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1.
Eur J Med Chem ; 215: 113268, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33636537

RESUMO

Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatment for MB includes surgical resection, radiotherapy and chemotherapy. Despite significant progress in its management, a portion of children relapse and tumor recurrence carries a poor prognosis. Based on their molecular and clinical characteristics, MB patients are clinically classified into four groups: Wnt, Hh, Group 3, and Group 4. With our increased understanding of relevant molecular pathways disrupted in MB, the development of targeted therapies for MB has also increased. Targeted drugs have shown unique privileges over traditional cytotoxic therapies in balancing efficacy and toxicity, with many of them approved and widely used clinically. The aim of this review is to present the recent progress on targeted chemotherapies for the treatment of all classes of MB.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Linhagem Celular Tumoral , Humanos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico
3.
Cancer Res ; 81(2): 264-265, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452214

RESUMO

Personalized therapies have remained elusive in medulloblastoma, resulting in treatment paradigms that have been largely stagnant for almost four decades. A recent study by Rusert and colleagues applies a novel integrated approach to the identification of new targets in medulloblastoma by combining genomics, transcriptomics, and high-throughput drug screening across a panel of molecularly characterized patient-derived models. Actinomysin D, a common chemotherapeutic agent, was identified as highly active in the most aggressive form of medulloblastoma, highlighting the power of this approach over genomic paradigms alone.See related article by Rusert et al.; Cancer Res 80(23):5393-407.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Preparações Farmacêuticas , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Genômica , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Medicina de Precisão
4.
Proc Natl Acad Sci U S A ; 117(39): 24205-24212, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32934143

RESUMO

The sonic hedgehog subtype of medulloblastoma (SHH MB) is associated with treatment failure and poor outcome. Current strategies utilizing whole brain radiation therapy result in deleterious off-target effects on the normal developing childhood brain. Most conventional chemotherapies remain limited by ineffective blood-brain barrier (BBB) penetrance. These challenges signify an unmet need for drug carriers that can cross the BBB and deliver drugs to targeted sites with high drug-loading efficiency and long-term stability. We herein leverage the enhanced stability and targeting ability of engineered high-density lipoprotein-mimetic nanoparticles (eHNPs) to cross the BBB and deliver a SHH inhibitor effectively to the cancer stem-like cell population in SHH MB. Our microfluidic technology enabled highly reproducible production of multicomponent eHNPs incorporated with apolipoprotein A1, anti-CD15, and a SHH inhibitor (LDE225). We demonstrate the dual-targeted delivery and enhanced therapeutic effect of eHNP-A1-CD15-LDE225 via scavenger receptor class B type 1 (SR-B1) and CD15 on brain SHH MB cells in vitro, ex vivo, and in vivo. Moreover, we show that eHNP-A1 not only serves as a stable drug carrier, but also has a therapeutic effect itself through SR-B1-mediated intracellular cholesterol depletion in SHH MB cells. Through the facilitated and targeted cellular uptake of drugs and direct therapeutic role of this engineered biomimetic nanocarrier in SHH MB, our multifunctional nanoparticle provides intriguing therapeutic promise as an effective and potent nanomedicine for the treatment of SHH MB.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Cerebelares/tratamento farmacológico , Portadores de Fármacos , Meduloblastoma/tratamento farmacológico , Nanopartículas/química , Animais , Materiais Biomiméticos , Barreira Hematoencefálica , Linhagem Celular Tumoral , HDL-Colesterol , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Camundongos Transgênicos , Terapia de Alvo Molecular , Gravidez , Tamoxifeno
5.
Cancer Res ; 80(13): 2818-2832, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32371475

