ABSTRACT
PURPOSE: While pediatric glioblastomas are molecularly distinct from adult counterparts, the activation of NF-kB is partially shared by both subsets, playing key roles in tumor propagation and treatment response. RESULTS: We show that, in vitro, dehydroxymethylepoxyquinomicin (DHMEQ) impairs growth and invasiveness. Xenograft response to the drug alone varied according to the model, being more effective in KNS42-derived tumors. In combination, SF188-derived tumors were more sensitive to temozolomide while KNS42-derived tumors responded better to the combination with radiotherapy, with continued tumor regression. CONCLUSION: Taken together, our results strengthen the potential usefulness of NF-kB inhibition in future therapeutic strategies to overcome this incurable disease.
Subject(s)
Glioblastoma , NF-kappa B , Child , Humans , NF-kappa B/metabolism , NF-kappa B/pharmacology , Glioblastoma/drug therapy , Apoptosis , Cell Line, TumorABSTRACT
Despite advances in the understanding of the molecular mechanisms underlying the basic biology and pathogenesis of pediatric central nervous system (CNS) malignancies, patients still have an extremely unfavorable prognosis. Over the years, a plethora of natural and synthetic compounds has emerged for the pharmacologic intervention of the NF-kB pathway, one of the most frequently dysregulated signaling cascades in human cancer with key roles in cell growth, survival, and therapy resistance. Here, we provide a review about the state-of-the-art concerning the dysregulation of this hub transcription factor in the most prevalent pediatric CNS tumors: glioma, medulloblastoma, and ependymoma. Moreover, we compile the available literature on the anti-proliferative effects of varied NF-kB inhibitors acting alone or in combination with other therapies in vitro, in vivo, and clinical trials. As the wealth of basic research data continues to accumulate, recognizing NF-kB as a therapeutic target may provide important insights to treat these diseases, hopefully contributing to increase cure rates and lower side effects related to therapy.
Subject(s)
Central Nervous System Neoplasms/pathology , NF-kappa B/metabolism , 2-Methoxyestradiol/chemistry , 2-Methoxyestradiol/metabolism , 2-Methoxyestradiol/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/metabolism , Child , Glioma/metabolism , Glioma/pathology , Hedgehog Proteins/antagonists & inhibitors , Hedgehog Proteins/metabolism , Humans , Medulloblastoma/metabolism , Medulloblastoma/pathology , NF-kappa B/antagonists & inhibitors , Wnt Proteins/antagonists & inhibitors , Wnt Proteins/metabolismABSTRACT
PURPOSE: Inhalation of perillyl alcohol (POH) recently emerged as an investigational promising antiglioma strategy. However, little attention has been paid to its therapeutic potential for other brain tumors, especially in the pediatric setting. METHODS: The effects of POH were explored in medulloblastoma cell models belonging to the SHH variant with activation of RAS (ONS-76) or with TP53 mutations (DAOY and UW402), by means of proliferation and invasion assays. Interactions with methotrexate, thiotepa, or ionizing radiation were also assessed. Mice bearing subcutaneous tumors were treated with intraperitoneal injections. Alternatively, animals with intracranial tumors were exposed to intranasal POH alone or combined with radiation. Tumor growth was measured by bioluminescence. Analyses of cytotoxicity to the nasal cavity were also performed, and the presence of POH in the brain, lungs, and plasma was surveyed through chromatography/mass spectrometry. RESULTS: POH decreased cell proliferation and colony formation, with conspicuous death, though the invasive capacity was only affected in the NRAS-mutated cell line. Median-drug effect analysis displayed synergistic combinations with methotrexate. Otherwise, POH showed to be a reasonable radiosensitizer. In vivo, intraperitoneal injection significantly decreased tumor volume. However, its inhalation did not affect orthotopic tumors, neither alone or followed by cranial irradiation. Nasal cavity epithelium showed unimportant alterations, though, no traces of POH or its metabolites were detected in tissue samples. CONCLUSION: POH presents robust in vitro antimedulloblastoma effects and sensitizes cell lines to other conventional therapeutics, reducing tumor volume when administered intraperitoneally. Nevertheless, further improvement of delivery devices and/or drug formulations are needed to better characterize its effectiveness through inhalation.
