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1.
bioRxiv ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38798357

RESUMO

Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function 1 . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) 2 , the most common embryonal brain tumor in children, and pineoblastoma 3 . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST 4 . However, their mechanism of action remains unresolved. Here, we elucidate the mechanistic basis by which KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2, the direct neomorphic target of the substrate receptor. Using deep mutational scanning, we systematically map the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy (cryo-EM) analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat propeller domains. The interface between HDAC1 and one of the KBTBD4 propellers is stabilized by the MB mutations, which directly insert a bulky side chain into the active site pocket of HDAC1. Our structural and mutational analyses inform how this hotspot E3-neo-substrate interface can be chemically modulated. First, our results unveil a converging shape complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface, the aberrant degradation of CoREST, and the growth of KBTBD4-mutant MB models. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions and pharmacological strategies to modulate their action for therapeutic applications.

2.
Neuro Oncol ; 25(10): 1895-1909, 2023 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-37534924

RESUMO

BACKGROUND: Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas. METHODS: We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques. RESULTS: We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study. CONCLUSION: Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar "lineage of origin."


Assuntos
Astrocitoma , Neoplasias Encefálicas , Neoplasias Cerebelares , Ependimoma , Glioma , Meduloblastoma , Criança , Humanos , Animais , Camundongos , Meduloblastoma/genética , Meduloblastoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Astrocitoma/genética , Ependimoma/genética , Ependimoma/patologia , Cerebelo/patologia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia
3.
Nature ; 609(7929): 1012-1020, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131015

RESUMO

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.


Assuntos
Linhagem da Célula , Neoplasias Cerebelares , Meduloblastoma , Metencéfalo , Animais , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/embriologia , Neoplasias Cerebelares/patologia , Cerebelo/embriologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/embriologia , Meduloblastoma/patologia , Metencéfalo/embriologia , Camundongos , Neurônios/patologia , Estudos Prospectivos
4.
Neuro Oncol ; 24(7): 1178-1190, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34935967

RESUMO

BACKGROUND: Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone. METHODS: PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS. Treatment included three 21-day cycles of induction therapy with vorinostat and isotretinoin, cisplatin, vincristine, cyclophosphamide, and etoposide; three 28-day cycles of consolidation therapy with carboplatin and thiotepa followed by stem cell rescue; and twelve 28-day cycles of maintenance therapy with vorinostat and isotretinoin. Patients with M0 medulloblastoma (MB) received focal radiation following consolidation therapy. Molecular classification was by DNA methylation array. RESULTS: Thirty-one patients with median age of 26 months (range 6-46) received treatment on study; 19 (61%) were male. Diagnosis was MB in 20 and supratentorial CNS embryonal tumor in 11. 24/31 patients completed induction therapy within a pre-specified feasibility window of 98 days. Five-year progression-free survival (PFS) and overall survival (OS) for all 31 patients were 55 ± 15 and 61 ± 13, respectively. Five-year PFS was 42 ± 13 for group 3 MB (n = 12); 80 ± 25 for SHH MB (n = 5); 33 ± 19 for embryonal tumor with multilayered rosettes (ETMR, n = 6). CONCLUSION: It was safe and feasible to incorporate vorinostat and isotretinoin into an intensive chemotherapy regimen. Further study to define efficacy in this high-risk group of patients is warranted.


Assuntos
Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Neoplasias Embrionárias de Células Germinativas , Tumores Neuroectodérmicos Primitivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/patologia , Neoplasias Cerebelares/tratamento farmacológico , Criança , Pré-Escolar , Ciclofosfamida , Etoposídeo , Feminino , Humanos , Lactente , Isotretinoína/uso terapêutico , Masculino , Meduloblastoma/patologia , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Estudos Prospectivos , Vincristina , Vorinostat
5.
JAMA Oncol ; 7(9): 1313-1321, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34292305

RESUMO

IMPORTANCE: Brain tumors are the leading cause of disease-related death in children. Medulloblastoma is the most common malignant embryonal brain tumor, and strategies to increase survival are needed. OBJECTIVE: To evaluate therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic agent in children with high-risk medulloblastoma in a randomized clinical trial and, with a correlative biology study, facilitate planned subgroup analysis according to World Health Organization consensus molecular subgroups of medulloblastoma. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical phase 3 trial was conducted from March 2007 to September 2018. Analysis was completed in September 2020. Patients aged 3 to 21 years with newly diagnosed high-risk medulloblastoma from Children's Oncology Group institutions within the US, Canada, Australia, and New Zealand were included. High-risk features included metastasis, residual disease, or diffuse anaplasia. INTERVENTIONS: Patients were randomized to receive 36-Gy craniospinal radiation therapy and weekly vincristine with or without daily carboplatin followed by 6 cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin during and following maintenance. MAIN OUTCOMES AND MEASURES: The primary clinical trial end point was event-free survival, using the log-rank test to compare arms. The primary biology study end point was molecular subgroup classification by DNA methylation array. RESULTS: Of 294 patients with medulloblastoma, 261 were evaluable after central radiologic and pathologic review; median age, 8.6 years (range, 3.3-21.2); 183 (70%) male; 189 (72%) with metastatic disease; 58 (22%) with diffuse anaplasia; and 14 (5%) with greater than 1.5-cm2 residual disease. For all participants, the 5-year event-free survival was 62.9% (95% CI, 55.6%-70.2%) and overall survival was 73.4% (95% CI, 66.7%-80.1%). Isotretinoin randomization was closed early owing to futility. Five-year event-free survival was 66.4% (95% CI, 56.4%-76.4%) with carboplatin vs 59.2% (95% CI, 48.8%-69.6%) without carboplatin (P = .11), with the effect exclusively observed in group 3 subgroup patients: 73.2% (95% CI, 56.9%-89.5%) with carboplatin vs 53.7% (95% CI, 35.3%-72.1%) without (P = .047). Five-year overall survival differed by molecular subgroup (P = .006): WNT pathway activated, 100% (95% CI, 100%-100%); SHH pathway activated, 53.6% (95% CI, 33.0%-74.2%); group 3, 73.7% (95% CI, 61.9%-85.5%); and group 4, 76.9% (95% CI, 67.3%-86.5%). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, therapy intensification with carboplatin improved event-free survival by 19% at 5 years for children with high-risk group 3 medulloblastoma. These findings further support the value of an integrated clinical and molecular risk stratification for medulloblastoma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00392327.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/efeitos adversos , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Humanos , Isotretinoína/efeitos adversos , Masculino , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Adulto Jovem
6.
J Clin Oncol ; 39(24): 2685-2697, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34110925