RESUMO

Aberrant activation of the Hedgehog (HH) signaling pathway underlines the initiation and progression of a multitude of cancers. The effectiveness of the leading drugs vismodegib (GDC-0449) and sonidegib (LDE225), both Smoothened (SMO) antagonists, is compromised by acquisition of mutations that alter pathway components, notably secondary mutations in SMO and amplification of GLI2, a transcriptional mediator at the end of the pathway. Pharmacologic blockade of GLI2 activity could ultimately overcome these diversified refractory mechanisms, which would also be effective in a broader spectrum of primary tumors than current SMO antagonists. To this end, we conducted a high-content screening directly analyzing the ciliary translocation of GLI2, a key event for GLI2 activation in HH signal transduction. Several prostaglandin compounds were shown to inhibit accumulation of GLI2 within the primary cilium (PC). In particular, prostaglandin E1 (PGE1), an FDA-approved drug, is a potent GLI2 antagonist that overcame resistance mechanisms of both SMO mutagenesis and GLI2 amplification. Consistent with a role in HH pathway regulation, EP4 receptor localized to the PC. Mechanistically, PGE1 inhibited HH signaling through the EP4 receptor, enhancing cAMP-PKA activity, which promoted phosphorylation and degradation of GLI2 via the ubiquitination pathway. PGE1 also effectively inhibited the growth of drug refractory human medulloblastoma xenografts. Together, these results identify PGE1 and other prostaglandins as potential templates for complementary therapeutic development to circumvent resistance to current generation SMO antagonists in use in the clinic. SIGNIFICANCE: These findings show that PGE1 exhibits pan-inhibition against multiple drug refractory activities for Hedgehog-targeted therapies and elicits significant antitumor effects in xenograft models of drug refractory human medulloblastoma mimicking GLI2 amplification.


Assuntos
Alprostadil/farmacologia , Neoplasias Cerebelares/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Amplificação de Genes , Proteínas Hedgehog/antagonistas & inibidores , Meduloblastoma/tratamento farmacológico , Proteínas Nucleares/genética , Proteína Gli2 com Dedos de Zinco/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Inibidores da Agregação Plaquetária/farmacologia , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Neuroimmunol ; 341: 577184, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32058173

RESUMO

We present an illustrative case of a 62-year-old woman with small cell lung cancer who developed progressive worsening of pre-existing anti-Hu antibody associated sensory neuronopathy after treatment with programmed cell death-1 (PD-1) inhibitor, nivolumab. We review the literature and identify 6 reported cases to understand the clinical outcomes of patients with anti-Hu paraneoplastic neurologic syndrome (PNS) treated with anti-PD-1 treatment. The PNS clinical spectrum comprised of encephalitis, a combination of sensory neuronopathy and anti-NMDAR encephalitis, isolated sensory neuronopathy, and encephalomyelitis. Immune checkpoint inhibitor have the potential to worsen pre-existing anti-Hu PNS and may promote the development of anti-Hu PNS.


Assuntos
Anticorpos Antinucleares/sangue , Antineoplásicos Imunológicos/efeitos adversos , Autoantígenos/imunologia , Proteínas ELAV/imunologia , Nivolumabe/efeitos adversos , Síndromes Paraneoplásicas do Sistema Nervoso/etiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Antinucleares/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma de Células Pequenas/complicações , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/imunologia , Carcinoma de Células Pequenas/secundário , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/secundário , Terapia Combinada , Progressão da Doença , Etoposídeo/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Síndromes Paraneoplásicas do Sistema Nervoso/induzido quimicamente , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Radioterapia Adjuvante , Resultado do Tratamento
7.
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
8.
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
9.
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
10.
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
11.
J Clin Oncol ; 38(3): 223-231, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31774708

RESUMO

PURPOSE: Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. PATIENTS AND METHODS: ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90%) with reduced treatment-related neurotoxicity. Secondary objectives included feasibility of timely central pathology review and evaluation of tumor molecular profile. RESULTS: Twenty-five eligible patients (15 males and 10 females; median age, 18.7 months) were enrolled. Eighteen patients had ND and 7 had MBEN histology. Three patients had residual disease at baseline. The study closed early because of a higher than expected relapse rate. Twelve patients experienced relapse-local (n= 6), distant (n = 3), and combined (n = 3)-at a median of 9.8 months from diagnosis (range, 8.9-13.7 months), and 2 patients died of disease. Two-year PFS and overall survival rates were 52% (95% CI, 32.4% to 71.6%) and 92% (95% CI, 80.8% to 100.0%) respectively. Patients older than 12 months of age (P = .036) and ND histology (P = .005) were associated with worse PFS. No patients with MBEN histology experienced relapse. All tumor samples clustered within the sonic hedgehog (SHH) group. Methylation analysis delineated 2 subgroups, SHH-I and SHH-II, which were associated with 2-year PFS rates of 30.0% (95% CI, 1.6% to 58.4%) and 66.7% (95% CI, 44.0% to 89.4%), respectively (P = .099). CONCLUSION: The proposed modified regimen of conventional systemic chemotherapy without serial intraventricular methotrexate injection failed to achieve the targeted 2-year PFS of 90%. With this cohort, we prospectively confirmed the existence of two SHH subgroups and observed a trend toward worse outcome for SHH-I patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/patologia , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Neoplasias Cerebelares/mortalidade , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/mortalidade , Intervalo Livre de Progressão
12.
Oncol Res ; 28(1): 95-102, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31753063

