RESUMO
Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. KEY POINTS: This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Qualidade de VidaRESUMO
Adenoviral vectors are useful tools in manipulating a gene of interest in vitro and in vivo, including in the vascular system. The transduction efficiencies of adenoviral vectors in vascular cells such as endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are known to be lower than those in epithelial cell types. The effective entry for adenoviral vectors is primarily mediated through the coxsackievirus and adenovirus receptor (CAR), which has been shown to be expressed in both cell types. Cationic liposomes have been used to enhance adenovirus transduction efficiency in nonepithelial cells. Accordingly, the aim of this study is to obtain new information regarding differences in transduction efficiencies, cationic liposome sensitivity, and CAR expression between ECs and VSMCs. Using cultured rat aortic ECs and VSMCs, here, we have compared transduction efficiency of adenoviruses with or without inclusion of liposomes and CAR expression. A significant increase in basal transduction efficiency was observed in ECs compared with VSMCs. Cationic liposome polybrene enhanced transduction efficiency in VSMCs, whereas decreased efficiency was observed in ECs. Western blotting demonstrated expression of the CAR in ECs but not in VSMCs. Proteomic analysis and mouse aorta immunostaining further suggests significant expression of the CAR in ECs but not in VSMCs. In conclusion, adenoviruses can effectively transduce the gene of interest in aortic ECs likely because of abundant expression of the CAR, whereas cationic liposomes such as polybrene enhance the transduction efficiency in VSMCs lacking CAR expression.
Assuntos
Adenoviridae/genética , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/metabolismo , Células Endoteliais/metabolismo , Vetores Genéticos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Transdução Genética , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Animais , Células Cultivadas , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Brometo de Hexadimetrina/química , Lipossomos , Masculino , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
Cancer cells seem to exploit mechanisms that evolve as part of physiological tolerance, which is a complementary and often beneficial form of defense. The study of physiological systems of tolerance can therefore provide insights into the development of a state of host tolerance of cancer, and how to break it. Analysis of these models has the potential to improve our understanding of existing immunological therapeutic targets, and help to identify future targets and rational therapeutic combinations. The treatment of cancer with immune checkpoint inhibitors aims to reverse the progression to tolerance of cancer, and achieve an immunogenic, rather than tolerogenic, homeostasis. Broadening the efficacy and durability of checkpoint inhibitors focuses on reversing tolerance and stimulating immunogenicity in the cancer, host, and environment. Two examples of important physiological states of tolerance that may inform tolerance of cancer are microbial infection and placental reproduction. These states of tolerance result from bilateral shaping of host and non-self, akin to immunoediting in cancer, and offer reliable models to study the immune tolerance paradigm.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Tolerância Imunológica/fisiologia , Infecções/imunologia , Neoplasias/imunologia , Placenta/fisiologia , Aloenxertos/imunologia , Animais , Feminino , Humanos , Microbiota , Myxoma virus/patogenicidade , Infecções por Poxviridae/mortalidade , Gravidez , Microambiente Tumoral/imunologiaRESUMO
Angiotensin II (AngII) has a crucial role in cardiovascular pathologies, including endothelial inflammation and premature vascular aging. However, the precise molecular mechanism underlying aging-related endothelial inflammation induced by AngII remains elusive. Here, we have tested a hypothesis in cultured rat aortic endothelial cells (ECs) that the removal of AngII-induced senescent cells, preservation of proteostasis, or inhibition of mitochondrial fission attenuates the pro-inflammatory EC phenotype. AngII stimulation in ECs resulted in cellular senescence assessed by senescence-associated ß galactosidase activity. The number of ß galactosidase-positive ECs induced by AngII was attenuated by treatment with a senolytic drug ABT737 or the chemical chaperone 4-phenylbutyrate. Monocyte adhesion assay revealed that the pro-inflammatory phenotype in ECs induced by AngII was alleviated by these treatments. AngII stimulation also increased mitochondrial fission in ECs, which was mitigated by mitochondrial division inhibitor-1. Pretreatment with mitochondrial division inhibitor-1 attenuated AngII-induced senescence and monocyte adhesion in ECs. These findings suggest that mitochondrial fission and endoplasmic reticulum stress have causative roles in endothelial senescence-associated inflammatory phenotype induced by AngII exposure, thus providing potential therapeutic targets in age-related cardiovascular diseases.