Subject(s)
Antineoplastic Agents , Cerebellar Neoplasms , Medulloblastoma , Animals , Antineoplastic Agents/pharmacology , Cerebellar Neoplasms/drug therapy , Child , Hedgehog Proteins , Humans , Medulloblastoma/drug therapy , Medulloblastoma/genetics , Mice , Monoterpenes , Tumor Suppressor Protein p53 , ras ProteinsABSTRACT
Even though the treatment of childhood cancer has evolved significantly in recent decades, aggressive central nervous system (CNS) tumors are still a leading cause of morbidity and mortality in this population. Consequently, the identification of molecular targets that can be incorporated into diagnostic practice, effectively predict prognosis, follow treatment response, and materialize into potential targeted therapeutic approaches are still warranted. Since the first evidence of the participation of miRNAs in cancer development and progression 20 years ago, notable progress has been made in the basic understanding of the contribution of their dysregulation as epigenetic driver of tumorigenesis. Nevertheless, among the plethora of articles in the literature, microRNA profiling of pediatric tumors are scarce. This article gives an overview of the recent advances in the diagnostic/prognostic potential of miRNAs in a selection of pediatric CNS tumors: medulloblastoma, ependymoma, pilocytic astrocytoma, glioblastoma, diffuse intrinsic pontine glioma, atypical teratoid/rhabdoid tumors, and choroid plexus tumors.
Subject(s)
Brain Neoplasms/genetics , Central Nervous System Neoplasms/genetics , MicroRNAs/biosynthesis , Age Factors , Animals , Brain Neoplasms/metabolism , Central Nervous System Neoplasms/metabolism , Child , Humans , MicroRNAs/geneticsABSTRACT
Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up-to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblastoma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated.
Subject(s)
Abdominal Neoplasms/genetics , MicroRNAs/genetics , Abdominal Neoplasms/metabolism , Animals , Child , Humans , MicroRNAs/biosynthesisABSTRACT
Musashi comprises an evolutionarily conserved family of RNA-binding proteins (RBP) that regulate cell fate decisions during embryonic development and play key roles in the maintenance of self-renewal and differentiation of stem cells and adult tissues. More recently, several studies have shown that any dysregulation of MSI1 and MSI2 can lead to cellular dysfunctions promoting tissue instability and tumorigenesis. Moreover, several reports have characterized many molecular interactions between members of the Musashi family with ligands and receptors of the signaling pathways responsible for controlling normal embryonic development: Notch, Transforming Growth Factor Beta (TGF-ß), Wingless (Wnt) and Hedgehog Signaling (Hh); all of which, when altered, are strongly associated with cancer onset and progression, especially in pediatric tumors. In this context, the present review aims to compile possible cross-talks between Musashi proteins and members of the above cited molecular pathways for which dysregulation plays important roles during carcinogenesis and may be modulated by these RBP.
