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1.
Hum Mutat ; 41(1): 255-264, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31544997

RESUMO

Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663-1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663-1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31876779

RESUMO

WT1-mutant Wilms tumors exhibit a high rate of concomitant CTNNB1 mutations, associated with activated Wnt signaling. Here, we show by laser and manual microdissection of different histologic cell types from 6 WT1-mutant tumor samples that 1 patient's tumor can contain up to 4 distinct mutations in CTNNB1 and/or WTX. Consecutive sections may also harbor different CTNNB1 mutations. The variability of activating CTNNB1 mutations demonstrates the multifocal nature of WT1-mutant Wilms tumors. As multiple independent tumors can occur in patients with constitutional WT1 mutations, they need to be surveyed more closely for tumor development.

3.
Nat Med ; 25(12): 1839-1842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768065

RESUMO

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.


Assuntos
Quinase do Linfoma Anaplásico/genética , Histiocitose/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Criança , Pré-Escolar , Feminino , Genoma Humano , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histiocitose/tratamento farmacológico , Histiocitose/patologia , Humanos , Lactente , Masculino , Mutação , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma , Adulto Jovem
4.
Epilepsy Behav ; 101(Pt B): 106544, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31753769

RESUMO

BACKGROUND: The diagnosis of nonconvulsive status epilepticus (NCSE) can pose a challenge. Electroencephalogram (EEG) patterns can be difficult to interpret, and the absence of an EEG correlate does not rule out the diagnosis of NCSE. In this setting, neuroimaging tools to help in the diagnosis are crucial. Our aim was to evaluate the role of 99mTc-hexamethyl propyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) and quantitative HMPAO-SPECT (QtSPECT) in patients with clinical suspicion of NCSE, and to evaluate their value in the final diagnosis of NCSE. METHODS: We recruited consecutive patients admitted in our center with suspicion of NCSE, and selected those who underwent an HMPAO-SPECT. All patients were admitted to the neurology ward and underwent an EEG. We divided the patients into those who were finally with diagnosed NCSE (NCSE-p) and those who were not (non-NCSE) according to the Salzburg Diagnostic EEG criteria. Sensitivity and specificity of the diagnostic tools were calculated. The SPECTs were acquired in a Skylight SPECT (Philips Healthcare, Amsterdam). The injections were done during the clinical episode suspected of being an NCSE. The HMPAO-SPECT was analyzed by two experts and was also quantified. All data were normalized to the SPM SPECT template. We used an external healthy normal database to obtain a Z-score map for each individual versus the normal database. The Z-score maximum (Zmax) was extracted from each region of the AAL atlas as was the percentage of voxels with a Z-score higher than 2.5 (N(%)). A logistic regression combining the Zmax, N(%), and the effect of patient age was fitted to predict the final NCSE diagnosis. A receiver operator characteristic (ROC) curve and the area under the curve (AUC) were obtained to evaluate the classification performance. RESULTS: We included 55 patients, 21 of them women (38.9%), with a median age of 62.1 years old (range 25-84). Thirty-six patients were with diagnosed NCSE (62.9%). Initial EEG had a sensitivity of 61.1% and a specificity of 89%. Most of the patients were critically ill with diagnostic difficulties, and it could be one of the main reasons to find low sensitivity of the Salzburg diagnostic EEG criteria. The Zmax and N(%) were significantly higher in NCSE-p than in non-NCSE (p = 0.005 and p < 0.001, respectively). The HMPAO-SPECT qualitative analysis had a sensitivity of 80.5% and specificity of 89.5% while QtSPECT had a sensitivity of 82% and specificity of 81%. CONCLUSION: Both 99mTc-HMPAO-SPECT and QtSPECT can be useful in the diagnosis of NCSE. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

5.
Acta Neuropathol ; 138(6): 1053-1074, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31428936

RESUMO

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.