Assuntos
Angiotensina II/farmacologia , Células Endoteliais/citologia , Mitocôndrias/metabolismo , Monócitos/citologia , Animais , Compostos de Bifenilo/farmacologia , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Nitrofenóis/farmacologia , Fenótipo , Fenilbutiratos/farmacologia , Piperazinas/farmacologia , Proteostase , Ratos , Sulfonamidas/farmacologia , Células THP-1RESUMO
Hypertension is a significant risk factor for the development of cardiovascular ailments, including ischemic heart disease and diastolic dysfunction. In a recent issue of Clinical Science, Li et al. [Clin. Sci. (2018) 132, 1855-1874] report that ß-2 microglobulin (ß2M) is a novel secreted soluble factor released by cardiac myocytes during pressure overload that promotes profibrotic gene expression in cardiac fibroblasts both in vitro and in vivo Their study further identifies elevated ß2M levels as a possible biomarker for hypertensive patients with cardiac complications. The authors propose a mechanism that mechanically stretched cardiomyocytes release soluble ß2M which, through paracrine communication with cardiac fibroblasts, transactivates epidermal growth factor receptor (EGFR) to initiate acute signal transduction and up-regulate profibrotic genes, thereby promoting fibrosis. Here, we will discuss the background, significance of the study, alternative mechanisms, and future directions.
Assuntos
Receptores ErbB , Miócitos Cardíacos , Fibroblastos , Fibrose , Humanos , Miocárdio , Estresse MecânicoRESUMO
BACKGROUND: TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma. METHODS: In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3â+â3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5â×â109, 7â×â109, and 9â×â109 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1â×â109 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651. FINDINGS: Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5â×â109 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5â×â109 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5â×â109 TargomiRs once weekly. We established that 5â×â109 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94-358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation. INTERPRETATION: The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors. FUNDING: Asbestos Diseases Research Foundation.
Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , MicroRNAs/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Segurança do Paciente , Neoplasias Pleurais/tratamento farmacológico , Adulto , Idoso , Austrália , Biópsia por Agulha , Institutos de Câncer , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Infusões Intravenosas , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Mesotelioma/diagnóstico por imagem , Mesotelioma/mortalidade , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Seleção de Pacientes , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. METHODS: In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. FINDINGS: Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. INTERPRETATION: Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. FUNDING: Pfizer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Quinazolinonas/administração & dosagem , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genéticaRESUMO
The vascular endothelium and smooth muscle form adjacent cellular layers that comprise part of the vascular wall. Each cell type can regulate the other's structure and function through a variety of paracrine effectors. Extracellular vesicles (EVs) are released from and transit between cells constituting a novel means of cell-cell communication. Here, we characterized the proteome of EVs released from each vascular cell type and examined the extent to which these vesicles participate in endothelial-vascular smooth muscle cell (VSMC) communication. EVs were collected by ultracentrifugation from media of rat aortic endothelial and smooth muscle cells cultured under serum-free conditions. Vesicle morphology, size and concentration were evaluated by transmission electron microscopy and nanoparticle tracking analysis. Western blot as well as shot gun proteomic analyses revealed sets of proteins common to both endothelial- and smooth muscle-derived EVs as well as proteins unique to each vascular cell type. Functionally, endothelial-derived EVs stimulated vascular cell adhesion molecule-1 (VCAM-1) expression and enhanced leukocyte adhesion in VSMCs while smooth muscle EVs did not elicit similar effects in endothelial cells (ECs). EVs from ECs also induced protein synthesis and senescence in VSMCs. Proteomic analysis of VSMCs following exposure to EC-derived EVs revealed upregulation of several proteins including pro-inflammatory molecules, high-mobility group box (HMGB) 1 and HMGB2. Pharmacological blockade HMGB1 and HMGB2 and siRNA depletion of HMGB1 in smooth muscle cells attenuated VCAM-1 expression and leukocyte adhesion induced by EC EVs. These data suggest that EC-derived EVs can enhance signalling pathways which influence smooth muscle cell phenotype.
RESUMO
Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses. In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 heterodeficient mice as well as endothelial Drp1 silenced mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB. In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.
