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1.
PLoS One ; 15(10): e0232858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33002018

RESUMO

Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiation attenuated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiation attenuated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an increase in the number of T-cells, including CD4+ and tissue-resident effector/ effector memory CD4+ T-cells, in comparison to long-term survivors that were mock-rechallenged, and in comparison to naïve untreated mice challenged with intracranial gliomas. These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Terapia Viral Oncolítica , Linfócitos T/imunologia , Zika virus/imunologia , Adjuvantes Imunológicos , Animais , Neoplasias Encefálicas/imunologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer , Glioblastoma/imunologia , Memória Imunológica , Imunoterapia , Camundongos , Camundongos Endogâmicos C57BL
2.
Jpn J Clin Oncol ; 50(11): 1231-1245, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-32984905

RESUMO

Treatment and resolution of primary and metastatic brain tumors have long presented a challenge to oncologists. In response to the dismal survival outcomes associated with conventional therapies, various immunotherapy modalities, such as checkpoint inhibitors, vaccine, cellular immunotherapy and viral immunotherapy have been actively explored over the past couple of decades. Although improved patient survival has been more frequently noted in treatment of brain metastases, little progress has been made in improving patient survival in cases of primary brain tumors, specifically glioblastoma, which is the representative primary brain tumor discussed in this review. Herein, we will first overview the findings of recent clinical studies for treatment of primary and metastatic brain tumors with immunotherapeutic interventions. The clinical efficacy of these immunotherapies will be discussed in the context of their ability or inability to overcome inherent characteristics of the tumor as well as restricted antigen presentation and its immunosuppressive microenvironment. Additionally, this review aims to briefly inform clinicians in the field of neuro-oncology on the relevant aspects of the immune system as it pertains to the central nervous system, with special focus on the differing modes of antigen presentation and tumor microenvironment of primary and metastatic brain tumors and the role these differences may play in the efficacy of immunotherapy in eradicating the tumor.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Imunoterapia/tendências , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Glioblastoma/imunologia , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Microambiente Tumoral/imunologia
3.
Clinics (Sao Paulo) ; 75: e1553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935821

RESUMO

OBJECTIVES: To assess the patterns of failure and prognostic factors in Brazilian patients with glioblastoma multiforme (GBM) treated with radiotherapy (RT) and concurrent and adjuvant temozolomide (TMZ). METHODS: Patients with diagnosed GBM post-resection received postoperative RT. TMZ was administered concurrently at 75 mg/m2/day for 28 consecutive days and adjuvant therapy at 150-200 mg/m2/day for 5 days every 28 days. Radiographic failure was defined as any new T1-enhancing lesion or biopsy-confirmed progressive enhancement inside of the radiation field. When possible, patients with recurrence were salvaged with metronomic TMZ, either in combination with a local treatment or alone (surgery or re-irradiation). Several prognostic factors were evaluated for overall survival (OS). Univariate and multivariate analyses were performed to identify significant factors. A p-value <0.05 was considered significant. RESULTS: This study included 50 patients. The median follow-up time was 21 months. The median RT dose was 60 Gy and all patients received concomitant TMZ. During follow-up, 41 (83.6%) failures were observed, including 34 (83%) in-field, 4 (9.7%) marginal, and 3 (7.3%) distant failures. Metronomic TMZ was used as salvage treatment in 22 (44%) cases and in combination with local treatment in 12 (24%) cases. The median OS and progression-free survival times for the entire cohort were 17 and 9 months, respectively. In univariate analysis, the following factors were significant for better OS: maximal surgical resection (p=0.03), Karnofsky Performance Score (KPS)>70 at diagnosis (p=0.01), metronomic TMZ treatment (p=0.038), recursive partitioning analysis class III (p=0.03), and time to failure >9 months (p=0.0001). In multivariate analysis, the following factors remained significant for better OS: metronomic TMZ (p=0.01) and time to failure >9 months (p=0.0001). CONCLUSION: The median OS of Brazilian patients with GBM treated with RT and TMZ was satisfactory. Although TMZ therapy has become the standard of care for patients with newly diagnosed GBM, the recurrence rate is extremely high. Metronomic TMZ as salvage treatment improved survival in these patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Glioblastoma/terapia , Recidiva Local de Neoplasia/epidemiologia , Temozolomida/uso terapêutico , Neoplasias Encefálicas/patologia , Brasil/epidemiologia , Quimioterapia Adjuvante , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Estudos Retrospectivos , Sobrevida , Resultado do Tratamento
4.
Nat Commun ; 11(1): 3912, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764562