6.
Eye (Lond) ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320737

RESUMO

PURPOSE: To describe retinal alterations detected by swept-source optical coherence tomography (SS-OCT) in paediatric patients with Usher syndrome type 1 (USH1) and to compare these findings to previously published reports. METHODS: Thirty-two eyes from 16 patients (11 males and 5 females) with a genetic diagnosis of USH1 because of MYO7A mutations underwent SS-OCT. Patients ranged in age from 4 to 17 years (mean, 11,13 ± 4,29). The subfoveal and macular area were analysed with SS-OCT at 1050 nm using 12 radial scans of 12.0 mm. Structural abnormalities were evaluated and correlated with best-corrected visual acuity (BCVA). RESULTS: The most common qualitative retinal abnormality was external layer damage in macular area. Specific alterations included external limiting membrane loss/disruption (27 eyes; 84.4%), disruption of the Myoid zone (27 eyes; 84.4%); Ellipsoid zone disruption (28 eyes; 87.5%), and loss of the outer segments (29 eyes; 90.6%). The damage of the retinal pigment epithelium was divided according to the loss of the different layers: phagosome zone (30 eyes; 93.8%), melanosome zone (29 eyes; 90.6%) and mitochondria zone (0 eyes; 0%). The presence of cystoid macular oedema (CMO) was significantly correlated with alterations in photoreceptors. Disruption or absence of the myoid and ellipsoid zones of the photoreceptors were the only variables independently associated with decreased BCVA. CONCLUSIONS: The findings of this study suggest that the physiopathologic basis of early-stage Usher syndrome (USH) may be changes in the outer retinal layer, particularly the photoreceptors, which in turn may cause alterations-such as CMO-in the inner retinal layers. Accordingly, monitoring the condition of photoreceptors during follow-up may be advisable for the early detection of pathologic changes.

7.
Mol Oncol ; 13(9): 1959-1975, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31293052

RESUMO

We have previously reported the expression of parathyroid hormone-like hormone (PTHLH) in well-differentiated, Schwannian stroma-rich neuroblastic tumors. The aim of this study was to functionally assess the role of PTHLH and its receptor, PTH1R, in neuroblastoma. Stable knockdown of PTHLH and PTH1R was conducted in neuroblastoma cell lines to investigate the succeeding phenotype induced both in vitro and in vivo. Downregulation of PTHLH reduced MYCN expression and subsequently induced cell cycle arrest, senescence, and migration and invasion impairment in a MYCN-amplified, TP53-mutated neuroblastoma cell line. These phenotypes were associated with reduced tumorigenicity in a murine model. We also show that PTHLH expression is not under the control of the calcium-sensing receptor in neuroblastoma. Conversely, its production is stimulated by epidermal growth factor receptor (EGFR). Accordingly, irreversible EGFR inhibition with canertinib abolished PTHLH expression. The oncogenic role of PTHLH appeared to be a consequence of its intracrine function, as downregulation of its receptor, PTH1R, increased anchorage-independent growth and induced a more undifferentiated, invasive phenotype. Respectively, high PTH1R mRNA expression was found in MYCN nonamplified primary tumors and also significantly associated with other prognostic factors of good outcome. This study provides the first evidence of the dual role of PTHLH in the behavior of neuroblastomas. Moreover, the identification of EGFR as a transcriptional regulator of PTHLH in neuroblastoma provides a novel therapeutic opportunity to promote a less aggressive tumor phenotype through irreversible inhibition of EGFR tyrosine kinase activity.

8.
Commun Biol ; 2: 156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31098401

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30951020

RESUMO

Osteopoikilosis (OPK) is a rare, benign, asymptomatic bone disease causing dense bone lesions, which could be interpreted as bone metastasis. The symmetric distribution, lack of bone destruction, and location differentiate OPK from metastatic disease. It is essential to be aware of this benign condition to prevent diagnostic errors. We present the case of a 10-year-old female patient with the concurrent diagnosis of secreting mixed germ cell tumor with Yolk Salk Tumor compound and OPK. Physical examination disclosed an abdominal mass, and blood tests showed increased alfa-fetoprotein and human chorionic gonadotropin levels. Computed tomography revealed a pelvic tumor associated with multiple radiodense lesions distributed throughout the bone skeleton. Lesions were inactive on scintigraphy and FDG-PET. Pathology of the bone showed normal bone tissue and ruled out metastasis. The patient achieved complete remission after chemotherapy and surgery and remains in continued complete remission 28 months from diagnosis. The genetic analysis confirmed the LEMD3 germline mutation confirming OPK.

