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2.
J Clin Oncol ; : JCO1902953, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32058846

RESUMO

Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.

3.
Br J Cancer ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31919403

RESUMO

For many tumours there is a lack of randomised data from which we can guide systemic treatments. Although gene expression profiling along with proteomics has led to advances in diagnosis, classification and prognosis, our ability to target many cancers has been further limited due to a lack of therapeutic options. The use of patient-derived xenograft (PDX) models in the setting of a rare malignancy is discussed here by Kamili et al, with the successful establishment of new model systems.

4.
Pharmaceutics ; 11(12)2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31795486

RESUMO

Thermosensitive liposome-mediated drug delivery has shown promising results in terms of improved therapeutic efficacy and reduced side effects compared to conventional chemotherapeutics. In order to facilitate our understanding of the transport mechanisms and their complex interplays in the drug delivery process, computational models have been developed to simulate the multiple steps involved in liposomal drug delivery to solid tumours. In this study we employ a multicompartmental model for drug-loaded thermosensitive liposomes, with an aim to identify the key transport parameters in determining therapeutic dosing and outcomes. The computational model allows us to not only examine the temporal and spatial variations of drug concentrations in the different compartments by utilising the tumour cord concept, but also assess the therapeutic efficacy and toxicity. In addition, the influences of key factors on systemic plasma concentration and intracellular concentration of the active drug are investigated; these include different chemotherapy drugs, release rate constants and heating duration. Our results show complex relationships between these factors and the predicted therapeutic outcome, making it difficult to identify the "best" parameter set. To overcome this challenge, a model-based optimisation method is proposed in an attempt to find a set of release rate constants and heating duration that can maximise intracellular drug concentration while minimising systemic drug concentration. Optimisation results reveal that under the operating conditions and ranges examined, the best outcome would be achieved with a low drug release rate at physiological temperature, combined with a moderate to high release rate at mild hyperthermia and 1 h heating after injection.

5.
Oncogene ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831835

RESUMO

The original version of this Article omitted the following from the Acknowledgements: Professor Stebbing sits on SABs for Celltrion, Singapore Biotech, Vor Biopharma, TLC Biopharmaceuticals and Benevolent AI, has consulted with Lansdowne partners, Vitruvian and Social Impact Capital and Chairs the Board of Directors for BB Biotech Healthcare Trust and Xerion Healthcare. This has now been corrected in both the PDF and HTML versions of the Article.

6.
Oncogene ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754213

RESUMO

EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Systematic genetic analysis is important to understand drug-resistant mechanisms; however, the clinical significance of co-occurring genetic alterations at baseline, co-acquired mutations at progressive disease (PD), and the clonal evolution remain underinvestigated. We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole-exome sequencing to infer the clonal evolution patterns. We observed a domain-dependent effect of PIK3CA mutation at baseline on patient progression-free survival (PFS). In addition, at baseline, 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) showed a co-deletion pattern, which was associated with a significantly worse PFS (p = 0.00079). T790M-postive patients with other concurrent acquired oncogenic mutations had a significantly shorter PFS (p = 0.005). Besides acquired T790M mutation, chromosomal instability (CIN) related genes, including AURKA and TP53 alterations, were the most frequently acquired events. CIN significantly increased during TKI treatment in T790M-negative patients and is a candidate resistance mechanism to the first-generation TKIs. Clonal evolution analyses suggest that the composition and relationship among resistant subclones, particularly relationship with T790M subclone, affect patients' outcomes. Overall, our findings of novel co-occurring alterations and clonal evolution patterns can be served as predictive biomarkers to stratify patients and help to better understand the drug-resistant mechanism to TKIs.

