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Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure that causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.
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Neoplasias Encefálicas/genética , Carcinogénesis/genética , Diferenciación Celular/genética , Neuronas/citología , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Eliminación de Gen , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Humanos , Células Madre Pluripotentes Inducidas , Organoides/citología , Organoides/fisiopatologíaRESUMEN
Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre-clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)-RNA-dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation-harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix-assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA-approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator-initiated registration-directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.
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Neoplasias Encefálicas/tratamiento farmacológico , Encéfalo/diagnóstico por imagen , Furanos/administración & dosificación , Glioblastoma/tratamiento farmacológico , Cetonas/administración & dosificación , Regiones Promotoras Genéticas/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Reposicionamiento de Medicamentos , Femenino , Furanos/farmacología , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Humanos , Inyecciones Intraperitoneales , Cetonas/farmacología , Ratones , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Telomerasa/genética , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Glioblastoma is the most common and devastating type of malignant brain tumor. We recently found that eribulin suppresses glioma growth in vitro and in vivo and that eribulin is efficiently transferred into mouse brain tumors at a high concentration. Eribulin is a non-taxane microtubule inhibitor approved for breast cancer and liposarcoma. Cells arrested in M-phase by chemotherapeutic agents such as microtubule inhibitors are highly sensitive to radiation-induced DNA damage. Several recent case reports have demonstrated the clinical benefits of eribulin combined with radiation therapy for metastatic brain tumors. In this study, we investigated the efficacy of a combined eribulin and radiation treatment on human glioblastoma cells. The glioblastoma cell lines U87MG, U251MG and U118MG, and SJ28 cells, a patient-derived sphere culture cell line, were used to determine the radiosensitizing effect of eribulin using western blotting, flow cytometry and clonogenic assay. Subcutaneous and intracerebral glioma xenografts were generated in mice to assess the efficacy of the combined treatment. The combination of eribulin and radiation enhanced DNA damage in vitro. The clonogenic assay of U87MG demonstrated the radiosensitizing effect of eribulin. The concomitant eribulin and radiation treatment significantly prolonged the survival of mice harboring intracerebral glioma xenografts compared with eribulin or radiation alone (P < .0001). In addition, maintenance administration of eribulin after the concomitant treatment further controlled brain tumor growth. Aberrant microvasculature was decreased in these tumors. Concomitant treatment with eribulin and radiation followed by maintenance administration of eribulin may serve as a novel therapeutic strategy for glioblastomas.
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Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/patología , Quimioradioterapia/métodos , Furanos/administración & dosificación , Glioblastoma/patología , Cetonas/administración & dosificación , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Radioterapia/métodos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: Intraoperative photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) is a widely adopted technique to enhance the extent of resection during high-grade glioma (HGG) surgery. Recent updates to the package insert for 5-ALA in Japan now allow its use in combination with drugs that may induce photosensitivity, such as talaporfin sodium (TS). TS is employed in intraoperative photodynamic therapy (PDT) and has been shown to improve overall survival. The combination of 5-ALA with TS is expected to offer further benefits. However, the safety of this combination had not been established. This study reports on the safety of 5-ALA-PDD with TS-PDT in the treatment of recurrent HGG. PATIENTS AND METHODS: Seven patients with recurrent HGG underwent tumor resection using a combination of 5-ALA-PDD and TS-PDT. The incidence of photosensitivity, as an adverse effect associated with 5-ALA and TS, was evaluated as described in the package insert. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Tumor-specific fluorescence intensity was strong in four cases and weak in three. Photosensitivity occurred in only one patient (14.3%). Three patients exhibited CTCAE grade 1 or 2 abnormal liver function, and one patient experienced CTCAE grade 1 γ-GTP elevation. All abnormalities improved during follow-up. CONCLUSION: The combined use of 5-ALA-PDD and TS-PDT for HGG surgery did not increase the risk of serious adverse events in our study. Further investigations with a larger number of cases are needed for a more accurate assessment of its safety and efficacy.