Assuntos
Dinaminas/fisiologia , Células Endoteliais/fisiologia , Endotélio Vascular/patologia , Dinâmica Mitocondrial/fisiologia , NF-kappa B/metabolismo , Vasculite/fisiopatologia , Células 3T3 , Animais , Aorta/citologia , Adesão Celular , Células Cultivadas , Dinaminas/antagonistas & inibidores , Dinaminas/genética , Células Endoteliais/efeitos dos fármacos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/fisiologia , Camundongos , Proteínas Mitocondriais/fisiologia , Mutação de Sentido Incorreto , Fosforilação , Fosfosserina/metabolismo , Processamento de Proteína Pós-Traducional , Proteoma , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Ratos , Salicilato de Sódio/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
PURPOSE: In the phase III FLAURA study, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib significantly improved progression-free survival (PFS) versus standard-of-care (SoC) EGFR-TKI (gefitinib or erlotinib) in patients with previously untreated EGFR (exon 19 deletion or L858R) mutation-positive advanced non-small cell lung cancer (NSCLC). Interim overall survival (OS) data were encouraging, but not formally statistically significant at current maturity (25%). Here we report exploratory postprogression outcomes. PATIENTS AND METHODS: Patients were randomized 1:1 to receive osimertinib (80 mg orally, once daily) or SoC EGFR-TKI (gefitinib 250 mg or erlotinib 150 mg, orally, once daily). Treatment beyond disease progression was allowed if the investigator judged ongoing clinical benefit. Patients receiving SoC EGFR-TKI could cross over to receive osimertinib after independently confirmed objective disease progression with documented postprogression T790M-positive mutation status. RESULTS: At data cutoff (June 12, 2017), 138 of 279 (49%) and 213 of 277 (77%) patients discontinued osimertinib and SoC EGFR-TKI, respectively, of whom 82 (59%) and 129 (61%), respectively, started a subsequent treatment. Median time to discontinuation of any EGFR-TKI or death was 23.0 months [95% confidence interval (CI), 19.5-not calculable (NC)] in the osimertinib arm and 16.0 months (95% CI, 14.8-18.6) in the SoC EGFR-TKI arm. Median second PFS was not reached (95% CI, 23.7-NC) in the osimertinib arm and 20.0 months (95% CI, 18.2-NC) in the SoC EGFR-TKI arm [hazard ratio (HR), 0.58; 95% CI, 0.44-0.78; P = 0.0004]. CONCLUSIONS: All postprogression endpoints showed consistent improvement with osimertinib versus SoC EGFR-TKI, providing further confidence in the interim OS data.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Receptores ErbB/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Padrão de Cuidado , Resultado do TratamentoRESUMO
The interplay between the actin cytoskeleton and mitochondria has been implicated in cell and tissue homeostasis and physiological function. In this issue of Science Signaling, Nishimura etâal. demonstrate that inhibiting the interaction of filamin A, an actin cytoskeleton regulator, with Drp1, a modulator of mitochondrial dynamics, attenuates mitochondrial hyperfission and cardiomyocyte senescence after myocardial infarction.
Assuntos
Mitocôndrias , Dinâmica Mitocondrial , Citoesqueleto , Filaminas , Humanos , HipóxiaRESUMO
Immune checkpoint inhibitors have shown efficacy in the treatment of non-small cell lung cancer (NSCLC) in the adjuvant, first- and subsequent-line settings. In metastatic disease, they provide hope of durable response where “best-case” scenario has long been inadequate. This progress has highlighted the immunogenic nature of NSCLC and invigorated research into immunotherapy in the field. In this review we consider the foundations of immunotherapy in NSCLC, canvass the current research and summarise the evidence guiding clinical practice.
