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1.
Phytother Res ; 34(3): 591-600, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32011040

RESUMO

Icariin (ICA) is obtained from Epimedium brevicornu maxim and exploited to remedy miscellaneous cancers. But the role of ICA in medulloblastoma remains hazy. The research delved into the antitumor activity of ICA in medulloblastoma DAOY cells. ICA with diverse concentrations was utilized to stimulate DAOY cells, and the biological functions of ICA in medulloblastoma DAOY cells were examined. Then, the relative SPARC expression was determined in ICA-managed DAOY cells, and the pc-SPARC vector was transfected into DAOY cells to further probe the influence of SPARC and JAK1/STAT3 and PI3K/AKT pathways in ICA-managed DAOY cells. A xenograft model was established to investigate the function of ICA in vivo. ICA restrained cell viability, expedited apoptosis, prohibited cell migration and invasion, and meanwhile affected the associative factors expression in DAOY cells. Additionally, SPARC expression was declined in ICA-stimulated DAOY cells. Overexpressed SPARC reversed the functions of ICA in above-involved cell behaviors of DAYO cells and the correlative protein levels. Besides, ICA notably frustrated JAK1/STAT3 and PI3K/AKT activations in DAOY cells. Beyond that, ICA prohibited tumor formation in vivo. The results concluded that ICA exhibited the antitumor activity in DAOY cells via decreasing SPARC and inactivating JAK1/STAT3 and PI3K/AKT pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Cerebelares/tratamento farmacológico , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Meduloblastoma/tratamento farmacológico , Osteonectina/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Invasividade Neoplásica/prevenção & controle , Proteína Oncogênica v-akt/genética , Proteína Oncogênica v-akt/metabolismo , Osteonectina/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
2.
J Clin Pathol ; 73(5): 243-249, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32034059

RESUMO

Medulloblastoma (MB) is the most common malignant primary intracranial neoplasm diagnosed in childhood. Although numerous efforts have been made during the past few years to exploit novel targeted therapies for this aggressive neoplasm, there still exist substantial hitches hindering successful management of MB. Lately, progress in cancer biology has shown evidence that a subpopulation of cells within the tumour, namely cancer stem cells (CSCs), are thought to be responsible for the resistance to most chemotherapeutic agents and radiation therapy, accounting for cancer recurrence. Hence, it is crucial to identify the molecular signatures and genetic aberrations that characterise those CSCs and develop therapies that specifically target them. In this review, we aim to give an overview of the main genetic and molecular cues that depict MB-CSCs and provide a synopsis of the novel therapeutic approaches that specifically target this population of cells to attain enhanced antitumorous effects and therefore overcome resistance to therapy.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Neoplasias Cerebelares , Resistencia a Medicamentos Antineoplásicos/fisiologia , Meduloblastoma , Células-Tronco Neoplásicas/fisiologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Meduloblastoma/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos
3.
Pediatr Blood Cancer ; 67(1): e28012, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31544362

RESUMO

BACKGROUND: Most childhood medulloblastoma (MB) cases are curable using multimodal treatment, including craniospinal irradiation (CSI). However, late effects are a serious problem for survivors. This prospective registry study evaluated Japanese patients to determine whether a reduced radiation dose was feasible. PATIENTS AND METHODS: Patients with MB were classified as an infant group (<3 years old) and a high-risk (HR) group (≥3 years old with metastasis). The HR group received intrathecal methotrexate (IT-MTX) and high-dose chemotherapy (HDC) using thiotepa and melphalan, as well as concomitant radiotherapy with a recommended CSI dose of 18 Gy and a total local dose of 50 Gy. Radiotherapy was only considered for infants if residual tumors were present after the HDC. RESULTS: Between 1997 and 2006, we identified 28 HR patients (M1: 9, M2/3: 19) and 17 infant patients (M0: 11, M1: 3, M2/3: 3). During the median follow-up of 9.4 years for the entire HR group, the 5-year progression-free survival (PFS) rate was 82.1 ± 7.2% and the 5-year overall survival (OS) rate was 85.7 ± 6.6%. Subanalyses of the patients who received the recommended treatment revealed that the 5-year PFS and OS rates were both 90.5 ± 6.4%. In the infant group, the 5-year PFS rate was 52.9 ± 12.1% and the 5-year OS rate was 51.8 ± 12.4%. There were no serious adverse events associated with the IT-MTX and HDC treatments. CONCLUSION: Intensified chemotherapy using HDC and IT-MTX might allow for a reduced prophylactic radiation dose in patients with MB with metastases. Further studies are needed to validate these findings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Sistema de Registros/estatística & dados numéricos , Adolescente , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/radioterapia , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Terapia Combinada , Irradiação Craniana , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Injeções Espinhais , Masculino , Meduloblastoma/patologia , Meduloblastoma/radioterapia , Melfalan/administração & dosagem , Metotrexato/administração & dosagem , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
4.
Pediatr Blood Cancer ; 67(1): e28032, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31595663