7.
Expert Opin Biol Ther ; 19(10): 987-992, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31507219

RESUMO

Introduction: CT-P6 (trastuzumab-pkrb, Herzuma) is a trastuzumab biosimilar approved for use in HER2 positive breast cancer and HER2 positive gastric cancer. CT-P6 has been shown to exhibit similar safety and efficacy profiles to its reference product, trastuzumab. Preclinical and clinical studies have been performed to prove equivalence between CT-P6 and the trastuzumab originator. Areas Covered: In this review, we examine the evidence comparing CT-P6 with its reference product, trastuzumab. Both monoclonal antibodies function to target cells that overexpress HER2 on the cell surface. Preclinical pharmacologic modeling of CT-P6 shows a similar mechanism of action to trastuzumab, similar pharmacologic properties and a phase I trial in healthy volunteers showed similar pharmacokinetics. A multicenter phase III randomized clinical trial in patients with early breast cancer showed equivalent safety and efficacy between CT-P6 and trastuzumab. One-year follow-up of patients showed identical rates of cardiotoxicity. Expert Opinion: Preclinical and clinical studies showed CT-P6 pharmacologic profile, safety and efficacy are equivalent to trastuzumab. As such, it is a safe and effective alternative for use in patients with HER2 positive breast cancer and gastric cancer. Its implementation into clinical practice can potentially increase patient access and help financially alleviate overburdened health-care systems.

9.
Commun Biol ; 2: 315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31453379

RESUMO

Glioblastoma (GBM) is one of the most aggressive solid tumors for which treatment options and biomarkers are limited. Small extracellular vesicles (sEVs) produced by both GBM and stromal cells are central in the inter-cellular communication that is taking place in the tumor bulk. As tumor sEVs are accessible in biofluids, recent reports have suggested that sEVs contain valuable biomarkers for GBM patient diagnosis and follow-up. The aim of the current study was to describe the protein content of sEVs produced by different GBM cell lines and patient-derived stem cells. Our results reveal that the content of the sEVs mirrors the phenotypic signature of the respective GBM cells, leading to the description of potential informative sEV-associated biomarkers for GBM subtyping, such as CD44. Overall, these data could assist future GBM in vitro studies and provide insights for the development of new diagnostic and therapeutic methods as well as personalized treatment strategies.

10.
Ann Surg ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373926

RESUMO

OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

11.
12.
Artigo em Inglês | MEDLINE | ID: mdl-31178825

RESUMO

The importance and role of the estrogen receptor (ER) pathway has been well-documented in both breast cancer (BC) development and progression. The treatment of choice in women with metastatic breast cancer (MBC) is classically divided into a variety of endocrine therapies, 3 of the most common being: selective estrogen receptor modulators (SERM), aromatase inhibitors (AI) and selective estrogen receptor down-regulators (SERD). In a proportion of patients, resistance develops to endocrine therapy due to a sophisticated and at times redundant interference, at the molecular level between the ER and growth factor. The progression to endocrine resistance is considered to be a gradual, step-wise process. Several mechanisms have been proposed but thus far none of them can be defined as the complete explanation behind the phenomenon of endocrine resistance. Although multiple cellular, molecular and immune mechanisms have been and are being extensively studied, their individual roles are often poorly understood. In this review, we summarize current progress in our understanding of ER biology and the molecular mechanisms that predispose and determine endocrine resistance in breast cancer patients.

13.
J Immunol ; 202(12): 3423-3433, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085591

RESUMO

Induction of programmed DNA damage and its recognition and repair are fundamental for B cell development. The ssDNA-binding protein SSB1 has been described in human cells as essential for the recognition and repair of DNA damage. To study its relevance for B cells, we recently developed Ssb1 -/- and conditional Ssb1 -/- mice. Although SSB1 loss did not affect B cell development, Ssb1 -/- cells exhibited compensatory expression of its homolog SSB2. We have now generated Ssb2 -/- mice and show in this study that SSB2 is also dispensable for B cell development and DNA damage response activation. In contrast to the single loss of Ssb1 or Ssb2, however, combined SSB1/2 deficiency caused a defect in early B cell development. We relate this to the sensitivity of B cell precursors as mature B cells largely tolerated their loss. Toxicity of combined genetic SSB1/2 loss can be rescued by ectopic expression of either SSB1 or SSB2, mimicked by expression of SSB1 ssDNA-binding mutants, and attenuated by BCL2-mediated suppression of apoptosis. SSB1/2 loss in B cell precursors further caused increased exposure of ssDNA associated with disruption of genome fragile sites, inefficient cell cycle progression, and increased DNA damage if apoptosis is suppressed. As such, our results establish SSB1/2 as safeguards of B cell development and unveil their differential requirement in immature and mature B lymphocytes.