RESUMO

PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Meduloblastoma/tratamento farmacológico , Meduloblastoma/radioterapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Adulto Jovem
7.
Nature ; 580(7803): 396-401, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32296180

RESUMO

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.


Assuntos
Neoplasias Cerebelares/metabolismo , Mutação em Linhagem Germinativa , Meduloblastoma/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Criança , Feminino , Humanos , Masculino , Meduloblastoma/genética , Linhagem , RNA de Transferência/metabolismo , Fatores de Elongação da Transcrição/genética
8.
Br J Community Nurs ; 25(2): 58-64, 2020 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-32040362

RESUMO

Clear, sensitive and timely communication with palliative and end-of-life (EoL) patients and their families is important. Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) conversations can help patients accept their impending death and achieve a more dignified death. This research explored the experiences and communication strategies of clinical nurse specialists (CNSs) in palliative care when managing DNACPR conversations in the community. Six semi-structured interviews were conducted with community palliative care CNSs, and the results were summarised using autoethnography. Delays in EoL discussions mean that some community palliative care CNSs are having DNACPR conversations at their first meeting with patients. Balancing being clear and sensitive is challenging, especially when patients and families have previously been informed inappropriately or insensitively about DNACPR decisions. DNACPR discussions should be initiated by exploring patient understanding and preferences while emphasising care continuation and a more dignified death.


Assuntos
Planejamento Antecipado de Cuidados , Reanimação Cardiopulmonar/psicologia , Enfermeiros Clínicos , Relações Enfermeiro-Paciente , Ordens quanto à Conduta (Ética Médica)/psicologia , Comunicação , Tomada de Decisões , Família/psicologia , Humanos , Cuidados Paliativos/psicologia , Preferência do Paciente , Pacientes/psicologia , Assistência Terminal/psicologia
9.
Nature ; 572(7767): 74-79, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31341285

RESUMO

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.


Assuntos
Genômica , Meduloblastoma/genética , Meduloblastoma/patologia , Análise de Célula Única , Transcriptoma , Adolescente , Adulto , Animais , Linhagem da Célula , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Ácido Glutâmico/metabolismo , Humanos , Lactente , Meduloblastoma/classificação , Camundongos , Neurônios/metabolismo , Neurônios/patologia
10.
Cancer Res ; 69(10): 4502-9, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19366800

RESUMO

Glioblastoma multiforme (GBM) are aggressive and uniformly fatal primary brain tumors characterized by their diffuse invasion of the normal-appearing parenchyma peripheral to the clinical imaging abnormality. Hypoxia, a hallmark of aggressive tumor behavior often noted in GBMs, has been associated with resistance to therapy, poorer survival, and more malignant tumor phenotypes. Based on the existence of a set of novel imaging techniques and modeling tools, our objective was to assess a hypothesized quantitative link between tumor growth kinetics [assessed via mathematical models and routine magnetic resonance imaging (MRI)] and the hypoxic burden of the tumor [assessed via positron emission tomography (PET) imaging]. Our biomathematical model for glioma kinetics describes the spatial and temporal evolution of a glioma in terms of concentration of malignant tumor cells. This model has already been proven useful as a novel tool to dynamically quantify the net rates of proliferation (rho) and invasion (D) of the glioma cells in individual patients. Estimates of these kinetic rates can be calculated from routinely available pretreatment MRI in vivo. Eleven adults with GBM were imaged preoperatively with (18)F-fluoromisonidazole (FMISO)-PET and serial gadolinium-enhanced T1- and T2-weighted MRIs to allow the estimation of patient-specific net rates of proliferation (rho) and invasion (D). Hypoxic volumes were quantified from each FMISO-PET scan following standard techniques. To control for tumor size variability, two measures of hypoxic burden were considered: relative hypoxia (RH), defined as the ratio of the hypoxic volume to the T2-defined tumor volume, and the mean intensity on FMISO-PET scaled to the blood activity of the tracer (mean T/B). Pearson correlations between RH and the net rate of cell proliferation (rho) reached significance (P < 0.04). Moreover, highly significant positive correlations were found between biological aggressiveness ratio (rho/D) and both RH (P < 0.00003) and the mean T/B (P < 0.0007).


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Divisão Celular/fisiologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Imageamento por Ressonância Magnética/métodos , Invasividade Neoplásica/patologia , Adulto , Simulação por Computador , Meios de Contraste , Feminino , Radioisótopos de Flúor , Gadolínio , Humanos , Aumento da Imagem , Pessoa de Meia-Idade , Misonidazol/análogos & derivados , Tomografia por Emissão de Pósitrons
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