RESUMO

Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and -active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Tolerância Imunológica , Imunofenotipagem , Imunoterapia , Isoenxertos , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Microambiente Tumoral/imunologia
5.
Pol J Pathol ; 71(2): 127-137, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32729303

RESUMO

Numerous genetic pathways associated with glioblastoma development have been identified. In this study, we investigated the prognostic significance of IDH1 and ATRX mutations and WT-1 and p53 expression in glioblastomas and that of surgical methods, radiotherapy and chemotherapy. 83 patients with glioblastomas were retrospectively evaluated. Immunohistochemical analysis was performed for IDH1, ATRX and WT-1 expression. Tumour cells were positive for IDH1 in 9.6% of the patients. In 4.8% of the patients, loss of ATRX expression was observed in tumour cells; 86.7% of the patients were WT-1 positive, and 12.05% of the patients were p53 positive. No statistically significant difference was found in the progression-free and overall survival according to IDH1, ATRX, WT-1 and p53 expression. There was a statistically significant difference in the progression-free and overall survival according to the radiotherapy status. There was a statistically significant difference in the overall survival according to the chemotherapy status. There was no statistically significant difference in the progression-free and overall survival according to the surgical method. IDH1 and ATRX mutations, p53 overexpression and WT-1 expression alone did not have a significant effect on the prognosis of patients with glioblastoma; however, radiotherapy and chemotherapy had a positive effect on survival.


Assuntos
Glioblastoma , Isocitrato Desidrogenase/genética , Proteínas WT1/genética , Proteína Nuclear Ligada ao X/genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Mutação , Prognóstico , Estudos Retrospectivos
6.
Nat Commun ; 11(1): 3288, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620753

RESUMO

The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Isocitrato Desidrogenase/genética , Proteogenômica/métodos , Proteômica/métodos , Benzamidas/farmacologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Isocitrato Desidrogenase/classificação , Isocitrato Desidrogenase/metabolismo , Estimativa de Kaplan-Meier , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Morfolinas/farmacologia , Mutação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia
7.
Nat Commun ; 11(1): 3406, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641768

RESUMO

Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.


Assuntos
Neoplasias Encefálicas/genética , Encéfalo/metabolismo , Glioblastoma/genética , Células-Tronco Neoplásicas/metabolismo , Análise de Sequência de RNA/métodos , Transcriptoma/genética , Adulto , Animais , Antineoplásicos Alquilantes/farmacologia , Encéfalo/embriologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Feminino , Feto , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Análise de Célula Única/métodos , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Zh Vopr Neirokhir Im N N Burdenko ; 84(3): 113-118, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32649821

RESUMO

A review is devoted to analysis of the prospects of theranostics for multiform glioblastoma with monoclonal antibodies to the epidermal growth factor receptor (EGFR). Treatment of various malignancies demonstrated high potential of the use of EGFR. However, in case of glioblastoma, the effectiveness of monoclonal antibodies to EGFR is constrained by the absence of informative criteria for assessing the effectiveness of diagnosis and treatment of disease.