Subject(s)
Gene Expression Regulation , Nerve Tissue Proteins/physiology , RNA-Binding Proteins/physiology , Signal Transduction , Animals , Carcinogenesis , Cell Differentiation , Embryonic Development , HumansABSTRACT
Cancer targeted therapy, either alone or in combination with conventional chemotherapy, could allow the survival of patients with neoplasms currently considered incurable. In recent years, the dysregulation of the Rho-associated coiled-coil kinases (ROCK1 and ROCK2) has been associated with increased metastasis and poorer patient survival in several tumor types, and due to their essential roles in regulating the cytoskeleton, have gained popularity and progressively been researched as targets for the development of novel anti-cancer drugs. Nevertheless, in a pediatric scenario, the influence of both isoforms on prognosis remains a controversial issue. In this review, we summarize the functions of ROCKs, compile their roles in human cancer and their value as prognostic factors in both, adult and pediatric cancer. Moreover, we provide the up-to-date advances on their pharmacological inhibition in pre-clinical models and clinical trials. Alternatively, we highlight and discuss detrimental effects of ROCK inhibition provoked not only by the action on off-targets, but most importantly, by pro-survival effects on cancer stem cells, dormant cells, and circulating tumor cells, along with cell-context or microenvironment-dependent contradictory responses. Together these drawbacks represent a risk for cancer cell dissemination and metastasis after anti-ROCK intervention, a caveat that should concern scientists and clinicians.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , rho-Associated Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/adverse effects , Humans , Molecular Targeted Therapy , Neoplasm Metastasis , Neoplasms/enzymology , Neoplasms/mortality , Neoplasms/pathology , Protein Kinase Inhibitors/adverse effects , Signal Transduction , Treatment Outcome , rho-Associated Kinases/metabolismABSTRACT
INTRODUCTION: Pilocytic astrocytoma (PA) is the most common brain tumor that affects the pediatric population. Even though PA is benign and treatment only involves surgery, recurrent or unresectable tumors require chemo- and radiotherapy. Besides BRAF, CDKN2A, or IDH mutations, the hyperactivation of the nuclear factor NF-κB contributes to tumor growth and survival. METHODS: In the present study, we used publicly available data for the in silico analysis of NF-κB subunits (RELA, RELB, REL, NF-κB1, and NF-κB2) expression in PA samples. Besides, in vitro assays were performed to evaluate proliferation, migration, cell death, on the PA cell line Res286 comparing to human primary astrocytes. Sensitization to radiation therapy and temozolomide (TMZ) was also assayed. RESULTS: Our results showed that all the members of the NF-kB family are upregulated in PA datasets compared to normal brain tissues. Moreover, DHMEQ treatment significantly reduced cell growth and motility, while sensitized cells to ionizing radiation and TMZ, as previously seen in high-grade gliomas. CONCLUSIONS: This drug presents a potential application in clinical practice for the treatment of recurrent or inoperable PA. Moreover, its use might assist adjuvant chemotherapy and reduce irradiation doses to avoid toxicity to the surrounding tissues.
Subject(s)
Astrocytoma , Brain Neoplasms , Astrocytoma/drug therapy , Brain Neoplasms/drug therapy , Cell Proliferation , Child , Humans , NF-kappa B , Temozolomide/pharmacologyABSTRACT
INTRODUCTION: Medulloblastoma (MB) is an embryonal tumour that originates from genetic deregulation of cerebellar developmental pathways and is classified into 4 molecular subgroups: SHH, WNT, group 3, and group 4. Hydroxymethylation levels progressively increases during cerebellum development suggesting a possibility of deregulation in MB pathogenesis. The aim of this study was to investigate global hydroxymethylation levels and changes in TET and IDH gene expression in MB samples compared to control cerebellum samples. METHODS: The methods utilized were qRT-PCR for gene expression, dot-blot and immunohistochemistry for global hydroxymethylation levels and sequencing for the investigation of IDH mutations. RESULTS: Our results show that global hydroxymethylation level was decreased in MB, and low 5hmC level was associated with the presence of metastasis. TET1 expression levels were decreased in the WNT subgroup, while TET3 expression levels were decreased in the SHH subgroup. Reduced TET3 expression levels were associated with the presence of events such as relapse and death. Higher expression of IDH1 was observed in MB group 3 samples, whereas no mutations were detected in exon 4 of IDH1 and IDH2. CONCLUSION: These findings suggest that reduction of global hydroxymethylation levels, an epigenetic event, may be important for MB development and/or maintenance, representing a possible target in this tumour and indicating a possible interaction of TET and IDH genes with the developmental pathways specifically activated in the MB subgroups. These genes could be specific targets and markers for each subgroup.
