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1.
Mol Cancer Res ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238439

RESUMO

To improve therapeutic responses in glioma patients, new combination therapies that exploit a mechanistic understanding of the inevitable emergence of drug resistance are needed. Intra-tumoral heterogeneity enables a low barrier to resistance in individual glioma patients. We reasoned that targeting two or more fundamental processes that gliomas are particularly dependent upon could result in pleiotropic effects that would reduce the diversity of resistant subpopulations allowing convergence to a more robust therapeutic strategy. In contrast to the cytostatic responses observed with each drug alone, the combination of the HDAC inhibitor panobinostat and the proteasome inhibitor bortezomib synergistically induced apoptosis of adult and pediatric glioma cell lines at clinically achievable doses. Resistance that developed was examined using RNA sequencing and pharmacological screening of resistant versus drug naïve cells. Quinolinic acid phosphoribosyltransferase (QPRT), the rate-determining enzyme for de novo synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan, exhibited particularly high differential gene expression in resistant U87 cells and protein expression in all resistant lines tested. Reducing QPRT expression reversed resistance, suggesting that QPRT is a selective and targetable dependency for the panobinostat-bortezomib resistance phenotype. Pharmacological inhibition of either NAD+ biosynthesis or processes such as DNA repair that consume NAD+ or their simultaneous inhibition with drug combinations, specifically enhanced apoptosis in treatment-resistant cells. Concomitantly, de novo vulnerabilities to known drugs were observed. Implications: These data provide new insights into mechanisms of treatment resistance in gliomas, hold promise for targeting recurrent disease, and provide a potential strategy for further exploration of next generation inhibitors.

2.
Cell Stem Cell ; 26(2): 187-204.e10, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31956038

RESUMO

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvß5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvß5 inhibition. Collectively, our studies identify integrin αvß5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.

3.
Cell ; 179(6): 1330-1341.e13, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31761532

RESUMO

Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.

5.
Sci Transl Med ; 11(504)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391321

RESUMO

Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

6.
Cancer Discov ; 9(11): 1556-1573, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31455674

RESUMO

Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSC). Here, we show that GSCs, differentiated glioblastoma cells (DGC), and nonmalignant brain cultures all displayed robust circadian rhythms, yet GSCs alone displayed exquisite dependence on core clock transcription factors, BMAL1 and CLOCK, for optimal cell growth. Downregulation of BMAL1 or CLOCK in GSCs induced cell-cycle arrest and apoptosis. Chromatin immunoprecipitation revealed that BMAL1 preferentially bound metabolic genes and was associated with active chromatin regions in GSCs compared with neural stem cells. Targeting BMAL1 or CLOCK attenuated mitochondrial metabolic function and reduced expression of tricarboxylic acid cycle enzymes. Small-molecule agonists of two independent BMAL1-CLOCK negative regulators, the cryptochromes and REV-ERBs, downregulated stem cell factors and reduced GSC growth. Combination of cryptochrome and REV-ERB agonists induced synergistic antitumor efficacy. Collectively, these findings show that GSCs co-opt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms. SIGNIFICANCE: Cancer stem cells are highly malignant tumor-cell populations. We demonstrate that GSCs selectively depend on circadian regulators, with increased binding of the regulators in active chromatin regions promoting tumor metabolism. Supporting clinical relevance, pharmacologic targeting of circadian networks specifically disrupted cancer stem cell growth and self-renewal.This article is highlighted in the In This Issue feature, p. 1469.

7.
Cancer Discov ; 9(9): 1248-1267, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201181

RESUMO

Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer landscapes of primary glioblastoma specimens and in vitro GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty-acid synthesis enzyme. Targeting ELOVL2 inhibited glioblastoma cell growth and tumor initiation. ELOVL2 depletion altered cellular membrane phospholipid composition, disrupted membrane structural properties, and diminished EGFR signaling through control of fatty-acid elongation. In support of the translational potential of these findings, dual targeting of polyunsaturated fatty-acid synthesis and EGFR signaling had a combinatorial cytotoxic effect on GSCs. SIGNIFICANCE: Glioblastoma remains a devastating disease despite extensive characterization. We profiled epigenomic landscapes of glioblastoma to pinpoint cell state-specific dependencies and therapeutic vulnerabilities. GSCs utilize polyunsaturated fatty-acid synthesis to support membrane architecture, inhibition of which impairs EGFR signaling and GSC proliferation. Combinatorial targeting of these networks represents a promising therapeutic strategy.See related commentary by Affronti and Wellen, p. 1161.This article is highlighted in the In This Issue feature, p. 1143.

