthermore, RICH2 downregulated MAPK/ERK/HIF-1 pathway. In conclusion, these results suggest that RICH2 could promote epilepsy by (i) inhibiting mitochondrial fusion via MFN downregulation and Drp-1 upregulation; (ii) altering the MAPK/ERK/Hif-1 signaling axis. RICH2 may be a potential target in the treatment of DLGG-related epilepsy.
Topics: Animals; Mice; Humans; Oligodendroglioma; Calcium; Mice, Nude; Quality of Life; Glioma; Mitochondria; Astrocytoma
PubMed: 37926169
DOI: 10.1016/j.nbd.2023.106344 -
Cell Reports Sep 2023Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic...
Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.
Topics: Humans; Lipid Metabolism; Glioblastoma; Formates; Neoplasm Invasiveness; Tumor Microenvironment
PubMed: 37651228
DOI: 10.1016/j.celrep.2023.113034