10.
Pediatr Blood Cancer ; 66(6): e27690, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30900392

RESUMO

BACKGROUND: Current antiemetic regimens are less effective in children than in adults. Fosaprepitant was recently approved for prevention of chemotherapy-induced nausea and vomiting (CINV) in children aged six months and older. PROCEDURE: The pharmacokinetic (PK)/pharmacodynamic (PD) profile, safety, and tolerability of a single intravenous dose of fosaprepitant administered concomitantly with ondansetron with/without dexamethasone were evaluated in pediatric patients with cancer receiving emetogenic chemotherapy. PK/PD from three doses of fosaprepitant (3.0, 1.2, and 0.4 mg/kg, up to 150, 60, and 20 mg, respectively) were compared with placebo in 2- to 17-year-old subjects; an open-label amendment evaluated a fourth dose (5.0 mg/kg, up to 150 mg) in those under 12 years old. Historical adult PK data were used for comparison. Efficacy was measured as an exploratory endpoint. RESULTS: PK data were evaluable for 167/234 subjects who completed cycle one. Aprepitant exposures were dose proportional; adolescents (12 to 17 years) receiving fosaprepitant 150 mg had exposures similar to adults at the same dose. Higher weight-normalized doses (5 mg/kg) were necessary for children aged < 12 years to achieve comparable adult exposures. The adverse event profile was typical of cancer patients receiving emetogenic chemotherapy. Drug-related adverse events were reported in 16 (6.8%) subjects, with hiccups being most common (n = 5; 2.1%). CONCLUSIONS: Intravenous fosaprepitant was well tolerated by pediatric subjects with cancer, and dose-proportional exposures were observed. Subjects < 12 years old required higher doses to achieve comparable adult exposures.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Morfolinas/farmacologia , Morfolinas/farmacocinética , Náusea/tratamento farmacológico , Neoplasias/tratamento farmacológico , Vômito/tratamento farmacológico , Adolescente , Antieméticos/administração & dosagem , Antieméticos/farmacocinética , Antieméticos/farmacologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Morfolinas/administração & dosagem , Náusea/induzido quimicamente , Neoplasias/patologia , Prognóstico , Distribuição Tecidual , Vômito/induzido quimicamente
12.
Sci Transl Med ; 11(476)2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674657

RESUMO

Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1 VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.

13.
Clin Cancer Res ; 25(4): 1343-1357, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30397176

RESUMO

PURPOSE: Novel targeted therapeutics have transformed the care of subsets of patients with cancer. In pediatric malignancies, however, with simple tumor genomes and infrequent targetable mutations, there have been few new FDA-approved targeted drugs. The cyclin-dependent kinase (CDK)4/6 pathway recently emerged as a dependency in Ewing sarcoma. Given the heightened efficacy of this class with targeted drug combinations in other cancers, as well as the propensity of resistance to emerge with single agents, we aimed to identify genes mediating resistance to CDK4/6 inhibitors and biologically relevant combinations for use with CDK4/6 inhibitors in Ewing. EXPERIMENTAL DESIGN: We performed a genome-scale open reading frame (ORF) screen in 2 Ewing cell lines sensitive to CDK4/6 inhibitors to identify genes conferring resistance. Concurrently, we established resistance to a CDK4/6 inhibitor in a Ewing cell line. RESULTS: The ORF screen revealed IGF1R as a gene whose overexpression promoted drug escape. We also found elevated levels of phospho-IGF1R in our resistant Ewing cell line, supporting the relevance of IGF1R signaling to acquired resistance. In a small-molecule screen, an IGF1R inhibitor scored as synergistic with CDK4/6 inhibitor treatment. The combination of CDK4/6 inhibitors and IGF1R inhibitors was synergistic in vitro and active in mouse models. Mechanistically, this combination more profoundly repressed cell cycle and PI3K/mTOR signaling than either single drug perturbation. CONCLUSIONS: Taken together, these results suggest that IGF1R inhibitors activation is an escape mechanism to CDK4/6 inhibitors in Ewing sarcoma and that dual targeting of CDK4/6 inhibitors and IGF1R inhibitors provides a candidate synergistic combination for clinical application in this disease.