Subject(s)
Cerebellar Neoplasms/metabolism , DNA Methylation , Isocitrate Dehydrogenase/metabolism , Medulloblastoma/metabolism , Proto-Oncogene Proteins/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cerebellar Neoplasms/genetics , Cerebellum/metabolism , Child , Child, Preschool , Female , Gene Expression Regulation, Neoplastic , Humans , Isocitrate Dehydrogenase/genetics , Male , Medulloblastoma/genetics , Mutation , Proto-Oncogene Proteins/geneticsABSTRACT
PURPOSE: Medulloblastoma (MB) is the most common malignant tumor of the central nervous system (CNS) in children. Despite its relative good survival rates, treatment can cause long time sequels and may impair patients' lifespan and quality, making the search for new treatment options still necessary. Polo like kinases (PLKs) constitute a five-member serine/threonine kinases family (PLK 1-5) that regulates different stages during cell cycle. Abnormal PLKs expression has been observed in several cancer types, including MB. As gene regulators, miRNAs have also been described with variable expression in cancer. METHODS: We evaluated gene expression profiles of all PLK family members and related miRNAs (miR-100, miR-126, miR-219, and miR-593*) in MB cell lines and tumor samples. RESULTS: RT-qPCR analysis revealed increased levels of PLK1-4 in all cell lines and in most MB samples, while PLK5 was found underexpressed. In parallel, miR-100 was also found upregulated while miR-129, miR-216, and miR-593* were decreased in MB cell lines. Variable miRNAs expression patterns were observed in MB samples. However, a correlation between miR-100 and PLK4 expression was observed, and associations between miR-100, miR-126, and miR-219 expression and overall and event free survival were also evinced in our cohort. Moreover, despite the lack of association with clinico-pathological features, when comparing primary tumors to those relapsed, we found a consistent decrease on PLK2, miR-219, and miR-598* and an increase on miR-100 and miR-126. CONCLUSION: Specific dysregulation on PLKs and associated miRNAs may be important in MB and can be used to predict prognosis. Although miRNAs sequences are fundamental to predict its target, the cell type may also be consider once that mRNA repertoire can define different roles for specific miRNA in a given cell.
Subject(s)
Cell Cycle Proteins/genetics , Cerebellar Neoplasms/genetics , Gene Expression Regulation, Neoplastic/genetics , Medulloblastoma/genetics , MicroRNAs/metabolism , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics , Adolescent , Adult , Age Factors , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cerebellar Neoplasms/enzymology , Cerebellar Neoplasms/mortality , Cerebellar Neoplasms/pathology , Child , Female , Humans , Male , Medulloblastoma/enzymology , Medulloblastoma/mortality , Medulloblastoma/pathology , MicroRNAs/genetics , Prognosis , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Statistics, Nonparametric , Survival Analysis , Polo-Like Kinase 1Subject(s)
Alemtuzumab/therapeutic use , Histiocytic Sarcoma/drug therapy , Alemtuzumab/pharmacology , Child , Humans , MaleABSTRACT
OBJECTIVE: This study aims to evaluate the impact of gross total resection of giant supratentorial brain tumors (GSBT) on survival and neurological outcome in a consecutive single-center pediatric series. METHODS: Clinical data of 23 patients under 18 years of age operated with GSBT (≥5 cm in diameter) were reviewed to determine epidemiological aspects, clinical presentation, associated factors, histopathological features, and outcome. Volumetric measurements were performed on magnetic resonance imaging or computed tomography scans obtained at the time of the initial surgical procedure. RESULTS: The group included 23 patients (mean age 4.5 years). Signs and symptoms of raised intracranial pressure were present in 19 patients (82.6%). The most frequent tumor location was the parietal lobe in 19 patients (82.6%), and the mean tumor volume was 208 cm(3). Gross total or radical resection was achieved in all patients. Histopathological analysis revealed malignant brain tumors in 18 cases (78.2%). The most common neoplasm was choroid plexus carcinoma in seven (30.4 %). Mean intraoperative blood transfusion volume was 51.2 ml/kg. Chemotherapy and/or radiotherapy were performed as adjuvant treatment in 16 patients (69.5%). Mean length of follow-up was 36.7 months. Tumor malignancy grade significantly correlated with recurrence of the disease (P = 0.03) and death (P = 0.01), as opposed to tumor location, size, and extension to the ventricles. CONCLUSIONS: Our clinical experience suggests that tumor mass reduction by en bloc surgery seems to be an effective approach in pediatric patients with GSBT, relieving symptoms related to raised intracranial pressure and providing a better response to adjuvant treatment.