RESUMO

Long noncoding RNA CRNDE (CRNDE) recently emerged as a carcinogenic promoter in various cancers including medulloblastoma. However, the functions and molecular mechanisms of CRNDE to the acquired drug resistance of medulloblastoma are still unclear. The transcript levels of CRNDE were examined in four medulloblastoma cell lines exposed to cisplatin treatment, and IC50 values were calculated. Effects of CRNDE knockdown or miR-29c-3p overexpression on cell viability, colony formation, apoptosis, migration, and invasion were assessed using the CCK-8, colony formation assay, flow cytometry, and Transwell assays, respectively. RNA pulldown and RNA-binding protein immunoprecipitation (RIP) were performed to confirm the molecular interactions between CRNDE and miR-29c-3p involved in medulloblastoma cells. The in vivo role of CRNDE knockdown or miR-29c-3p overexpression on tumor growth and apoptosis was evaluated in a xenograft mouse model of human medulloblastoma. The transcript levels of lncRNA CRNDE were significantly higher in cisplatin-treated tumor cells with higher IC50 values. Depletion of CRNDE inhibited tumor cell proliferation and colony formation, induced cell apoptosis, and suppressed migration and invasion in medulloblastoma cells. Moreover, overexpression of miR-29c-3p inhibited tumor cell proliferation and colony formation, migration, and invasion, and enhanced apoptosis and chemosensitivity to cisplatin. In addition, CRNDE was found to act as a miR-29c-3p sponge. Furthermore, in vivo experiments showed the CRNDE/miR-29c-3p interactions involved in medulloblastoma. Our study demonstrates that CRNDE acts as a critical mediator of proliferation, apoptosis, migration, invasion, and resistance to chemotherapeutics via binding to and negatively regulating miR-29c-3p in medulloblastoma cells. These results provide novel molecular targets for treatment of medulloblastoma.


Assuntos
Neoplasias Cerebelares/genética , Resistencia a Medicamentos Antineoplásicos/genética , Meduloblastoma/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/metabolismo , Cisplatino/farmacologia , Feminino , Humanos , Masculino , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Camundongos , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
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
14.
J Pharm Pharm Sci ; 22(1): 612-629, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815662

RESUMO

PURPOSE: Cyclophosphamide is widely used to treat children with medulloblastoma; however, little is known about its brain penetration. We performed cerebral microdialysis to characterize the brain penetration of cyclophosphamide (130 mg/kg, IP) and its metabolites [4-hydroxy-cyclophosphamide (4OH-CTX) and carboxyethylphosphoramide mustard (CEPM)] in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma. METHODS: A plasma pharmacokinetic study was performed in non-tumor-bearing CD1- nude mice, and four cerebral microdialysis studies were performed in non-tumor-bearing (M1 and M3) and tumor- bearing mice (M2 and M4). Plasma samples were collected up to 6-hours post-dose, and extracellular fluid (ECF) samples were collected over 60-minute intervals for 24-hours post-dose. To stabilize and quantify 4OH-CTX, a derivatizing solution was added in blood after collection, and either directly in the microdialysis perfusate (M1 and M2) or in ECF collection tubes (M3 and M4). Plasma/ECF cyclophosphamide and CEPM, and 4OH-CTX concentrations were separately measured using different LC-MS/MS methods. RESULTS: All plasma/ECF concentrations were described using a population-based pharmacokinetic model. Plasma exposures of cyclophosphamide, 4OH-CTX, and CEPM were similar across studies (mean AUC=112.6, 45.6, and 80.8 µmol∙hr/L). Hemorrhage was observed in brain tissue when the derivatizing solution was in perfusate compared with none when in collection tubes, which suggested potential sample contamination in studies M1 and M2. Model-derived unbound ECF to plasma partition coefficients (Kp,uu) were calculated to reflect CNS penetration of the compounds. Lower cyclophosphamide Kp,uu was obtained in tumor-bearing mice versus non-tumor bearing mice (mean 0.15 versus 0.22, p=0.019). No differences in Kp,uu were observed between these groups for 4OH- CTX and CEPM (overall mean 0.10 and 0.07). CONCLUSIONS: Future studies will explore potential mechanisms at the brain-tumor barrier to explain lower cyclophosphamide brain penetration in tumor-bearing mice. These results will be used to further investigate exposure-response relationships in medulloblastoma xenograft models.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Ciclofosfamida/farmacologia , Meduloblastoma/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/sangue , Sistema Nervoso Central/metabolismo , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Cromatografia Líquida , Ciclofosfamida/administração & dosagem , Ciclofosfamida/sangue , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Camundongos , Camundongos Nus , Espectrometria de Massas em Tandem
15.
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
16.
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
17.
Biochem Biophys Res Commun ; 520(2): 250-256, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31594641