8.
Nature ; 572(7767): 67-73, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31043743

RESUMO

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Evolução Molecular , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Transcrição Genética , Animais , Neoplasias Cerebelares/classificação , Cerebelo/citologia , Cerebelo/embriologia , Cerebelo/metabolismo , Criança , Feminino , Feto/citologia , Glioma/classificação , Glioma/genética , Glioma/patologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Tempo , Transcriptoma/genética
9.
Cancer Cell ; 35(5): 782-797.e8, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31085178

RESUMO

High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Histonas/genética , Histonas/metabolismo , Acetilação , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Cromatina/metabolismo , Elementos Facilitadores Genéticos/efeitos dos fármacos , Epigenômica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Mutação
10.
J Exp Med ; 216(5): 1071-1090, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-30948495

RESUMO

Glioblastoma is an incurable brain cancer characterized by high genetic and pathological heterogeneity. Here, we mapped active chromatin landscapes with gene expression, whole exomes, copy number profiles, and DNA methylomes across 44 patient-derived glioblastoma stem cells (GSCs), 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super-enhancer (SE)-associated genes and the core transcription factors that establish SEs and maintain GSC identity. GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core transcription factor regulatory programs. Group-specific transcription factors enforce GSC identity; they exhibit higher activity in glioblastomas versus NSCs, are associated with poor clinical outcomes, and are required for glioblastoma growth in vivo. Although transcription factors are commonly considered undruggable, group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches.

12.
Future Oncol ; 14(30): 3175-3186, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30418040

RESUMO

Advances in genomic, transcriptomic and epigenomic profiling now identifies pediatric ependymoma as a defined biological entity. Molecular interrogation has segregated these tumors into distinct biological subtypes based on anatomical location, age and clinical outcome, which now defines the need to tailor therapy even for histologically similar tumors. These findings now provide reasons for a paradigm shift in therapy, which should profile future clinical trials focused on targeted therapeutic strategies and risk-based treatment. The need to diagnose and differentiate the aggressive variants, which include the posterior fossa group A and the supratentorial RELA fusion subtypes, is imperative to escalate therapy and improve survival.


Assuntos
Ependimoma/terapia , Animais , Ensaios Clínicos como Assunto , Terapia Combinada , Gerenciamento Clínico , Ependimoma/diagnóstico , Ependimoma/etiologia , Ependimoma/mortalidade , Humanos , Resultado do Tratamento
13.
Cell ; 175(5): 1228-1243.e20, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30392959

RESUMO

Genetic drivers of cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N6-methyladenine (N6-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N6-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N6-mA levels were dynamically regulated by the DNA demethylase ALKBH1, depletion of which led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility. Targeting the N6-mA regulator ALKBH1 in patient-derived human glioblastoma models inhibited tumor cell proliferation and extended the survival of tumor-bearing mice, supporting this novel DNA modification as a potential therapeutic target for glioblastoma. Collectively, our results uncover a novel epigenetic node in cancer through the DNA modification N6-mA.


Assuntos
Adenina/análogos & derivados , Neoplasias Encefálicas/patologia , Metilação de DNA , Glioblastoma/patologia , Adenina/análise , Adenina/química , Adulto , Idoso , Homólogo AlkB 1 da Histona H2a Dioxigenase/antagonistas & inibidores , Homólogo AlkB 1 da Histona H2a Dioxigenase/genética , Homólogo AlkB 1 da Histona H2a Dioxigenase/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Hipóxia Celular , Criança , Epigenômica , Feminino , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Heterocromatina/metabolismo , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína Supressora de Tumor p53/metabolismo
14.
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
15.
Acta Neuropathol ; 136(2): 211-226, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29909548

RESUMO

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.