Subject(s)
Neurosurgery/methods , Supratentorial Neoplasms/surgery , Treatment Outcome , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Intracranial Hypertension/etiology , Kaplan-Meier Estimate , Magnetic Resonance Angiography , Magnetic Resonance Imaging , Male , Radiotherapy, Adjuvant , Retrospective Studies , Supratentorial Neoplasms/drug therapy , Supratentorial Neoplasms/radiotherapyABSTRACT
BACKGROUND: Glioblastoma is the most common tumor of the central nervous system and one of the hardest tumors to treat. Consequently, the search for novel therapeutic options is imperative. 7-epiclusianone, a tetraprenylated benzophenone isolated from the epicarp of the native plant Garcinia brasiliensis, exhibits a range of biological activities but its prospect anticancer activity is underexplored. Thus, the aim of the present study was to evaluate the influence of 7-epiclusianone on proliferation, clonogenic capacity, cell cycle progression and induction of apoptosis in two glioblastoma cell lines (U251MG and U138MG). METHODS: Cell viability was measured by the MTS assay; for the clonogenic assay, colonies were stained with Giemsa and counted by direct visual inspection; For cell cycle analysis, cells were stained with propidium iodide and analyzed by cytometry; Cyclin A expression was determined by immunoblotting; Apoptotic cell death was determined by annexin V fluorescein isothiocyanate labeling and Caspase-3 activity in living cells. RESULTS: Viability of both cell lines was drastically inhibited; moreover, the colony formation capacity was significantly reduced, demonstrating long-term effects even after removal of the drug. 7-epiclusianone treatment at low concentrations also altered cell cycle progression, decreased the S and G2/M populations and at higher concentrations increased the number of cells at sub-G1, in concordance with the increase of apoptotic cells. CONCLUSION: The present study demonstrates for the first time the anticancer potential of 7-epiclusianone against glioblastoma cells, thus meriting its further investigation as a potential therapeutic agent.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Benzophenones/pharmacology , Benzoquinones/pharmacology , Garcinia/chemistry , Glioblastoma/physiopathology , Plant Extracts/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Glioblastoma/drug therapy , HumansABSTRACT
Teratomas are very rare intracranial tumors and cytogenetic information on this group remains rare. We report a case of a mature teratoma with abnormal +21 trisomy in tumor karyotype ocurring in a non-Down syndrome(DS) infant. Additionally, the evidence for the contribution of chromosome 21 trisomy in this neoplasia are briefly reviewed. The 6-month-old male baby presented with a posterior fossa tumor. Histological evaluation of tumor specimen showed a mature teratoma composed of fully differentiated ectodermal, mesodermal and endodermal components. Although somatic karyotyping of the index case was normal, composite tumor karyotype depicted 47,XY,+21[6]/46,XY[6]. Besides previous reports of children with DS and intracranial teratomas, this is the first report to describe the occurrence of an isolated chromosome 21 trisomy within the tumor of a non-DS child. The participation of chromosome 21 in this rare pediatric tumor, either somatic or restricted to tumor specimen,may deserve special interest and further investigation.
Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/pathology , Down Syndrome/genetics , Down Syndrome/pathology , Infratentorial Neoplasms/genetics , Infratentorial Neoplasms/pathology , Teratoma/genetics , Teratoma/pathology , Chromosomes, Human, Pair 21/genetics , Cytogenetic Analysis , Humans , Infant , MaleABSTRACT
Tumor heterogeneity poses a significant challenge in osteosarcoma (OS) treatment. In this regard, the "omics" era has constantly expanded our understanding of biomarkers and altered signaling pathways (i.e., PI3K/AKT/mTOR, WNT/ß-catenin, NOTCH, SHH/GLI, among others) involved in OS pathophysiology. Despite different players and complexities, many commonalities have been described, among which the nuclear factor kappa B (NF-κB) stands out. Its altered activation is pervasive in cancer, with pleiotropic action on many disease-relevant traits. Thus, in the scope of this article, we highlight the evidence of NF-κB dysregulation in OS and its integration with other cancer-related pathways while we summarize the repertoire of compounds that have been described to interfere with its action. In silico strategies were used to demonstrate that NF-κB is closely coordinated with other commonly dysregulated signaling pathways not only by functionally interacting with several of their members but also by actively participating in the regulation of their transcription. While existing inhibitors lack selectivity or act indirectly, the therapeutic potential of targeting NF-κB is indisputable, first for its multifunctionality on most cancer hallmarks, and secondly, because, as a common downstream effector of the many dysregulated pathways influencing OS aggressiveness, it turns complex regulatory networks into a simpler picture underneath molecular heterogeneity.
ABSTRACT
Estrogen deficiency, long-term immobilization, and/or aging are commonly related to bone mass loss, thus increasing the risk of fractures. One option for bone replacement in injuries caused by either traumas or pathologies is the use of orthopedic cement based on polymethylmethacrylate (PMMA). Nevertheless, its reduced bioactivity may induce long-term detachment from the host tissue, resulting in the failure of the implant. In view of this problem, we developed an alternative PMMA-based porous cement (pPMMA) that favors cell invasion and improves osteointegration with better biocompatibility. The cement composition was changed by adding bioactive strontium-nanoparticles that mimic the structure of bone apatite. The nanoparticles were characterized regarding their physical-chemical properties, and their effects on osteoblasts and osteoclast cultures were assessed. Initial in vivo tests were also performed using 16 New Zealand rabbits as animal models, in which the pPMMA-cement containing the strontium nanoparticles were implanted. We showed that the apatite nanoparticles in which 90% of Ca2+ ions were substituted by Sr2+ (NanoSr 90%) upregulated TNAP activity and increased matrix mineralization. Moreover, at the molecular level, NanoSr 90% upregulated the mRNA expression levels of, Sp7, and OCN. Runx2 was increased at both mRNA and protein levels. In parallel, in vivo tests revealed that pPMMA-cement containing NanoSr 90%, upregulated two markers of bone maturation, OCN and BMP2, as well as the formation of apatite minerals after implantation in the femur of rabbits. The overall data support that strontium nanoparticles hold the potential to up-regulate mineralization in osteoblasts when associated with synthetic biomaterials.
Subject(s)
Osteoblasts , Strontium , Animals , Strontium/pharmacology , Strontium/chemistry , Rabbits , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoblasts/cytology , Nanoparticles/chemistry , Polymethyl Methacrylate/chemistry , Polymethyl Methacrylate/pharmacology , Bone Cements/pharmacology , Bone Cements/chemistry , Osteoclasts/drug effects , Osteoclasts/metabolism , MiceABSTRACT
PURPOSE: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. PATIENTS AND METHODS: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. RESULTS: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. CONCLUSION: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.