RESUMO
It has been proposed that membrane microdomains, caveolae, in vascular cells are critical for signal transduction and downstream functions induced by angiotensin II (AngII). We have tested our hypothesis that caveolin-1 (Cav1), a major structural protein of vascular caveolae, plays a critical role in the development of vascular remodeling by AngII via regulation of epidermal growth factor receptor and vascular endothelial adhesion molecule-1. Cav1-/- and control Cav+/+ mice were infused with AngII for 2 weeks to induce vascular remodeling and hypertension. On AngII infusion, histological assessments demonstrated medial hypertrophy and perivascular fibrosis of aorta and coronary and renal arteries in Cav1+/+ mice compared with sham-operated Cav1+/+ mice. AngII-infused Cav1+/+ mice also showed a phenotype of cardiac hypertrophy with increased heart weight to body weight ratio compared with control Cav1+/+ mice. In contrast, Cav1-/- mice infused with AngII showed attenuation of vascular remodeling but not cardiac hypertrophy. Similar levels of AngII-induced hypertension were found in both Cav1+/+ and Cav1-/- mice as assessed by telemetry. In Cav1+/+ mice, AngII enhanced tyrosine-phosphorylated epidermal growth factor receptor staining in the aorta, which was attenuated in Cav1-/- mice infused with AngII. Enhanced Cav1 and vascular endothelial adhesion molecule-1 expression was also observed in aorta from AngII-infused Cav1+/+ mice but not in Cav1-/- aorta. Experiments with vascular cells further provided a potential mechanism for our in vivo findings. These data suggest that Cav1, and presumably caveolae, in vascular smooth muscle and the endothelium plays a critical role in vascular remodeling and inflammation independent of blood pressure or cardiac hypertrophy regulation.
Assuntos
Angiotensina II/farmacologia , Caveolina 1/genética , Deleção de Genes , Hipertensão/genética , Remodelação Vascular/genética , Animais , Pressão Sanguínea/fisiologia , Caveolina 1/metabolismo , Modelos Animais de Doenças , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Remodelação Vascular/efeitos dos fármacosRESUMO
Angiotensin II (AngII)-activated epidermal growth factor receptor has been implicated in abdominal aortic aneurysm (AAA) development. In vascular smooth muscle cells (VSMCs), AngII activates epidermal growth factor receptor via a metalloproteinase, ADAM17 (a disintegrin and metalloproteinase domain 17). We hypothesized that AngII-dependent AAA development would be prevented in mice lacking ADAM17 in VSMCs. To test this concept, control and VSMC ADAM17-deficient mice were cotreated with AngII and a lysyl oxidase inhibitor, ß-aminopropionitrile, to induce AAA. We found that 52.4% of control mice did not survive because of aortic rupture. All other surviving control mice developed AAA and demonstrated enhanced expression of ADAM17 in the AAA lesions. In contrast, all AngII and ß-aminopropionitrile-treated VSMC ADAM17-deficient mice survived and showed reduction in external/internal diameters (51%/28%, respectively). VSMC ADAM17 deficiency was associated with lack of epidermal growth factor receptor activation, interleukin-6 induction, endoplasmic reticulum/oxidative stress, and matrix deposition in the abdominal aorta of treated mice. However, both VSMC ADAM17-deficient and control mice treated with AngII and ß-aminopropionitrile developed comparable levels of hypertension. Treatment of C57Bl/6 mice with an ADAM17 inhibitory antibody but not with control IgG also prevented AAA development. In conclusion, VSMC ADAM17 silencing or systemic ADAM17 inhibition seems to protect mice from AAA formation. The mechanism seems to involve suppression of epidermal growth factor receptor activation.
Assuntos
Proteína ADAM17 , Aminopropionitrilo/metabolismo , Angiotensina II/metabolismo , Aneurisma da Aorta Abdominal , Hipertensão , Músculo Liso Vascular , Proteína ADAM17/antagonistas & inibidores , Proteína ADAM17/metabolismo , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/prevenção & controle , Receptores ErbB/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Proteína-Lisina 6-Oxidase/metabolismo , Proteínas Modificadoras da Atividade de Receptores/metabolismo , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Salivary duct carcinomas (SDCa) are rare highly aggressive malignancies. Most patients die from distant metastatic disease within three years of diagnosis. There are limited therapeutic options for disseminated disease. RESULTS: 11 cases showed androgen receptor expression and 6 cases showed HER2 amplification. 6 Somatic mutations with additional available targeted therapies were identified: EGFR (p.G721A: Gefitinib), PDGFRA (p.H845Y: Imatinib and Crenolanib), PIK3CA (p.H1047R: Everolimus), ERBB2 (p.V842I: Lapatinib), HRAS (p.Q61R: Selumetinib) and KIT (p.T670I: Sorafenib). Furthermore, alterations in PTEN, PIK3CA and HRAS that alter response to androgen deprivation therapy and HER2 inhibition were also seen. MATERIALS AND METHODS: Somatic mutation analysis was performed on DNA extracted from 15 archival cases of SDCa using the targeted Illumina TruSeq Amplicon Cancer Panel. Potential targetable genetic alterations were identified using extensive literature and international somatic mutation database (COSMIC, KEGG) search. Immunohistochemistry for androgen receptor and immunohistochemistry and fluorescent in situ hybridization for HER2 were also performed. CONCLUSIONS: SDCa show multiple somatic mutations, some that are amenable to pharmacologic manipulation and others that confer resistance to treatments currently under investigation. These findings emphasize the need to develop testing and treatment strategies for SDCa.