Assuntos
Glioblastoma/terapia , Anticorpos Monoclonais , Receptores ErbB , Humanos , Nanomedicina Teranóstica
9.
Anticancer Res ; 40(6): 3231-3237, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487617

RESUMO

BACKGROUND/AIM: We previously established a novel type of epidermal growth factor receptor variant III (EGFRvIII)-specific chimeric antigen receptor (CAR)-expressing natural killer (NK) cell line, designated EvCAR-KHYG-1, which inhibited the growth of glioblastoma (GBM) cells in vitro via apoptosis. MATERIALS AND METHODS: We investigated the cytokine-producing effect of EvCAR-KHYG-1 cells on GBM-like cell lines and their antitumour effect using in vivo xenograft assays. RESULTS: EvCAR-KHYG-1 cells produced interleukin-2, interferon-γ, and tumour necrosis factor-α on EGFRvIII-expressing U87MG cells. In vivo xenograft assays showed that EvCAR-KHYG-1 cells did not reduce the volume of subcutaneous tumours derived from EGFRvIII-expressing U87MG cells but did reduce tumour cell occupancy. CONCLUSION: EvCAR-KHYG-1 cells led to expression of cellular immunity-related cytokines on EGFRvIII-expressing U87MG in vitro but did not inhibit tumour progression due to the induction of a pseudo progression-like pathological feature. Future studies investigating the effect of different conditions in vivo are required to study the inhibition of tumour progression in GBM.


Assuntos
Neoplasias Encefálicas/terapia , Receptores ErbB/imunologia , Glioblastoma/terapia , Células Matadoras Naturais/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Citocinas/biossíntese , Citocinas/imunologia , Progressão da Doença , Feminino , Glioblastoma/genética , Glioblastoma/imunologia , Glioblastoma/patologia , Células HEK293 , Humanos , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Distribuição Aleatória , Receptores de Antígenos Quiméricos/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Commun ; 11(1): 2978, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532977

RESUMO

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Monoacilglicerol Lipases/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Células Cultivadas , Feminino , Glioblastoma/genética , Glioblastoma/terapia , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Ativação de Macrófagos/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Monoacilglicerol Lipases/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/genética , Interferência de RNA , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Arch Biochem Biophys ; 689: 108462, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32590068

RESUMO

Silver nanoparticles (AgNP) emerged as a promising reagent for cancer therapy with oxidative stress implicated in the toxicity. Meanwhile, studies reported cold atmospheric plasma (CAP) generation of reactive oxygen and nitrogen species has selectivity towards cancer cells. Gold nanoparticles display synergistic cytotoxicity when combined with CAP against cancer cells but there is a paucity of information using AgNP, prompting to investigate the combined effects of CAP using dielectric barrier discharge system (voltage of 75 kV, current is 62.5 mA, duty cycle of 7.5kVA and input frequency of 50-60Hz) and 10 nm PVA-coated AgNP using U373MG Glioblastoma Multiforme cells. Cytotoxicity in U373MG cells was >100-fold greater when treated with both CAP and PVA-AgNP compared with either therapy alone (IC50 of 4.30 µg/mL with PVA-AgNP alone compared with 0.07 µg/mL after 25s CAP and 0.01 µg/mL 40s CAP). Combined cytotoxicity was ROS-dependent and was prevented using N-Acetyl Cysteine. A novel darkfield spectral imaging method investigated and quantified AgNP uptake in cells determining significantly enhanced uptake, aggregation and subcellular accumulation following CAP treatment, which was confirmed and quantified using atomic absorption spectroscopy. The results indicate that CAP decreases nanoparticle size, decreases surface charge distribution of AgNP and induces uptake, aggregation and enhanced cytotoxicity in vitro.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Gases em Plasma/farmacologia , Prata/farmacologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Nanopartículas Metálicas/análise , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Prata/farmacocinética
13.
J Neurol Surg A Cent Eur Neurosurg ; 81(4): 348-354, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32361984