Assuntos
Ependimoma/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Infratentoriais/genética , Mutação/genética , Proteínas Oncogênicas/genética , Metilação de DNA , Ependimoma/classificação , Ependimoma/patologia , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Histonas/genética , Humanos , Neoplasias Infratentoriais/classificação , Neoplasias Infratentoriais/patologia , Masculino , Transfecção
16.
Cell Stem Cell ; 23(1): 86-100.e6, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29910151

RESUMO

Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Because of their unique biology, developing effective methods to eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic overexpression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential. Further, we report that the central metabolic stress regulator AMPK is also intrinsically activated in LSC populations and is upstream of FIS1. Inhibition of AMPK signaling recapitulates the biological effect of FIS1 loss. These data suggest a model in which LSCs co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autorrenovação Celular , Leucemia Mieloide Aguda/patologia , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Células Cultivadas , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos
17.
Cell Stem Cell ; 22(4): 514-528.e5, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625067

RESUMO

Glioblastoma is the most lethal primary brain tumor; however, the crosstalk between glioblastoma stem cells (GSCs) and their supportive niche is not well understood. Here, we interrogated reciprocal signaling between GSCs and their differentiated glioblastoma cell (DGC) progeny. We found that DGCs accelerated GSC tumor growth. DGCs preferentially expressed brain-derived neurotrophic factor (BDNF), whereas GSCs expressed the BDNF receptor NTRK2. Forced BDNF expression in DGCs augmented GSC tumor growth. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, revealing preferential VGF expression by GSCs, which patient-derived tumor models confirmed. VGF serves a dual role in the glioblastoma hierarchy by promoting GSC survival and stemness in vitro and in vivo while also supporting DGC survival and inducing DGC secretion of BDNF. Collectively, these data demonstrate that differentiated glioblastoma cells cooperate with stem-like tumor cells through BDNF-NTRK2-VGF paracrine signaling to promote tumor growth.


Assuntos
Neoplasias Encefálicas/metabolismo , Progressão da Doença , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Neoplasias Encefálicas/patologia , Diferenciação Celular , Glioblastoma/patologia , Humanos , Células-Tronco Neoplásicas/patologia
18.
Curr Neuropharmacol ; 16(7): 1045-1058, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29189165

RESUMO

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children, currently treated uniformly based on histopathology and clinico-radiological risk stratification leading to unpredictable relapses and therapeutic failures. Identification of molecular subgroups have thrown light on the reasons for these and now reveals clues to profile molecularly based personalized therapy against these tumors. METHODS: Research and online contents were evaluated for pediatric medulloblastoma which included latest information on the molecular subgroups and their clinical relevance and update on efforts to translate them into clinics. RESULTS: Scientific endeavors over the last decade have clearly identified four molecular variants (WNT, SHH, Group 3, and Group 4) and their demographic, genomic, and epigenetic profile. Latest revelations include significant heterogeneity within these subgroups and 12 different subtypes of MB are now identified with disparate outcomes and biology. These findings have important implications for stratification and profiling future clinical trials against these formidable tumors. CONCLUSION: With the continued outpouring of genomic/epigenomic data of these molecular subgroups and evolution of further subtypes in each subgroup, the challenge lies in comprehensive evaluation of these informations. Current and future endeavors are now needed to profile personalized therapy for each child based on the molecular risk stratification of medulloblastoma, with a hope to improve survival outcome and reduce relapses.


Assuntos
Neoplasias Encefálicas/terapia , Meduloblastoma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Criança , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo
19.
Nature ; 553(7686): 101-105, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29258295

RESUMO

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.


Assuntos
Elementos Facilitadores Genéticos/genética , Ependimoma/tratamento farmacológico , Ependimoma/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/genética , Terapia de Alvo Molecular , Oncogenes/genética , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Ependimoma/classificação , Ependimoma/patologia , Feminino , Humanos , Camundongos , Medicina de Precisão , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nat Med ; 23(11): 1352-1361, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29035367

RESUMO

Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.


Assuntos
Neoplasias Encefálicas/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Glioblastoma/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Complexo Repressor Polycomb 1/antagonistas & inibidores , Animais , Epigênese Genética , Humanos , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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