14.
Clin Cancer Res ; 25(14): 4255-4263, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30992300

RESUMO

PURPOSE: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer. EXPERIMENTAL DESIGN: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X). RESULTS: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5-24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling. CONCLUSIONS: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.

15.
Crit Rev Oncol Hematol ; 134: 39-45, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30771872

RESUMO

BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IVaggressive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggressive (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggressive, p < 0.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggressive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Estadiamento de Neoplasias/normas , Células Neoplásicas Circulantes/patologia , Seleção de Pacientes , Consenso , Prova Pericial , Feminino , Humanos , Agências Internacionais
16.
Oncogene ; 38(13): 2320-2336, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30478450

RESUMO

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.


Assuntos
Proliferação de Células , Melanoma/patologia , Melanoma/terapia , Terapia de Alvo Molecular , Sistema Renina-Angiotensina/fisiologia , Amidas/farmacologia , Amidas/uso terapêutico , Angiotensina II/farmacologia , Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Embrião não Mamífero , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Melanoma/genética , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Metástase Neoplásica , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
17.
Eur J Cancer Prev ; 28(1): 54-57, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29384759

RESUMO

Although the major burden of disease caused by smoking is observed in the adult population, two-third of smokers start before the age of 18 years. Reducing the number of young smokers could lead to marked improvements to the health of the UK population and save billions of pounds in National Health Service finances. However, very little is known about what makes children decide to not smoke or to quit early. We believe that increased awareness of the health risks associated with smoking will reduce smoking uptake among children. This study identifies a significant lack of knowledge among children aged 11-17 years at two London secondary schools and potentially identifies an area for improving our antismoking programmes. Although 80% of pupils cited lung cancer as being a smoking-related disease, very few other conditions could be recalled. We must do all we can to reduce smoking uptake in children. Understanding their baseline knowledge is the first step towards addressing the deficits in our current antismoking programmes.


Assuntos
Fumar Cigarros/efeitos adversos , Fumar Cigarros/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Prevenção do Hábito de Fumar/métodos , Adolescente , Criança , Fumar Cigarros/psicologia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/prevenção & controle , Masculino , Abandono do Hábito de Fumar/métodos , Abandono do Hábito de Fumar/psicologia , Estudantes/psicologia , Inquéritos e Questionários
18.
Oncoimmunology ; 7(12): e1396403, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524878

RESUMO

Purpose: To investigate the impact of programmed death-ligand 1 (PD-L1) expression, oncogenic mutations, and clinical characteristics on survival after treatment with anti-PD-1/PD-L1 antibodies versus chemotherapy in non-small cell lung cancer (NSCLC). Patients and Methods: This meta-analysis included randomized trials comparing anti-PD-1/PD-L1 antibodies with chemotherapy. Hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS) for the trial population and prespecified subgroups were extracted. We calculated pooled estimates of treatment efficacy using the fixed-effects or random-effects model when appropriate. All statistical tests were two sided. Results: Seven trials involving 3871 patients were included. The pooled results showed that anti-PD-1/PD-L1 immunotherapy significantly prolonged OS (HR: 0.73; 95% CI, 0.63 to 0.84) and PFS (HR: 0.84; 95% CI, 0.71 to 0.99) compared to chemotherapy. OS benefit from immunotherapy were observed in all PD-L1 expression subgroups (negative: HR, 0.79; 95% CI, 0.67 to 0.93; weak-positive: HR, 0.80; 95% CI, 0.67 to 0.95; strong-positive: HR, 0.61; 95% CI, 0.47 to 0.78). Strong-positive PD-L1 expression showed a trend towards more benefit compared to weak-positive PD-L1 expression (interaction P = 0.08). KRAS mutant (HR: 0.60; 95% CI, 0.39 to 0.93), EGFR wild-type (HR: 0.73; 95% CI, 0.61 to 0.87) and smoker (HR: 0.70; 95% CI, 0.60 to 0.83) subgroups achieved significant OS benefit from immunotherapy compared to corresponding subgroups. Survival benefit to immunotherapy was not significantly associated with histology, CNS metastases, age, gender and performance status. Conclusion: This study confirmed that treatment with anti-PD-1/PD-L1 improves overall survival compared with chemotherapy. Benefit was seen, regardless of PD-L1 expression levels; however, PD-L1 strong-positive patients trended to have greatest benefit. Patients with a KRAS mutant or EGFR wild-type tumor have improved survival benefit from immunotherapy compared with KRAS wild-type or EGFR mutant NSCLC, respectively.