RESUMO

Medulloblastoma (MB) is a highly aggressive, malignant brain tumor in children with poor prognosis. Cyclin-dependent kinase 9 (CDK9), a serine-threonine kinase, is widely implicated in the control of basal gene expression by phosphorylating Serine 2 (Ser2) of the heptad repeat in the RNA Polymerase II (RNA Pol II) C-terminal domain (CTD). Although CDK9 plays a pathogenic role in various cancers, its function in MB remains unknown. Here, we show that CDK9 is highly expressed in MB tumors and increased CDK9 expression is correlated with high risk MB patients. CDK9 expression along with phospho-Ser2 RNA Pol II (pRNA Pol II ser2) and bromodomain-binding protein 4 (BRD4), which recruits CDK9, were elevated in multiple MB cell lines and in MB tumors originated spontaneously from Ptch1+/-p53-/- mice. Inhibition of CDK9 with LDC067 suppressed MB cell growth, reduced pRNA Pol II ser2 level and expression of oncogenic markers, including MYC. Moreover, LDC067 treatment synergistically sensitizes MB cells to chemotherapeutic agent cisplatin. Further, LDC067 in combination with BRD4 inhibitor decreased MB cells growth, delayed cell migration and attenuated pRNA Pol II ser2 occupancy to CCND1 and BCL2 gene promoters as revealed by chromatin immunoprecipitation assay (ChIP). Together, these findings highlight the importance of CDK9 in MB pathogenesis and suggest that it may serve as a promising therapeutic target for the treatment of MB.


Assuntos
Neoplasias Cerebelares/tratamento farmacológico , Quinase 9 Dependente de Ciclina/metabolismo , Meduloblastoma/tratamento farmacológico , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Cisplatino/administração & dosagem , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos Mutantes , Terapia de Alvo Molecular , Neoplasias Experimentais , Pirimidinas/administração & dosagem , RNA Polimerase II/metabolismo , Serina/metabolismo , Sulfonamidas/administração & dosagem , Fatores de Transcrição/metabolismo
18.
Cell Death Dis ; 10(11): 785, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619667

RESUMO

Medulloblastoma (MB) is the most common malignant solid paediatric brain tumour. The standard treatment for MB is surgical resection of the tumour, radiation and chemotherapy. This therapy is associated with high morbidity and adverse side effects. Hence, more targeted and less toxic therapies are vitally needed to improve the quality of life of survivors. NPI-0052 is a novel proteasome inhibitor that irreversibly binds the 20S proteasome subunit. This compound has anti-tumour activity in metastatic solid tumours, glioblastoma and multiple myeloma with a good safety profile. Importantly, NPI-0052 has a lipophilic structure and can penetrate the blood-brain barrier, making it a suitable treatment for brain tumours. In the present study, we performed an in silico gene expression analysis to evaluate the proteasome subunit expression in MB. To evaluate the anticancer activity of NPI-0052, we used a range of MB patient-derived MB cells and cell lines. The synergistic cell death of NPI-0052 with γ-radiation was evaluated in tumour organoids derived from patient-derived MB cells. We show that high expression of proteasome subunits is a poor prognostic factor for MB patients. Also, our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with γ-radiation, a component of the current MB therapy. Here, we present compelling preclinical evidence that NPI-0052 can be used as an adjuvant treatment for p53-family-expressing MB tumours.