RESUMO

AIM: To assess objective response after two cycles of temozolomide and topotecan (TOTEM) in children with refractory or relapsed miscellaneous extracranial solid and central nervous system (CNS) tumors, including medulloblastoma and primitive neuroectodermal tumors (PNET). PROCEDURE: Multicenter, nonrandomized, phase 2 basket trial including children with solid tumors, completed by a one-stage design confirmatory cohort for medulloblastoma, and an exploratory cohort for PNET. Main eligibility criteria were refractory/relapsed measurable disease and no more than two prior treatment lines. Temozolomide was administered orally at 150 mg/m2 /day followed by topotecan at 0.75 mg/m2 /day intravenously for five consecutive days every 28 days. Tumor response was assessed every two cycles according to WHO criteria and reviewed independently. RESULTS: Thirty-two patients were enrolled and treated in the miscellaneous solid tumor and 33 in the CNS strata; 20 patients with medulloblastoma and six with PNET were included in the expansion cohorts. The median age at inclusion was 10.0 years (range, 0.9-20.9). In the basket cohorts, confirmed complete and partial responses were observed in one glioma, four medulloblastoma, and one PNET, leading to the extension. The overall objective response rate (ORR) in medulloblastoma was 28% (95% CI, 12.7-47.2) with 1/29 complete and 7/29 partial responses, those for PNET 10% (95% CI, 0.3-44.5). Post hoc Bayesian analysis estimates that the true ORR in medulloblastoma is probably between 20% and 30% and below 20% in PNET. The most common treatment-related toxicities of the combination therapy were hematologic. CONCLUSIONS: Temozolomide-topotecan results in significant ORR in children with recurrent and refractory medulloblastoma with a favorable toxicity profile.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Meduloblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Teorema de Bayes , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Meduloblastoma/patologia , Recidiva Local de Neoplasia/patologia , Tumores Neuroectodérmicos Primitivos/patologia , Prognóstico , Taxa de Sobrevida , Temozolomida/administração & dosagem , Topotecan/administração & dosagem , Adulto Jovem
5.
Cancer Metastasis Rev ; 38(4): 683-694, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31797181

RESUMO

Wilms tumor (or nephroblastoma), rhabdomyosarcoma, and medulloblastoma, common embryonal tumors in children, can occasionally occur in adults, for whom survival is significantly inferior than pediatric patients. Available data on adults with Wilms tumor consist of case or case series reports. Among other factors, the unfamiliarity of adult oncologists and pathologists with nephroblastoma and consequent delays in initiating the appropriate risk-adapted chemotherapy may negatively influence outcomes. The survival decrement in adults with rhabdomyosarcoma has been attributed to the lack of centralized care, the inconsistent use of standard protocol-driven multimodal therapy, and lower chemotherapy tolerance in adult patients. In children with medulloblastoma, evidence from randomized clinical trials has led to risk-tailored therapies tuned on histology, extent of initial disease, and biological features. Such refinements are still missing for adults due to the lack of similar trials and studies that might provide the same or a different understanding regarding patients' individual prognosis, treatment morbidity, and quality of life. Recent experiences have suggested that applying or adjusting pediatric protocols to adult patients with these tumors is feasible and can improve survival. Here, we provide an evaluation of the current evidence for the management of Wilms tumor, rhabdomyosarcoma, and medulloblastoma arising in adults. This review aims to promote the referral of adolescents and adults with pediatric tumors to pediatric centers for inclusion into pediatric protocols, or into protocols and studies specifically designed for that age group with the cooperation between pediatric and adult oncologists.


Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Renais/diagnóstico , Meduloblastoma/diagnóstico , Rabdomiossarcoma/diagnóstico , Tumor de Wilms/diagnóstico , Adulto , Fatores Etários , Neoplasias Cerebelares/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Tumor de Wilms/tratamento farmacológico
6.
Nat Commun ; 10(1): 5829, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863004

RESUMO

Targeting oncogenic pathways holds promise for brain tumor treatment, but inhibition of Sonic Hedgehog (SHH) signaling has failed in SHH-driven medulloblastoma. Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq and lineage tracing, we analyzed cellular diversity in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. In untreated tumors, we find expected stromal cells and tumor-derived cells showing either a spectrum of neural progenitor-differentiation states or glial and stem cell markers. Vismodegib reduces the proliferative population and increases differentiation. However, specific cell types in vismodegib-treated tumors remain proliferative, showing either persistent SHH-pathway activation or stem cell characteristics. Our data show that even in tumors with a single pathway-activating mutation, diverse mechanisms drive tumor growth. This diversity confers early resistance to targeted inhibitor therapy, demonstrating the need to target multiple pathways simultaneously.


Assuntos
Neoplasias Cerebelares/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Hedgehog/antagonistas & inibidores , Meduloblastoma/genética , Transdução de Sinais/genética , Anilidas/farmacologia , Anilidas/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/patologia , Cerebelo/citologia , Cerebelo/patologia , Feminino , Mutação com Ganho de Função , Proteínas Hedgehog/genética , Humanos , Masculino , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular/métodos , Proteína MyoD/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/uso terapêutico , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Receptor Smoothened/genética , Fatores de Transcrição HES-1/genética
7.
BMC Cancer ; 19(1): 1056, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694585

RESUMO

BACKGROUND: MYC amplification or overexpression is common in Group 3 medulloblastoma and is associated with the worst prognosis. Recently, protein arginine methyl transferase (PRMT) 5 expression has been closely associated with aberrant MYC function in various cancers, including brain tumors such as glioblastoma. However, the role of PRMT5 and its association with MYC in medulloblastoma have not been explored. Here, we report the role of PRMT5 as a novel regulator of MYC and implicate PRMT5 as a potential therapeutic target in MYC-driven medulloblastoma. METHODS: Expression and association between PRMT5 and MYC in primary medulloblastoma tumors were investigated using publicly available databases. Expression levels of PRMT5 protein were also examined using medulloblastoma cell lines and primary tumors by western blotting and immunohistochemistry, respectively. Using MYC-driven medulloblastoma cells, we examined the physical interaction between PRMT5 and MYC by co-immunoprecipitation and co-localization experiments. To determine the functional role of PRMT5 in MYC-driven medulloblastoma, PRMT5 was knocked-down in MYC-amplified cells using siRNA and the consequences of knockdown on cell growth and MYC expression/stability were investigated. In vitro therapeutic potential of PRMT5 in medulloblastoma was also evaluated using a small molecule inhibitor, EPZ015666. RESULTS: We observed overexpression of PRMT5 in MYC-driven primary medulloblastoma tumors and cell lines compared to non-MYC medulloblastoma tumors and adjacent normal tissues. We also found that high expression of PRMT5 is inversely correlated with patient survival. Knockdown of PRMT5 using siRNA in MYC-driven medulloblastoma cells significantly decreased cell growth and MYC expression. Mechanistically, we found that PRMT5 physically associated with MYC by direct protein-protein interaction. In addition, a cycloheximide chase experiment showed that PRMT5 post-translationally regulated MYC stability. In the context of therapeutics, we observed dose-dependent efficacy of PRMT5 inhibitor EPZ015666 in suppressing cell growth and inducing apoptosis in MYC-driven medulloblastoma cells. Further, the expression levels of PRMT5 and MYC protein were downregulated upon EPZ015666 treatment. We also observed a superior efficacy of this inhibitor against MYC-amplified medulloblastoma cells compared to non-MYC-amplified medulloblastoma cells, indicating specificity. CONCLUSION: Our results reveal the regulation of MYC oncoprotein by PRMT5 and suggest that targeting PRMT5 could be a potential therapeutic strategy for MYC-driven medulloblastoma.


Assuntos
Neoplasias Cerebelares/metabolismo , Meduloblastoma/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Humanos , Isoquinolinas/farmacologia , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Ligação Proteica , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Proteínas Proto-Oncogênicas c-myc/genética , Pirimidinas/farmacologia , Interferência de RNA , Análise de Sobrevida
9.
EMBO Mol Med ; 11(8): e9830, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31328883

RESUMO

Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFß/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFß/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.