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Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single-cell RNA-Seq, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validations of 2 isoform switching events in CERS5 and MPZL1 show regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. Overall, our data highlights the role of AS in affecting glioma malignancy and heterogeneity and its potential as a therapeutic vulnerability for treating adult gliomas.
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Empalme Alternativo , Glioma , Proteína de Unión al Tracto de Polipirimidina , Glioma/genética , Glioma/patología , Glioma/metabolismo , Glioma/terapia , Humanos , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Animales , Ratones , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Adulto , Células Madre Pluripotentes Inducidas/metabolismo , Línea Celular Tumoral , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismoRESUMEN
Glioblastoma (GBM) represents the most aggressive subtype of glioma, noted for its profound invasiveness and molecular heterogeneity. The mesenchymal (MES) transcriptomic subtype is frequently associated with therapy resistance, rapid recurrence, and increased tumor-associated macrophages. Notably, activation of the NF-κB pathway and alterations in the PTEN gene are both associated with this malignant transition. Although PTEN aberrations have been shown to be associated with enhanced NF-κB signaling, the relationships between PTEN, NF-κB and MES transition are poorly understood in GBM. Here, we show that PTEN regulates the chromatin binding of bromodomain and extraterminal (BET) family proteins, BRD2 and BRD4, mediated by p65/RelA localization to the chromatin. By utilizing patient-derived glioblastoma stem cells and CRISPR gene editing of the RELA gene, we demonstrate a crucial role for RelA lysine 310 acetylation in recruiting BET proteins to chromatin for MES gene expression and GBM cell invasion upon PTEN loss. Remarkably, we found that BRD2 is dependent on chromatin associated acetylated RelA for its recruitment to MES gene promoters and their expression. Furthermore, loss of BRD2 results in the loss of MES signature, accompanied by an enrichment of proneural signature and enhanced therapy responsiveness. Finally, we demonstrate that disrupting the NFκB/BRD2 interaction with a brain penetrant BET-BD2 inhibitor reduces mesenchymal gene expression, GBM invasion, and therapy resistance in GBM models. This study uncovers the role of hitherto unexplored PTEN-NF-κB-BRD2 pathway in promoting MES transition and suggests inhibiting this complex with BET-BD2 specific inhibitors as a therapeutic approach to target the MES phenotype in GBM.
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Background: Among primary brain tumors, glioblastoma (GBM) is the most common and aggressive in adults, with limited treatment options. Our previous study showed that autologous formalin-fixed tumor vaccine (AFTV) contributed to prognostic improvements in newly diagnosed GBM patients. However, some patients died early despite the treatment. The discovery of predictive factors in the treatment was warranted for efficient patient recruitment and studies to overcome resistance mechanisms. Identifying prognostic factors will establish AFTV guidelines for patients who may respond to the therapy. Methods: Data from 58 patients with newly diagnosed GBM, including 29 who received standard therapy plus AFTV (AFTV group) and 29 who received standard treatment (control group) were analyzed. Several data including patient age, sex, the extent of removal, and various cell immunohistochemistry (IHC) parameters were also included in the analysis. Results: Both univariate and multivariate analyses revealed that gross total resection (GTR) and negative p53 were associated with a better prognosis only in the AFTV group. In the IHC parameters, CD8 staining status was also one of the predictive factors in the univariate analysis. For blood cell-related data, lymphocyte counts of 1100 or more and monocyte counts of 280 or more before chemo-radiotherapy were significant factors for good prognosis in the univariate analysis. Conclusions: A p53-negative status in IHC and GTR were the predictive factors for AFTV treatment in newly diagnosed GBM patients. Microenvironment-targeted treatment and pretreatment blood cell status may be key factors to enhance therapy effects.