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive intracranial malignancy that confers a poor prognosis despite maximum surgical resection and chemoradiotherapy. Survival decreases further with deep-seated lesions. Laser interstitial thermal therapy (LITT) is an emerging minimally invasive technique for tumor ablation shown to reduce tumor burden effectively, particularly in deep-seated locations less amenable to gross total resection. We describe our initial technical experience of using the combination of LITT followed by surgical resection in patients with GBMs that exhibit both an easily accessible and deep-seated component. MATERIALS AND METHODS: Patients with GBM who received concurrent LITT and surgical resection at our institution were identified. Patient demographic and clinical information was procured from the University of Texas MD Anderson Cancer Center electronic medical record along with preoperative, postoperative, and 1-month follow-up magnetic resonance imaging (MRI). RESULTS: Four patients (n = 2 male, n = 2 female) with IDH-wild type GBM who received combined LITT and surgical resection were identified and analyzed retrospectively. All patients received chemoradiotherapy before presentation. All but one patient (75%) received resection before presentation. Median age was 54 years (range: 44-56 years). Median length of hospital stay was 6.5 days (range: 2-47 days). Median extent of combined ablation/resection was 90.4%. One of the four patients experienced complications in the perioperative or immediate follow-up periods. Local recurrence was observed in one patient during the follow-up period. CONCLUSION: Malignant gliomas in deep-seated locations or in close proximity to white matter structures are challenging to manage. LITT followed by surgical resection may provide an alternative for tumor debulking that minimizes potential morbidities and extent of residual tumor. Further studies comparing this approach with standard resection techniques are warranted.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Terapia a Laser/métodos , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Terapia Combinada , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
14.
Int J Nanomedicine ; 15: 2809-2828, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368056

RESUMO

Introduction: Glioblastoma (GBM) is the most common and lethal of the central nervous system (CNS) malignancies. The initiation, progression, and infiltration ability of GBMs are attributed in part to the dysregulation of microRNAs (miRNAs). Thus, targeting dysregulated miRNAs with RNA oligonucleotides (RNA interference, RNAi) has been proposed for GBM treatment. Despite promising results in the laboratory, RNA oligonucleotides have clinical limitations that include poor RNA stability and off-target effects. RNAi therapies against GBM confront an additional obstacle, as they need to cross the blood-brain barrier (BBB). Methods: Here, we developed gold-liposome nanoparticles conjugated with the brain targeting peptides apolipoprotein E (ApoE) and rabies virus glycoprotein (RVG). First, we functionalized gold nanoparticles with oligonucleotide miRNA inhibitors (OMIs), creating spherical nucleic acids (SNAs). Next, we encapsulated SNAs into ApoE, or RVG-conjugated liposomes, to obtain SNA-Liposome-ApoE and SNA-Liposome-RVG, respectively. We characterized each nanoparticle in terms of their size, charge, encapsulation efficiency, and delivery efficiency into U87 GBM cells in vitro. Then, they were administered intravenously (iv) in GBM syngeneic mice to evaluate their delivery efficiency to brain tumor tissue. Results: SNA-Liposomes of about 30-50 nm in diameter internalized U87 GBM cells and inhibited the expression of miRNA-92b, an aberrantly overexpressed miRNA in GBM cell lines and GBM tumors. Conjugating SNA-Liposomes with ApoE or RVG peptides increased their systemic delivery to the brain tumors of GBM syngeneic mice. SNA-Liposome-ApoE demonstrated to accumulate at higher extension in brain tumor tissues, when compared with non-treated controls, SNA-Liposomes, or SNA-Liposome-RVG. Discussion: SNA-Liposome-ApoE has the potential to advance the translation of miRNA-based therapies for GBM as well as other CNS disorders.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Lipossomos/administração & dosagem , Interferência de RNA , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Técnicas de Transferência de Genes , Glioblastoma/genética , Glioblastoma/patologia , Ouro/química , Humanos , Lipossomos/química , Masculino , Nanopartículas Metálicas/química , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ácidos Nucleicos/química , Oligonucleotídeos/química , Oligonucleotídeos/genética , Oligonucleotídeos/farmacocinética , Proteínas do Envelope Viral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Crit Rev Oncol Hematol ; 151: 102965, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32442903