14.
Clin Cancer Res ; 25(7): 2228-2240, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30420447

RESUMO

PURPOSE: Endoglin (ENG; CD105) is a coreceptor of the TGFß family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFß, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease. EXPERIMENTAL DESIGN: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma. RESULTS: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts in a dose-dependent manner. CONCLUSIONS: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.

15.
Ophthalmic Surg Lasers Imaging Retina ; 49(11): 897-900, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30457650

RESUMO

The authors present the first case of macular hole (MH) after a single inhalation of poppers. A 13-year-old girl presented with vision loss in the left eye (OS). Pediatric and neurology exams were normal. Funduscopy revealed bilateral papilledema and yellow foveal spot OS. Optic neuritis was diagnosed and treated. Due to foveal alteration, optical coherence tomography was performed, and MH was diagnosed. Twenty-three-gauge pars plana vitrectomy, peeling of the internal limiting membrane, and SF6 exchange were performed. Postoperatively, vision restoration and MH closure were observed. Although MH mechanism in the poppers context is unknown, the classic surgery is effective. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:897-900.].


Assuntos
Angiofluoresceinografia/métodos , Macula Lutea/patologia , Perfurações Retinianas/induzido quimicamente , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Administração por Inalação , Adolescente , Feminino , Fundo de Olho , Humanos , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/cirurgia , Vitrectomia
16.
17.
Oncotarget ; 9(59): 31397-31410, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30140378

RESUMO

Purpose: Epigenetic regulation is crucial in mammalian development and maintenance of tissue-cell specific functions. Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy. Previous studies in Ewing sarcoma (ES) have shown that the Nucleosome Remodeling Deacetylase (NuRD) complex binds directly to EWS-FLI1 oncoprotein and modulates its transcriptional activity. The role of EWS-FLI1 as a driver of proliferation and transformation in ES is widely known, but the effect of epigenetic drugs on fusion activity remains poorly described. The present study evaluated the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI-2509) on different biological functions in ES and in comparison to monotherapy treatments. Results: The study of proliferation and cell viability showed a synergistic effect in most ES cell lines analyzed. An enhanced effect was also observed in the induction of apoptosis, together with accumulation of cells in G1 phase and a blockage of the migratory capacity of ES cell lines. Treatment, either in monotherapy or in combination, caused a significant decrease of EWS-FLI1 mRNA and protein levels and this effect is mediated in part by fusion gene promoter regulation. The anti-tumor effect of this combination was confirmed in patient-derived xenograft mouse models, in which only the combination treatment led to a statistically significant decrease in tumor volume. Conclusions: The combination of SAHA and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth.

18.
Acta Neuropathol ; 136(2): 227-237, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30019219

RESUMO

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.


Assuntos
Variações do Número de Cópias de DNA/genética , Ependimoma/classificação , Ependimoma/genética , Neoplasias Infratentoriais/classificação , Neoplasias Infratentoriais/genética , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Metilação de DNA/genética , Ependimoma/patologia , Ependimoma/cirurgia , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Infratentoriais/patologia , Neoplasias Infratentoriais/cirurgia , Estimativa de Kaplan-Meier , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Adulto Jovem
19.
Nat Med ; 24(8): 1204-1215, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29967352

RESUMO

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Glioblastoma/patologia , Animais , Neoplasias do Tronco Encefálico/genética , Carcinogênese/patologia , Separação Celular , Criança , Células Clonais , Genótipo , Glioblastoma/genética , Humanos , Camundongos Nus , Fenótipo , Células Tumorais Cultivadas
20.
Mol Cancer Ther ; 17(9): 1902-1916, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29997151

RESUMO

Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n = 17; IC50 range, 81 -1,593 nmol/L), in contrast resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50 > 300 µmol/L). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Mol Cancer Ther; 17(9); 1902-16. ©2018 AACR.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Criança , Estresse do Retículo Endoplasmático/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Interferência de RNA , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Bibliotecas de Moléculas Pequenas/farmacologia
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