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In silico interrogation of glioblastoma (GBM) in The Cancer Genome Atlas (TCGA) revealed upregulation of GNA12 (Gα12), encoding the alpha subunit of the heterotrimeric G-protein G12, concomitant with overexpression of multiple G-protein coupled receptors (GPCRs) that signal through Gα12. Glioma stem cell lines from patient-derived xenografts also showed elevated levels of Gα12. Knockdown (KD) of Gα12 was carried out in two different human GBM stem cell (GSC) lines. Tumors generated in vivo by orthotopic injection of Gα12KD GSC cells showed reduced invasiveness, without apparent changes in tumor size or survival relative to control GSC tumor-bearing mice. Transcriptional profiling of GSC-23 cell tumors revealed significant differences between WT and Gα12KD tumors including reduced expression of genes associated with the extracellular matrix, as well as decreased expression of stem cell genes and increased expression of several proneural genes. Thrombospondin-1 (THBS1), one of the genes most repressed by Gα12 knockdown, was shown to be required for Gα12-mediated cell migration in vitro and for in vivo tumor invasion. Chemogenetic activation of GSC-23 cells harboring a Gα12-coupled DREADD also increased THBS1 expression and in vitro invasion. Collectively, our findings implicate Gα12 signaling in regulation of transcriptional reprogramming that promotes invasiveness, highlighting this as a potential signaling node for therapeutic intervention.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Animales , Ratones , Subunidades alfa de la Proteína de Unión al GTP G12-G13/genética , Subunidades alfa de la Proteína de Unión al GTP G12-G13/metabolismo , Glioblastoma/genética , Glioblastoma/patología , Transducción de Señal , Procesos Neoplásicos , Regulación hacia Arriba , Línea Celular Tumoral , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Proliferación CelularRESUMEN
Caspase-8 is a cysteine protease that plays an essential role in apoptosis. Consistently with its canonical proapoptotic function, cancer cells may genetically or epigenetically downregulate its expression. Unexpectedly, Caspase-8 is often retained in cancer, suggesting the presence of alternative mechanisms that may be exploited by cancer cells to their own benefit. In this regard, we reported that Src tyrosine kinase, which is aberrantly activated in many tumors, promotes Caspase-8 phosphorylation on Tyrosine 380 (Y380) preventing its full activation. Here, we investigated the significance of Caspase-8 expression and of its phosphorylation on Y380 in glioblastoma, a brain tumor where both Caspase-8 expression and Src activity are often aberrantly upregulated. Transcriptomic analyses identified inflammatory response as a major target of Caspase-8, and in particular, NFκB signaling as one of the most affected pathways. More importantly, we could show that Src-dependent phosphorylation of Caspase-8 on Y380 drives the assembly of a multiprotein complex that triggers NFκB activation, thereby inducing the expression of inflammatory and pro-angiogenic factors. Remarkably, phosphorylation on Y380 sustains neoangiogenesis and resistance to radiotherapy. In summary, our work identifies a novel interplay between Src kinase and Caspase-8 that allows cancer cells to hijack Caspase-8 to sustain tumor growth.
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Caspasa 8 , Glioblastoma , Familia-src Quinasas , Humanos , Apoptosis , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Glioblastoma/genética , Fosforilación , Transducción de Señal/fisiología , Familia-src Quinasas/metabolismoRESUMEN
Diffuse midline glioma (DMG) is a leading cause of brain tumor death in children. In addition to hallmark H3.3K27M mutations, significant subsets also harbor alterations of other genes, such as TP53 and PDGFRA. Despite the prevalence of H3.3K27M, the results of clinical trials in DMG have been mixed, possibly due to the lack of models recapitulating its genetic heterogeneity. To address this gap, we developed human iPSC-derived tumor models harboring TP53R248Q with or without heterozygous H3.3K27M and/or PDGFRAD842V overexpression. The combination of H3.3K27M and PDGFRAD842V resulted in more proliferative tumors when gene-edited neural progenitor (NP) cells were implanted into mouse brains compared to NP with either mutation alone. Transcriptomic comparison of tumors and their NP cells of origin identified conserved JAK/STAT pathway activation across genotypes as characteristic of malignant transformation. Conversely, integrated genome-wide epigenomic and transcriptomic analyses, as well as rational pharmacologic inhibition, revealed targetable vulnerabilities unique to the TP53R248Q; H3.3K27M; PDGFRAD842V tumors and related to their aggressive growth phenotype. These include AREG-mediated cell cycle control, altered metabolism, and vulnerability to combination ONC201/trametinib treatment. Taken together, these data suggest that cooperation between H3.3K27M and PDGFRA influences tumor biology, underscoring the need for better molecular stratification in DMG clinical trials.