Assuntos
Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/radioterapia , Raios gama/uso terapêutico , Lactonas/farmacologia , Meduloblastoma/tratamento farmacológico , Meduloblastoma/radioterapia , Pirróis/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Neoplasias Cerebelares/patologia , Quimiorradioterapia , Humanos , Meduloblastoma/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia
19.
Sci Rep ; 9(1): 13902, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554835

RESUMO

G-protein coupled receptor kinase 2 (GRK2; ADRBK1, BARK1) is most known as a regulator of G-protein coupled receptors. However, GRK2 also has other functions. Medulloblastomas are the most common malignant brain cancers in children. GRK2 has not been implicated in medulloblastoma biology. Here we report that GRK2 knockdown slowed cell growth, diminished proliferation, and enhanced cisplatin- and etoposide-induced apoptosis in medulloblastoma cell lines UW228-2 and Daoy. Reciprocally, GRK2 overexpression attenuated apoptosis induced by these chemotherapy drugs. Cisplatin and etoposide increased phosphorylation of AKT (S473) and GRK2 knockdown mitigated this increase. Cisplatin and etoposide attenuated ERK phosphorylation, but GRK2 knockdown did not alter this effect. Wildtype GRK2 reversed the increase in cisplatin- and etoposide-induced apoptosis caused by GRK2 knockdown. GRK2-K220R (kinase dead) and GRK2-S670A (unphosphorylated, constitutively active) conferred protection from cisplatin that was similar to wildtype GRK2, suggesting that this protection may be mediated though a kinase-independent activity of GRK2. These data demonstrate that GRK2 contributes to proliferation and survival of these medulloblastoma cell lines and to their protection from cisplatin- and etoposide-induced apoptosis.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Neoplasias Cerebelares/metabolismo , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Meduloblastoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Cisplatino/farmacologia , Etoposídeo/farmacologia , Células HEK293 , Humanos , Meduloblastoma/tratamento farmacológico , Fosforilação/efeitos dos fármacos
20.
Acta Neuropathol Commun ; 7(1): 123, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362788

RESUMO

BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumour in children but also rarely occur in adults. Sonic Hedgehog (SHH) driven MB is associated with aberrant activation of the SHH signalling pathway. SMO inhibitors, sonidegib and vismodegib, have been used as selective antagonist of the hedgehog pathway that acts by binding to SMO, and inhibits activation of the downstream hedgehog target genes. Several clinical trials investigating SMO inhibitors for the treatment of relapsed MB patients have been published. METHODS: We conducted a systemic review and meta-analysis among these Phase I and II clinical trials. The pooled effect of SMO inhibitors in relapsed MB were analysed using Reviewer Manager 5.3 software. The clinical efficacy of SMO inhibitors on SHH subtype of MB were measured by the objective response rate. The risk difference was obtained by comparing the ORR between SHH and non-SHH subtypes of MB. RESULTS: The five studies all had clear criteria for patient recruitment, adequate follow-up time for endpoint assessment and clear definition of tumour responses. MB patients had good compliance in the trials. The pooled objective response rate (ORR) of SMO inhibitor was 37% and 0 against SHH-driven and other MBs. The pooled ORR of sonidegib was 55% among MBSHH and 0 among MBnon-SHH subgroup. Vismodegib also had no efficacy on non-SHH subtype of MB. The sonidegib against SHH-driven MB produced the ORR 1.87-fold higher than that of vismodegib (95%CI 1.23, 6.69). Among paediatric patients, the efficacy of sonidegib was 3.67-fold higher than vismodegib (p < 0.05). A total of 320 cases received SMO inhibitor therapy and 36 cases reported grade 3/4 dose-limiting toxicity (DLT). The rate of grade 3/4 DLT was similar between patients receiving vismodegib and sonidegib (11.6% vs. 11.2%). CONCLUSION: Sonidegib and vismodegib were well tolerated and demonstrated anti-tumour activity in SHH-driven paediatric and adult MB by effectively inhibiting Hh signalling. These results support the ongoing clinical trials using SMO inhibitors in combination with conventional chemotherapies for the treatment of relapsed MBSHH.


Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Piridinas/uso terapêutico , Neoplasias Cerebelares/metabolismo , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Transdução de Sinais , Receptor Smoothened/metabolismo , Resultado do Tratamento
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