RESUMO
INTRODUCTION: The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression. METHODS: PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from samples from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay. RESULTS: In a series of 72 patients with MPM, 18 (25%) had positive PD-L1 staining, and this was more common in patients with the nonepithelioid subtype (p = 0.01). PD-L1 expression was associated with poor survival (median overall survival 4.0 versus 9.2 months with positive versus negative PD-L1 expression [p < 0.001]), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (hazard ratio = 2.2, 95% confidence interval: 1.2-4.1, p < 0.01). In the same patient series, PD-L1 expression was also associated with downregulation of microRNAs previously shown to have tumor suppressor activity in MPM. The median microRNA expression levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the PD-L1-positive samples. Transfecting MPM cell lines with mimics corresponding to miR-15a and miR-16, both of which are predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative G-U-containing target site, also caused PD-L1 downregulation. CONCLUSIONS: Together, these data suggest that tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM.
Assuntos
Antígeno B7-H1/biossíntese , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mesotelioma/genética , Mesotelioma/metabolismo , MicroRNAs/genética , Neoplasias Pleurais/genética , Neoplasias Pleurais/metabolismo , Idoso , Antígeno B7-H1/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Neoplasias Pleurais/patologia , Prognóstico , Regulação para CimaRESUMO
PURPOSE: Positron emission tomography (PET) is a costly new technology with potential to improve preoperative evaluation for patients with non-small-cell lung cancer (NSCLC). There is increasing pressure for PET to be included in standard diagnostic work-up before decisions about surgical management of NSCLC. The resource implications of its widespread use in staging NSCLC are significant. METHODS: A randomized controlled trial was conducted to investigate the impact of PET on clinical management and surgical outcomes for patients with stage I-II NSCLC. The primary hypothesis was that PET would reduce the proportion of patients with stage I-II NSCLC who underwent thoracotomy by at least 10% through identification of patients with inoperable disease. RESULTS: One hundred eighty-four patients with stage I-II NSCLC were recruited and randomly assigned; 92% had stage I disease. Following exclusion of one ineligible patient, 92 patients were assigned to no PET and 91 to PET. Compared with conventional staging, PET upstaged 22 patients, confirmed staging in 61 and staged two patients as benign. Stage IV disease was rarely detected (two patients). PET led to further investigation or a change in clinical management in 13% of patients and provided information that could have affected management in a further 13% of patients. There was no significant difference between the trial arms in the number of thoracotomies avoided (P =.2). CONCLUSION: For patients who are carefully and appropriately staged as having stage I-II disease, PET provides potential for more appropriate stage-specific therapy but may not lead to a significant reduction in the number of thoracotomies avoided.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Estadiamento de NeoplasiasRESUMO
PURPOSE: Pemetrexed and vinorelbine are active antineoplastic agents in non-small cell lung cancer (NSCLC). Phase I objectives include maximum tolerated dose (MTD) and recommended phase II dose determination, and pharmacokinetics of the pemetrexed-vinorelbine doublet in locally advanced or metastatic solid tumor patients (pts). Phase II objectives include tumor response evaluation, efficacy, and toxicity for first-line treatment of advanced NSCLC. EXPERIMENTAL DESIGN: Phase I pts received pemetrexed (day 1, 300-700 mg/m2) and vinorelbine (days 1 and 8, 15-30 mg/m2) every 21 days. Pharmacokinetics determined at cycle 1. Beginning with dose-level 3, folic acid and Vitamin B12 supplementation were given. RESULTS: Thirty-one phase I pts were enrolled. MTD was pemetrexed 700 mg/m2 and vinorelbine 30 mg/m2; and recommended phase II dose was pemetrexed 500 mg/m2 and vinorelbine 30 mg/m2. When administered in combination, pemetrexed and vinorelbine pharmacokinetics were consistent with single-agent