Assuntos
Comunicação Autócrina , Neoplasias Cerebelares/metabolismo , Subunidades beta de Inibinas/metabolismo , Meduloblastoma/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidades beta de Inibinas/genética , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Meduloblastoma/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Nus , Fosforilação , Pirazóis/farmacologia , Quinolinas/farmacologia , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta3/genética , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cancer Radiother ; 23(5): 370-377, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31331843

RESUMO

PUPOSE: Medulloblastoma is the most common primary malignant central nervous system tumor in childhood, accounting for 16-25% of cases (1). New treatment approaches have led to improved survival rates; however toxicities are still a major concern. PATIENTS AND METHODS: Participants were selected from the records of patients who were treated with craniospinal irradiation for medulloblastoma. Between January 2008 and December 2012, 62 patients were diagnosed with medulloblastoma at the national institute of oncology Rabat, 27 patients were still alive at the time of the study, of which n=16 patients were included in the study. The mean age of patients at the time of the study was 9.6 years. All children were treated with radiation therapy and chemotherapy, according to standard protocols. Median follow-up between treatment and evaluation was 4 years. All the children were assessed with the Wechsler Intelligence Scale for Children - fourth Edition (WISC-IV) three to five years after completion of radiotherapy. The test was administered by two well-trained psychologists in a distraction-free environment. The scoring was then reviewed by a psychologist from Brooklyn College. RESULTS: The mean standard score Full-Scale Intelligence Quotient (FSIQ) (M=63, SD=12.6) was found to be in the extremely low range and in the 1st percentile rank (PR), compared to the general population. All the measured primary index scales were below typical performance: verbal comprehension (M=67.7, SD=13.1), perceptual reasoning (M=63.5, SD=13.8) and processing speed (M=62.7, SD=15.5) were all found to be in the extremely low range, while xorking memory (M=75.5, SD=10.8) was found to be in the borderline range compared to the general population. To identify factors influencing the results, we performed both univariate and multivariate analyses. Age at the time of radiotherapy, initial clinical stage, total cranial radiotherapy dose, socioeconomic status, and the time of evaluation were identified as significantly impacting cognitive scores in the univariate analysis. In the multivariate analysis, only age at the time of radiotherapy and initial clinical stage remained factors significantly impacting cognitive outcomes with P=0.001 and P<0.001 respectively. CONCLUSION: Our study is evidence that tremendous efforts are still to be made in low-income countries to correctly measure neurocognitive dysfunction in medulloblastoma survivors and to prepare those patients to a typical life after the completion of treatment.


Assuntos
Neoplasias Cerebelares/radioterapia , Irradiação Craniana/efeitos adversos , Meduloblastoma/radioterapia , Transtornos Neurocognitivos/etiologia , Fatores Etários , Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Criança , Pré-Escolar , Terapia Combinada , Seguimentos , Substância Cinzenta/lesões , Substância Cinzenta/patologia , Hipocampo/lesões , Hipocampo/patologia , Humanos , Meduloblastoma/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Transtornos Neurocognitivos/patologia , Tamanho do Órgão , Modelos de Riscos Proporcionais , Escalas de Wechsler , Substância Branca/lesões , Substância Branca/patologia
12.
Nat Commun ; 10(1): 2400, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160565

RESUMO

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.


Assuntos
Azepinas/farmacologia , Ciclo Celular/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Proteínas/antagonistas & inibidores , Triazóis/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sistemas CRISPR-Cas , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Neoplasias Cerebelares/genética , Ciclina D2/efeitos dos fármacos , Ciclina D2/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Humanos , Meduloblastoma/genética , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Fase S/efeitos dos fármacos
13.
Exp Mol Pathol ; 109: 42-50, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085184