Subject(s)
Protein Kinase Inhibitors , Pyrazoles , Humans , Child , Male , Female , Adolescent , Pyrazoles/therapeutic use , Child, Preschool , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Receptor, trkA/genetics , Receptor, trkA/antagonists & inhibitors , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Sarcoma/drug therapy , Sarcoma/genetics , Neuroblastoma/drug therapy , Neuroblastoma/genetics , Infant , Receptor, trkB/genetics , Receptor, trkC/genetics , Clinical Trials as TopicSubject(s)
Astrocytoma/genetics , Astrocytoma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , DNA Methylation/genetics , Exome/genetics , Eye Diseases/genetics , Eye Diseases/pathology , Lipomatosis/genetics , Lipomatosis/pathology , Neurocutaneous Syndromes/genetics , Neurocutaneous Syndromes/pathology , Adult , Child , Child, Preschool , Female , Gene Duplication , Genes, ras/genetics , High-Throughput Nucleotide Sequencing , Humans , Male , Neoplasm Proteins/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , Exome SequencingABSTRACT
PURPOSE: John Cunningham (JC) viral DNA sequence has seldom been reported in patients with brain tumors such as high grade gliomas and medulloblastomas, pointing to a role in the etiopathogenesis of such tumors. RESULTS: We present a unique clinical case of an HIV-positive pediatric patient with multifocal leukoencephalopathy and confirmed JC virus (JCV) infection that developed a giant-cell glioblastoma. CONCLUSIONS: Experimental data with infected primates has previously hypothesized an association of human giant-cell glioblastoma with JCV or progressive multifocal leukoencephalopathy, though such association has not been documented in the literature for humans. Future studies with larger cohorts and molecular pathological analyses are still needed to corroborate the role of the widely spread human neurotropic virus in early transformation and in the development of brain tumors with different histology in the setting of HIV-related severe immunosuppression.
Subject(s)
Brain Neoplasms/etiology , Glioblastoma/etiology , HIV Infections/complications , Polyomavirus Infections/complications , Adolescent , Brain Neoplasms/virology , Female , Glioblastoma/virology , Humans , JC Virus/genetics , JC Virus/pathogenicity , Karyotype , Magnetic Resonance Imaging , Viral Matrix Proteins/metabolismABSTRACT
PURPOSE: Glioblastoma (GBM) is a very aggressive and lethal brain tumor with poor prognosis. Despite new treatment strategies, patients' median survival is still lower than 1 year in most cases. The expression of the BUB gene family has demonstrated to be altered in a variety of solid tumors, pointing to a role as putative therapeutic target. The purpose of this study was to determine BUB1, BUB3, and BUBR1 gene expression profiles in glioblastoma and to analyze the effects of BUB1 and BUBR1 inhibition combined or not with Temozolomide and radiation in the pediatric SF188 GBM cell line. METHODS: For gene expression analysis, 8 cell lines and 18 tumor samples were used. The effect of BUB1 and BUBR1 inhibition was evaluated using siRNA. Apoptosis, cell proliferation, cell cycle kinetics, micronuclei formation, and clonogenic capacity were analyzed after BUB1 and BUBR1 inhibition. Additionally, combinatorial effects of gene inhibition and radiation or Temozolomide (TMZ) treatment were evaluated through proliferation and clonogenic capacity assays. RESULTS: We report the upregulation of BUB1 and BUBR1 expression and the downregulation of BUB3 in GBM samples and cell lines when compared to white matter samples (p < 0.05). Decreased cell proliferation and colony formation after BUB1 and BUBR1 inhibition were observed, along with increased micronuclei formation. Combinations with TMZ also caused cell cycle arrest and increased apoptosis. Moreover, our results demonstrate that BUB1 and BUBR1 inhibition sensitized SF188 cells to γ-irradiation as shown by decreased growth and abrogation of colony formation capacity. CONCLUSION: BUB1 and BUBR1 inhibition decreases proliferation and shows radiosensitizing effects on pediatric GBM cells, which could improve treatment strategies for this devastating tumor. Collectively, these findings highlight the potentials of BUB1 and BUBR1 as putative therapeutic targets for glioblastoma treatment.