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Recently, laparoscopy (also referred to as minimally invasive surgery) has been used during peritoneal catheter implantation in shunt placement for hydrocephalus; however, the procedure and devices for this technique have not yet been well established. We adopted umbilical and paraumbilical laparoscopy for peritoneal catheter insertion. In this paper, we describe the technique we used and its clinical results and benefits. Ten consecutive patients with hydrocephalus who underwent laparoscopic shunt surgery (6 cases of ventriculoperitoneal shunt and 4 of lumboperitoneal shunt) were enrolled for this study. The follow-up period ranged from 21 to 434 days (mean, 263 days). After a standard cranial/spinal procedure, an approximately 5-mm incision was made in the lateral side of the umbilicus, where the abdominal catheter was introduced subcutaneously. Thereafter, we inserted a laparoscope into the peritoneal cavity via a small incision beneath or just on the umbilicus. A shunt catheter was laparoscopically inserted through a peel-off cannula and placed after taking note of the outflow of cerebrospinal fluid (CSF) from the catheter tip. In all patients, the shunt was inserted with no complications, and good patency was achieved. Laparoscopy allows implantation of the catheter into the peritoneal cavity, and the outflow of CSF can be confirmed intraoperatively. Furthermore, the abdominal surgical wounds are minimal, even for obese patients, and fascia/muscle incisions are not needed. Laparoscopy-assisted shunt surgery for hydrocephalus is effective and safe and also has cosmetic advantages.
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Derivaciones del Líquido Cefalorraquídeo/métodos , Hidrocefalia/cirugía , Laparoscopía , Derivación Ventriculoperitoneal/métodos , Adulto , Anciano , Anciano de 80 o más Años , Catéteres , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos , Resultado del TratamientoRESUMEN
BACKGROUND: Heterozygous TERT (telomerase reverse transcriptase) promoter mutations (TPMs) facilitate TERT expression and are the most frequent mutation in glioblastoma (GBM). A recent analysis revealed this mutation is one of the earliest events in gliomagenesis. However, no appropriate human models have been engineered to study the role of this mutation in the initiation of these tumors. METHOD: We established GBM models by introducing the heterozygous TPM in human induced pluripotent stem cells (hiPSCs) using a two-step targeting approach in the context of GBM genetic alterations, CDKN2A/B and PTEN deletion, and EGFRvIII overexpression. The impact of the mutation was evaluated through the in vivo passage and in vitro experiment and analysis. RESULTS: Orthotopic injection of neuronal precursor cells (NPCs) derived from hiPSCs with the TPM into immunodeficient mice did not enhance tumorigenesis compared to TERT promoter wild type NPCs at initial in vivo passage presumably due to relatively long telomeres. However, the mutation recruited GA-Binding Protein and engendered low-level TERT expression resulting in enhanced tumorigenesis and maintenance of short telomeres upon secondary passage as observed in human GBM. These results provide the first insights regarding increased tumorigenesis upon introducing a TPM compared to isogenic controls without TPMs. CONCLUSION: Our novel GBM models presented the growth advantage of heterozygous TPMs for the first time in the context of GBM driver mutations relative to isogenic controls, thereby allowing for the identification and validation of TERT promoter-specific vulnerabilities in a genetically accurate background.
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Glioblastoma , Células Madre Pluripotentes Inducidas , Telomerasa , Humanos , Ratones , Animales , Acortamiento del Telómero/genética , Telomerasa/genética , Telómero/genética , Glioblastoma/genética , Mutación , CarcinogénesisRESUMEN
The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.