RESUMO

Subfertility is a major concern of long-term cancer survivors at the reproductive age. We have previously demonstrated that a potent humanin analogue, HNG, protected chemotherapy-induced apoptosis in germ cells but not cancer cells in a metastatic melanoma allograft model. In this study, we utilized severe combined immuno-deficiency (SCID) mice bearing human medulloblastoma to study the effect of HNG in Temozolomide (TMZ) induced male germ cell apoptosis and white blood cell (WBC) suppression. Human medulloblastoma DAOY cells were injected subcutaneously into the right flank of male SCID mice. Three weeks later, groups of tumor-bearing mice received one of the following treatments: vehicle, HNG, TMZ, or TMZ + HNG. 24 h after last injection, the tumors weights, complete blood counts, liver and spleen weights, male germ cell apoptosis was assessed. HNG did not affect TMZ's significant anti-tumor action. HNG significantly prevented TMZ-induced germ cell apoptosis and attenuated the suppressed total WBC and granulocyte counts in SCID mice with or without TMZ treatment. HNG also attenuated TMZ-induced body weight loss and decrease of spleen and liver weights. In conclusion, HNG ameliorated TMZ-induced germ cell apoptosis; WBC and granulocytes loss; and decreased body/organ weights without compromising the TMZ's anti-cancer action on medulloblastoma xenografts in SCID mice.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Meduloblastoma/tratamento farmacológico , Espermatozoides/efeitos dos fármacos , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Neoplasias Cerebelares/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Meduloblastoma/patologia , Camundongos SCID , Tamanho do Órgão/efeitos dos fármacos , Espermatozoides/citologia , Baço/efeitos dos fármacos , Baço/patologia , Carga Tumoral/efeitos dos fármacos
14.
Radiother Oncol ; 136: 50-55, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31015129

RESUMO

BACKGROUND AND PURPOSE: While survival times after treatment of medulloblastoma are increasing, little is known about radiochemotherapy (RCT)-induced cerebrovascular changes. High resolution vessel wall imaging (VWI) sequences are an emerging tool for the evaluation of cerebrovascular diseases. We performed VWI in medulloblastoma long-term survivors to screen for late sequelae of RCT. MATERIAL AND METHODS: Twenty-two pediatric medulloblastoma survivors (mean age 25.8 years (10-53 years); 16.3 years (mean) post primary RCT (range 1-45 years)) underwent 2D VWI-MRI. Vessel wall thickening, contrast enhancement and luminal narrowing were analyzed. The findings were correlated with the patients' radiation protocols. RESULTS: Vessel wall changes were observed the intracranial internal carotid artery (ICA) and the vertebrobasilar circulation (VBC) in 14 of 22 patients (63.6%). In multivariate analysis, time after RCT (OR = 1.38, p < 0.05) was strongest independent predictor for development of vessel wall alterations. The dose of radiation was not a relevant predictor. CONCLUSIONS: With longer follow-up time intracranial vessel wall changes are observed more frequently in medulloblastoma survivors. Thus VWI is a useful tool to monitor vessel wall alterations of cranially irradiated patients, creating the prerequisite for further treatment of late sequelae.


Assuntos
Artéria Carótida Interna/efeitos da radiação , Neoplasias Cerebelares/radioterapia , Artérias Cerebrais/efeitos da radiação , Circulação Cerebrovascular/efeitos da radiação , Meduloblastoma/radioterapia , Adolescente , Sobreviventes de Câncer , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/etiologia , Artéria Carótida Interna/diagnóstico por imagem , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/tratamento farmacológico , Artérias Cerebrais/diagnóstico por imagem , Criança , Pré-Escolar , Irradiação Craniana/efeitos adversos , Irradiação Craniana/métodos , Feminino , Humanos , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/etiologia , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética/métodos , Masculino , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/tratamento farmacológico , Lesões por Radiação/diagnóstico por imagem , Lesões por Radiação/etiologia
15.
BMC Cancer ; 19(1): 300, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943920

RESUMO

BACKGROUND: Solid tumours are less oxygenated than normal tissues. This is called tumour hypoxia and leads to resistance to radiotherapy and chemotherapy. The molecular mechanisms underlying such resistance have been investigated in a range of tumour types, including the adult brain tumours glioblastoma, yet little is known for paediatric brain tumours. Medulloblastoma (MB) is the most common malignant brain tumour in children. We aimed to elucidate the impact of hypoxia on the sensitivity of MB cells to chemo- and radiotherapy. METHODS: We used two MB cell line (D283-MED and MEB-Med8A) and a widely used glioblastoma cell line (U87MG) for comparison. We applied a range of molecular and cellular techniques to measure cell survival, cell cycle progression, protein expression and DNA damage combined with a transcriptomic micro-array approach in D283-MED cells, for global gene expression analysis in acute and chronic hypoxic conditions. RESULTS: In D283-MED and U87MG, chronic hypoxia (5 days), but not acute hypoxia (24 h) induced resistance to chemotherapy and X-ray irradiation. This acquired resistance upon chronic hypoxia was present but less pronounced in MEB-Med8A cells. Using transcriptomic analysis in D283-MED cells, we found a large transcriptional remodelling upon long term hypoxia, in particular the expression of a number of genes involved in detection and repair of double strand breaks (DSB) was altered. The levels of Nibrin (NBN) and MRE11, members of the MRN complex (MRE11/Rad50/NBN) responsible for DSB recognition, were significantly down-regulated. This was associated with a reduction of Ataxia Telangiectasia Mutated (ATM) activation by etoposide, indicating a profound dampening of the DNA damage signalling in hypoxic conditions. As a consequence, p53 activation by etoposide was reduced, and cell survival enhanced. Whilst U87MG shared the same dampened p53 activity, upon chemotherapeutic drug treatment in chronic hypoxic conditions, these cells used a different mechanism, independent of the DNA damage pathway. CONCLUSION: Together our results demonstrate a new mechanism explaining hypoxia-induced resistance involving the alteration of the response to DSB in D283-MED cells, but also highlight the cell type to cell type diversity and the necessity to take into account the differing tumour genetic make-up when considering re-sensitisation therapeutic protocols.