RESUMO

Glioblastoma (GBM) is the most common malignant tumour in the brain, and current treatments are not curative and cannot control recurrence. This limitation indirectly places immunotherapy at the focus of translational GBM research. Many studies on the PD-1/PD-L1 axis in GBM are ongoing, and the immunosuppressive mechanism of PD-1/PD-L1 in GBM is different from that in other solid tumours. This review focuses on the effect of the PD-1/PD-L1 axis on infiltrating immune cells in the suppressive GBM immune microenvironment and summarizes the recent progress in PD-1/PD-L1 axis-related therapies reported in preclinical and clinical GBM studies, providing a reference for the systematic study of PD-1/PD-L1 axis-related anti-GBM immunity.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Recidiva Local de Neoplasia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral
16.
Int J Nanomedicine ; 15: 2717-2732, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368051

RESUMO

Background: Phototherapy is a potential new candidate for glioblastoma (GBM) treatment. However inadequate phototherapy due to stability of the photosensitizer and low target specificity induces the proliferation of neovascular endothelial cells for angiogenesis and causes poor prognosis. Methods: In this study, we constructed c(RGDfk)-modified glycolipid-like micelles (cRGD-CSOSA) encapsulating indocyanine green (ICG) for dual-targeting neovascular endothelial cells and tumor cells, and cRGD-CSOSA/ICG mediated dual effect of PDT/PTT with NIR irradiation. Results: In vitro, cRGD-CSOSA/ICG inhibited cell proliferation and blocked angiogenesis with NIR irradiation. In vivo, cRGD-CSOSA/ICG exhibited increased accumulation in neovascular endothelial cells and tumor cells. Compared with that of CSOSA, the accumulation of cRGD-CSOSA in tumor tissue was further improved after dual-targeted phototherapy pretreatment. With NIR irradiation, the tumor-inhibition rate of cRGD-CSOSA/ICG was 80.00%, significantly higher than that of ICG (9.08%) and CSOSA/ICG (42.42%). Histological evaluation showed that the tumor vessels were reduced and that the apoptosis of tumor cells increased in the cRGD-CSOSA/ICG group with NIR irradiation. Conclusion: The cRGD-CSOSA/ICG nanoparticle-mediated dual-targeting phototherapy could enhance drug delivery to neovascular endothelial cells and tumor cells for anti-angiogenesis and improve the phototherapy effect of glioblastoma, providing a new strategy for glioblastoma treatment.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/terapia , Verde de Indocianina/administração & dosagem , Nanopartículas/administração & dosagem , Neovascularização Patológica/tratamento farmacológico , Fototerapia/métodos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Glioblastoma/patologia , Glicolipídeos/química , Humanos , Verde de Indocianina/química , Camundongos Nus , Micelas , Nanopartículas/química , Oligopeptídeos/química , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
17.
BMC Neurol ; 20(1): 178, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393192

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumors. Intracranial GBM metastases to the spine are rarely detected clinically. Secondary gliosarcomas after treatment of primary GBM are rarely described. CASE PRESENTATION: Herein, we report the case of a 53-year-old woman who presented to our emergency room with progressive headache and weakness on the left side. Plain computed tomography and contrast magnetic resonance imaging of the brain revealed an approximately 6.8 cm × 4.5 cm right temporoparietooccipital intraaxial cystic tumor with surrounding diffuse perifocal edema that caused midline shift toward the left. Emergency craniotomy was performed to remove the tumor, and pathological examination revealed GBM. The patient received proton beam therapy, Gliadel implantation, and oral temozolomide chemotherapy as well as targeted therapy with bevacizumab. Approximately 15 months after diagnosis, she underwent surgical resection of the right temporal recurrent tumor and was newly diagnosed as having a metastatic spinal tumor. Pathologically, the right temporal and metastatic spinal tumors were gliosarcoma and GBM, respectively. CONCLUSIONS: Concurrent spinal metastasis and gliosarcomatous transformation, which are two types of GBM complications, are rare. To our knowledge, this is the first report of a case of recurrent GBM with gliosarcoma after proton bean therapy.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Glioblastoma/secundário , Gliossarcoma/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Coluna Vertebral/secundário , Antineoplásicos Alquilantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Craniotomia , Evolução Fatal , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/terapia , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/terapia , Terapia com Prótons , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgia , Temozolomida/uso terapêutico , Tomografia Computadorizada por Raios X
18.
Aust J Gen Pract ; 49(4): 194-199, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32233347