administration. Thirty-seven (36 chemonaive) phase II NSCLC pts received pemetrexed-vinorelbine. Evaluable tumor response was 40%, with intent-to-treat 38%. One drug-related death occurred from febrile neutropenia with Staphylococcal infection. Grade 3/4 hematologic toxicities were neutropenia (65%) and febrile neutropenia (11%), while prevalent grade 3/4 non-hematologic toxicity was fatigue (27%). CONCLUSION: The pemetrexed-vinorelbine combination is well tolerated and shows activity as first-line treatment in advanced NSCLC patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glutamatos/administração & dosagem , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Vimblastina/análogos & derivados , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Creatinina/metabolismo , Suplementos Nutricionais , Feminino , Glutamatos/farmacocinética , Guanina/administração & dosagem , Guanina/farmacocinética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pemetrexede , Fatores de Tempo , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/farmacocinética , Vinorelbina , Vitamina B 12/farmacologiaRESUMO
Pemetrexed is a novel folic acid antimetabolite that exerts its activity by the inhibition of multiple enzyme targets. It has been evaluated in a series of phase I clinical trials that explored different administration schedules. The schedule that has been carried forward into phase II trials involves the administration of pemetrexed as a 10-minute intravenous infusion every 21 days with no standard pretreatment with folic acid or vitamin B(12). When given in this manner, the dose-limiting toxicities were neutropenia and thrombocytopenia. Other toxicities included mucositis, rash, and fatigue. The recommended phase II dose was 600 mg/m(2) administered intravenous every 21 days, although this was subsequently modified to 500 mg/m(2) when several early patients experienced toxicities requiring dose reduction in phase II studies. On the basis of preclinical studies suggesting additive or synergistic effects, pemetrexed has also been evaluated in phase I studies in combination with several other agents including cisplatin, carboplatin, oxaliplatin, irinotecan, the taxanes, and anthracyclines. Encouraging anticancer activity has been observed in many of these studies.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Guanina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Timidilato Sintase/antagonistas & inibidores , Ensaios Clínicos Fase I como Assunto , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Humanos , PemetrexedeRESUMO
BACKGROUND: Many studies have examined specific mutations in patients with resected lung adenocarcinoma across heterogeneous stages, comprising predominantly advanced/metastatic disease, but there is little data regarding the mutation profile of patients with early stage node negative disease. The aim of this study was to identify patterns of mutations in early stage node negative lung adenocarcinoma. METHODS: A total of 204 patients who underwent resection for stage IB (sixth Ed American Joint Committee on Cancer) lung adenocarcinoma and received no neoadjuvant or adjuvant treatments were identified. Tumors were genotyped using the OncoCarta v1.0 kit (Sequenom, San Diego, CA) on the Sequenom MassARRAY platform. Fluorescence in situ hybridization for ALK rearrangement was also performed. RESULTS: A total of 110 (54%) patients' tumors harbored at least one mutation. KRAS, EGFR, PIK3CA, ALK, PDGFRA, AKT1, BRAF, FGFR1, and HRAS mutations were detected in tumors from 77 (37.7%), 29 (14.2%), 9 (4.4%), 2 (1%), 2 (1%), 1 (0.5%), 1 (0.5%), 1 (0.5%), and 1 (0.5%) patients respectively. Synchronous mutations (either comutations or double mutations) were identified in 18 (8.8%) patients. KRAS and PIK3CA mutations were associated with poorly differentiated tumors (p = 0.03; p = 0.02), whereas EGFR mutations were associated with well-differentiated tumors (p = 0.001). Five tumours contained EGFR mutations (one T790M and four exon 20 insertions), which are associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). CONCLUSIONS: Diverse patterns of mutations are seen in resected node-negative lung adenocarcinoma including an unexpectedly low rate of ALK rearrangement, EGFR mutations associated with resistance to EGFR-TKIs and a high rate of synchronous mutations. These data may influence the design of future adjuvant targeted therapy trials.