19.
Front Immunol ; 9: 2344, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405602

RESUMO

Pulmonary aspergillosis is an opportunistic fungal infection affecting immunocompromised individuals. Increasing understanding of natural killer (NK) cell immunobiology has aroused considerable interest around the role of NK cells in pulmonary aspergillosis in the immunocompromised host. Murine studies indicate that NK cells play a critical role in pulmonary clearance of A. fumigatus. We show that the in vitro interaction between NK cells and A. fumigatus induces partial activation of NK cell immune response, characterised by low-level production of IFN-γ, TNF-α, MIP-1α, MIP-1ß, and RANTES, polarisation of lytic granules and release of fungal DNA. We observed a contact-dependent down-regulation of activatory receptors NKG2D and NKp46 on the NK cell surface, and a failure of full granule release. Furthermore, the NK cell cytokine-mediated response to leukaemic cells was impaired in the presence of A. fumigatus. These observations suggest that A. fumigatus-mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis.


Assuntos
Aspergilose/imunologia , Aspergilose/microbiologia , Aspergillus fumigatus/imunologia , Degranulação Celular/imunologia , Hifas , Sinapses Imunológicas/imunologia , Células Matadoras Naturais/imunologia , Animais , Apresentação do Antígeno , Aspergillus fumigatus/genética , Antígeno CD56/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Citocinas/metabolismo , DNA Fúngico , Humanos , Hospedeiro Imunocomprometido , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Leucemia , Ativação Linfocitária/imunologia , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fenótipo , Transporte Proteico
20.
Mol Cancer ; 17(1): 132, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30165850

RESUMO

Glioblastoma (GBM) is the most aggressive type of primary brain tumours. Anti-angiogenic therapies (AAT), such as bevacizumab, have been developed to target the tumour blood supply. However, GBM presents mechanisms of escape from AAT activity, including a speculated direct effect of AAT on GBM cells. Furthermore, bevacizumab can alter the intercellular communication of GBM cells with their direct microenvironment. Extracellular vesicles (EVs) have been recently described as main acts in the GBM microenvironment, allowing tumour and stromal cells to exchange genetic and proteomic material. Herein, we examined and described the alterations in the EVs produced by GBM cells following bevacizumab treatment. Interestingly, bevacizumab that is able to neutralise GBM cells-derived VEGF-A, was found to be directly captured by GBM cells and eventually sorted at the surface of the respective EVs. We also identified early endosomes as potential pathways involved in the bevacizumab internalisation by GBM cells. Via MS analysis, we observed that treatment with bevacizumab induces changes in the EVs proteomic content, which are associated with tumour progression and therapeutic resistance. Accordingly, inhibition of EVs production by GBM cells improved the anti-tumour effect of bevacizumab. Together, this data suggests of a potential new mechanism of GBM escape from bevacizumab activity.


Assuntos
Bevacizumab/farmacologia , Neoplasias Encefálicas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Vesículas Extracelulares/metabolismo , Glioblastoma/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Vesículas Extracelulares/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Humanos , Espectrometria de Massas , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Proteômica , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
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