Assuntos
Proteínas de Ciclo Celular/genética , Neoplasias Cerebelares/genética , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica/métodos , Meduloblastoma/genética , Proteínas Nucleares/genética , Ciclo Celular , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias Cerebelares/tratamento farmacológico , Etoposídeo/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Meduloblastoma/tratamento farmacológico , Análise de Sequência com Séries de Oligonucleotídeos , Tolerância a Radiação
16.
Gene ; 705: 67-76, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991098

RESUMO

Medulloblastoma (MB) is characterized by highly invasive embryonal neuro-epithelial tumors that metastasize via cerebrospinal fluid. MB is difficult to treat and the chemotherapy is associated with significant toxicities and potential long-term disabilities. Previously, we showed that small molecule, clotam (tolfenamic acid: TA) inhibited MB cell proliferation and tumor growth in mice by targeting, survivin. Overexpression of survivin is associated with aggressiveness and poor prognosis in several cancers, including MB. The aim of this study was to test combination treatment involving Vincristine® (VCR), a standard chemotherapeutic drug for MB and TA against MB cells. DAOY and D283 MB cells were treated with 10 µg/mL TA or VCR (DAOY: 2 ng/mL; D283: 1 ng/mL) or combination (TA + VCR). These optimized doses were lower than individual IC50 values. The effect of single or combination treatment on cell viability (CellTiterGlo kit), Combination Index (Chou-Talalay method based on median-drug effect analysis), activation of apoptosis and cell cycle modulation (by flow cytometry using Annexin V and propidium iodide respectively) and the expression of associated markers including survivin (Western immunoblot) were determined. Combination Index showed moderate synergistic cytotoxic effect in both cells. When compared to individual agents, the combination of TA and VCR increased MB cell growth inhibition, induced apoptosis and caused cell cycle (G2/M phase) arrest. Survivin expression was also decreased by the combination treatment. TA is effective for inducing the anti-proliferative response of VCR in MB cells. MB has four distinct genetic/molecular subgroups. Experiments were conducted with MB cells representing two subgroups (DAOY: SHH group; D283: group 4/3). TA-induced inhibition of survivin expression potentially destabilizes mitotic microtubule assembly, sensitizing MB cells and enhancing the efficacy of VCR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Cerebelares/metabolismo , Meduloblastoma/metabolismo , Survivina/metabolismo , Vincristina/farmacologia , ortoaminobenzoatos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Relação Dose-Resposta a Droga , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Meduloblastoma/tratamento farmacológico
17.
Mol Cancer Res ; 17(6): 1305-1315, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842251

RESUMO

Medulloblastoma is a highly malignant pediatric brain tumor associated with poor outcome. Developing treatments that target the cancer stem cell (CSC) population in medulloblastoma are important to prevent tumor relapse and induce long-lasting clinical responses. We utilized medulloblastoma neurospheres that display CSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. Of all class IA PI3Ks, only the PI3Kα isoform was required for sphere formation by medulloblastoma cells. Knockdown of p110α, but not p110ß or p110δ, significantly disrupted cancer stem cell frequencies as determined by extreme limiting dilution analysis (ELDA), indicating an essential role for the PI3Kα catalytic isoform in medulloblastoma CSCs. Importantly, pharmacologic inhibition of the MAPK-interacting kinase (MNK) enhanced the antineoplastic effects of targeted PI3Kα inhibition in medulloblastoma. This indicates that MNK signaling promotes survival in medulloblastoma, suggesting dual PI3Kα and MNK inhibition may provide a novel approach to target and eliminate medulloblastoma CSCs. We also observed a significant reduction in tumor formation in subcutaneous and intracranial mouse xenograft models, which further suggests that this combinatorial approach may represent an efficient therapeutic strategy for medulloblastoma. IMPLICATIONS: These findings raise the possibility of a unique therapeutic approach for medulloblastoma, involving MNK targeting to sensitize medulloblastoma CSCs to PI3Kα inhibition.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Cerebelares/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , ATPases Transportadoras de Cobre/antagonistas & inibidores , Meduloblastoma/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Cerebelares/metabolismo , Feminino , Humanos , Meduloblastoma/metabolismo , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
Pediatr Blood Cancer ; 66(6): e27694, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30848061