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Antineoplásicos/farmacología , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Reposicionamiento de Medicamentos , Metabolismo Energético/efectos de los fármacos , Fluoxetina/farmacología , Glioblastoma/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Registros Electrónicos de Salud , Receptores ErbB/metabolismo , Femenino , Fluoxetina/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Ratones Desnudos , Permeabilidad , Estudios Retrospectivos , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Esfingomielina Fosfodiesterasa/metabolismo , Esfingomielinas/metabolismo , Temozolomida/farmacología , Carga Tumoral/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Telomerase reverse transcriptase promoter (TERTp) hotspot mutations are the most frequent mutations in primary glioblastomas (GBM). Previous studies have shown that the combination of TERTp and isocitrate dehydrogenase (IDH) status may serve as a useful diagnostic marker for oligodendroglioma and glioblastoma. In oligodendrogliomas, TERTp and IDH mutations, along with the 1p/19q codeletion, usually coexist and are likely to be founder mutations. However, in contrast to oligodendroglioma, the role of the TERTp status in GBM remains obscure. Here, we used Sanger sequencing, pyrosequencing, and digital PCR (dPCR) to examine the TERTp status in 15 pairs of frozen tissue samples from primary and recurrent IDH wild-type GBM, all of which were operated in a single institute. We showed that the TERTp status was stable between primary and recurrent GBM but this consistency was only detected by dPCR. The results suggest that dPCR is a powerful, highly sensitive tool to detect TERTp mutations, especially in a mixed cell population (e.g., a recurrent GBM tissue) where earlier treatment may have grossly altered the tumor microenvironment.
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Neoplasias Encefálicas/genética , Análisis Mutacional de ADN/métodos , Glioblastoma/genética , Mutación , Recurrencia Local de Neoplasia/genética , Reacción en Cadena de la Polimerasa/métodos , Regiones Promotoras Genéticas/genética , Telomerasa/genética , Humanos , Isocitrato Deshidrogenasa/genética , Sensibilidad y EspecificidadRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Many cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that captures authentic cancer pathobiology. Orthotopic engraftment of the neural progenitor cells derived from hiPSCs that have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) results in formation of high-grade gliomas. Similar to patient-derived GBM, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, intra-tumor heterogeneity, and extrachromosomal DNA amplification. Re-engraftment of these primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. These cancer avatar models provide a platform for comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.
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Ingeniería Genética , Glioblastoma/genética , Glioblastoma/patología , Células Madre Pluripotentes/patología , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Diferenciación Celular , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Genoma , Glioblastoma/metabolismo , Glioma/genética , Glioma/patología , Humanos , Ratones , Ratones SCID , Mutación , Trasplante de Neoplasias , Células Madre Neoplásicas/patología , Neurofibromina 1/genética , Fosfohidrolasa PTEN/genética , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.
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Neoplasias Encefálicas/terapia , Núcleo Celular/metabolismo , Glioma/terapia , Fosfohidrolasa PTEN/metabolismo , Pirimidinas/administración & dosificación , Tolerancia a Radiación/efectos de los fármacos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Reparación del ADN/efectos de los fármacos , Femenino , Glioma/metabolismo , Humanos , Masculino , Ratones , Fosforilación/efectos de los fármacos , Pirimidinas/farmacología , Recombinasa Rad51/metabolismo , Tirosina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Gliomas that show extensive diffuse infiltration from the cerebellum to the brainstem without masslike expansion are extremely rare. The efficacy of bevacizumab treatment for diffusely infiltrating gliomas remains uncertain. CASE DESCRIPTION: A 75-year-old man presented with a cerebellar anaplastic astrocytoma showing diffuse infiltration to the brainstem without a definite mass. He had experienced rapidly progressive nausea and dysarthria, as well as vertigo and headache for 2 months. Magnetic resonance imaging (MRI) revealed a poorly demarcated T2 high-intensity area in the right cerebellum and brainstem. The tumor in the right cerebellum showed sparse enhancement with gadolinium (Gd). Suboccipital decompressive craniotomy and partial removal of the tumor was emergently performed because of the rapid progression of symptoms and severe tonsillar herniation demonstrated on MRI. The pathologic diagnosis was anaplastic astrocytoma, and genomic analyses revealed no mutation in IDH1, H3F3A, or BRAF. During concomitant chemoradiotherapy with temozolomide, rapid worsening of the neurologic symptoms developed and significant enlargement of the T2 high-intensity area extending to the cerebral peduncle was seen, as well as a new Gd-enhancing lesion in the midbrain. After administration of bevacizumab, the neurologic symptoms gradually improved, the T2 high-intensity area decreased, and the Gd-enhancing lesion disappeared. At follow-up 2 years after the operation, no worsening of neurologic symptoms was seen and the residual T2 high-intensity area remained unchanged on MRI. CONCLUSIONS: Bevacizumab treatment may be a salvage treatment option for patients with diffusely infiltrating cerebellar gliomas that exhibits rapid progression during standard treatment.