RESUMO

BACKGROUND: Despite their rarity, primary tumours of the central nervous system have a devastating impact on patient survival and quality of life. The classification of glial tumours has recently changed, and large trials have provided data on treatment impact; however, the treatment armamentarium remains the same, and many questions persist. OBJECTIVE: The aim of this narrative review is to discuss the current understanding and management of the most common glial brain tumours to equip general practitioners (GPs) and other non-neuro-oncological specialists with appropriate knowledge to share care and support patients. DISCUSSION: Treatment of brain tumours is complex and multifaceted, and it involves many different specialists. Recent advances in translational research and molecular understanding of brain tumours raise hope that new treatments are imminent, and patients should be encouraged to participate in clinical trials. The GP has an important role in patient support and coordination of care.


Assuntos
Glioblastoma/diagnóstico , Glioblastoma/terapia , Gerenciamento Clínico , Medicina Geral/métodos , Glioblastoma/classificação , Cefaleia/etiologia , Humanos , Imagem por Ressonância Magnética/métodos , Procedimentos Neurocirúrgicos/métodos , Procedimentos Neurocirúrgicos/tendências
19.
Adv Exp Med Biol ; 1244: 183-203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301015

RESUMO

Immunotherapy has changed the landscape of treatment of many solid and hematological malignancies and is at the forefront of cancer breakthroughs. Several circumstances unique to the central nervous system (CNS) such as limited space for an inflammatory response, difficulties with repeated sampling, corticosteroid use for management of cerebral edema, and immunosuppressive mechanisms within the tumor and brain parenchyma have posed challenges in clinical development of immunotherapy for intracranial tumors. Nonetheless, the success of immunotherapy in brain metastases (BMs) from solid cancers such as melanoma and non-small cell lung cancer (NSCLC) proves that the CNS is not an immune-privileged organ and is capable of initiating and regulating immune responses that lead to tumor control. However, the development of immunotherapeutics for the most malignant primary brain tumor, glioblastoma (GBM), has been challenging due to systemic and profound tumor-mediated immunosuppression unique to GBM, intratumoral and intertumoral heterogeneity, low mutation burden, and lack of stably expressed clonal antigens. Here, we review recent advances in the field of immunotherapy for neuro-oncology with a focus on BM and GBM.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Imunoterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Glioblastoma/patologia , Humanos , Melanoma/patologia
20.
Int J Clin Oncol ; 25(7): 1215-1222, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32347433

RESUMO

Glioblastoma (GBM) is one of the most malignant neural tumors, and patients with GBM often die soon after the onset. The pathogenesis of GBM is very complicated, and there is no effective treatment for GBM. The current research results show that a variety of microRNA (miRNA) are involved in the regulation of GBM occurrence and development through specific signal pathways. Meanwhile, as a non-invasive biological indicator, there is an important clinical value of miRNA in the diagnosis and prognosis of GBM. The research of targeted miRNA treatment for GBM is still in the cell and animal model stage, although the basic research shows a good result, there is still a certain distance to the clinical application.


Assuntos
Biomarcadores Tumorais/genética , Glioblastoma/genética , MicroRNAs/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Masculino , Prognóstico
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