RESUMO

Most medulloblastoma protocols worldwide include vincristine during radiation and chemotherapy. A significant dose-limiting toxicity is peripheral neuropathy; however, there is a paucity of data to support the view that omission of vincristine does not impact survival. Herein we report two adolescent patients with Group 4 and SHH medulloblastoma, where vinblastine successfully replaced vincristine with resolution of their peripheral neuropathy. We furthermore show vinblastine is highly active in vitro and demonstrates equivalent antitumoral activity compared to vincristine. Substitution of vincristine with vinblastine in future studies should be considered for all patients with medulloblastoma, particularly those with hereditary neuropathy, severe vincristine toxicity, and adults.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Vimblastina/uso terapêutico , Adolescente , Neoplasias Cerebelares/patologia , Feminino , Humanos , Meduloblastoma/patologia , Prognóstico
19.
Cancer Epidemiol ; 59: 71-74, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30703618

RESUMO

INTRODUCTION: Methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) has been identified as a potential prognostic biomarker of outcomes in various cancers. We evaluated the prognostic value of blood-derived mdNLR within a retrospective cohort of pediatric medulloblastoma patients. MATERIALS AND METHODS: DNA methylation was measured in archival peripheral blood samples collected on 56 pediatric medulloblastoma patients. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between mdNLR and survival were evaluated using Cox proportional hazard models. RESULTS: Compared to patients who were alive at last follow-up (n = 43), the mean mdNLR value was slightly higher in deceased patients (n = 13) (12.3 vs. 5.2,P = 0.163). Elevated log-transformed mdNLR was suggestively associated with an increased likelihood of death in unadjusted models (HR=1.43, 95%CI: 0.92-2.22) and significantly associated with mortality in adjusted models (HR=1.61, 95%CI: 1.01-2.58). DISCUSSION: Future work is warranted to investigate the relationship between mdNLR outcomes in specific pediatric medulloblastoma molecular subgroups.


Assuntos
Neoplasias Cerebelares/genética , Metilação de DNA , Meduloblastoma/genética , Adolescente , Neoplasias Cerebelares/sangue , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Contagem de Leucócitos , Linfócitos , Masculino , Meduloblastoma/sangue , Meduloblastoma/diagnóstico , Meduloblastoma/tratamento farmacológico , Neutrófilos , Projetos Piloto , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
20.
J Neurooncol ; 142(3): 411-422, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30725256

RESUMO

PURPOSE: Pediatric brain cancer medulloblastoma (MB) standard-of-care results in numerous comorbidities. MB is comprised of distinct molecular subgroups. Group 3 molecular subgroup patients have the highest relapse rates and after standard-of-care have a 20% survival. Group 3 tumors have high expression of GABRA5, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABAAR). We are advancing a therapeutic approach for group 3 based on GABAAR modulation using benzodiazepine-derivatives. METHODS: We performed analysis of GABR and MYC expression in MB tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional 'druggable' GABAAR in group 3 cells. RESULTS: Analysis of expression of 763 MB tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of GABR genes, which code for GABAAR subunits α5, ß3 and γ2 and 3. There are ~ 1000 functional α5-GABAARs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2 × 109 ions/s. Benzodiazepines, designed to prefer α5-GABAAR, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine ('KRM-II-08') binds to the α5-GABAAR (0.8 µM EC50) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response, TP53 upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter protein localization. CONCLUSION: GABRA5 expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABAAR is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis.


Assuntos
Benzodiazepinas/farmacologia , Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Receptores de GABA-A/química , Regulação Alostérica , Morte Celular/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/metabolismo , Perfilação da Expressão Gênica , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Receptores de GABA-A/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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