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Antineoplásicos Inmunológicos/uso terapéutico , Astrocitoma/diagnóstico por imagen , Astrocitoma/tratamiento farmacológico , Bevacizumab/uso terapéutico , Neoplasias Cerebelosas/diagnóstico por imagen , Neoplasias Cerebelosas/tratamiento farmacológico , Anciano , Humanos , MasculinoRESUMEN
A 48-year-old man with right hemi-facial palsy and cerebellar ataxia was referred to our hospital. Three years and 10 months earlier he had undergone gamma knife radiosurgery (GKRS) at the referring hospital for an 18 mm right vestibular schwannoma. Slight tumor enlargement had been observed on MRI performed at the referring hospital 3 years after the GKRS. On close follow-up after another 6 months an MRI showed an obvious enlargement of the tumor. An MRI on admission revealed an iso-intense mass lesion measuring 36 mm in maximum diameter at the right cerebellopontine angle. A two stage surgery was conducted using a retrosigmoid approach because bleeding from the tumor wall was difficult to control intraoperatively during the first operation. At the second operation, the majority of the tumor capsule had converted to necrotic tissue. A large hematoma cavity was present inside the tumor capsule which explained the rapid increase in size over a short period of time. Near total removal was achieved. Histopathological examination revealed massive intratumoral hemorrhage within a typical vestibular schwannoma with no malignancy. The complication of intratumoral hemorrhage is very rare and the utility of stereotactic radiation surgery/therapy, including GKRS, for vestibular schwannoma is well known. However, we must emphasize that careful follow-up is still required, even after several years.
Asunto(s)
Hemorragia Cerebral/terapia , Neuroma Acústico/complicaciones , Neuroma Acústico/cirugía , Complicaciones Posoperatorias/terapia , Radiocirugia/efectos adversos , Ataxia Cerebelosa/etiología , Hemorragia Cerebral/etiología , Parálisis Facial/etiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Resultado del TratamientoRESUMEN
We evaluated the feasibility of 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) in the biopsy for primary central nervous system lymphoma (PCNSL). 5-ALA (20 mg kg(-1) ) was administered orally 4 hours preoperatively. Forty-one biopsies obtained under PDD in 47 consecutive biopsies (46 patients) that were finally pathologically diagnosed as PCNSL were evaluated. Positive fluorescence was observed in 34 of those 41 biopsies (82.9%). An intraoperative pathological diagnosis (IOD) of suspected PCNSL was made in 21 of the biopsies with positive fluorescence (61.8%). However, the eight IODs in the remaining 13 biopsies (23.5%) were not correct (atypical cell, 4; high-grade glioma, 1; gliosis, 1; unremarkable, 2). In those 8 biopsies, PCNSL was confirmed by the final pathological diagnosis. There was no difference in the mean Mib-1 labeling index between the biopsies with positive fluorescence (86.5%) and those without positive fluorescence (90.0%). IOD was not performed in 6 biopsies; however, 5 of those biopsies (83.3%) showed positive fluorescence and were finally pathologically diagnosed as PCNSL. Use of PDD in biopsies for patients with suspected PCNSL is a reliable way of obtaining specimens of adequate quality for the final pathological diagnosis and may lead to improved diagnostic yield in the biopsy of PCNSL.