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1.
Medicine (Baltimore) ; 99(12): e19577, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195970

RESUMO

RATIONALE: The diagnosis of anaplastic lymphoma kinase (ALK)-negative inflammatory myofibroblastic tumors (IMT) remains challenging because of their morphological resemblance with spindle cell sarcoma with myofibroblastic characteristics. PATIENT CONCERNS: A 69-year-old female patient presented with loco-regional recurrent IMT several times within 8 years after primary treatment and neck lymph node metastasis 3.5 years after last recurrence. DIAGNOSIS: The primary, recurrence, and lymph node metastasis lesions were diagnosed as ALK-negative IMTs based on the histopathological features. INTERVENTIONS: Biopsy samples were obtained during repeated surgeries and evaluated for genomic alterations during first and recurrent presentations. The evaluation was done using pathway-driven massive parallel sequencing, and genomic alterations between primary and recurrent tumors were compared. OUTCOMES: Copy number gains and overexpression of mouse double minute 2 homolog (MDM2) and cyclin dependent kinase 4 (CDK4) were observed in the primary lesion, and additional gene amplification of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), Succinate Dehydrogenase Complex II subunit C (SDHC), and thyroid stimulating hormone receptor (TSHR) Q720H were found in the recurrent tumors. Metastases to the neck lymph node were observed 3.5 years after recurrence. LESSONS: Our results indicated genetic evolution in a microscopically benign condition and highlighted the importance of molecular characterization of fibro-inflammatory lesions of uncertain malignant potential.


Assuntos
Granuloma de Células Plasmáticas/metabolismo , Neoplasias de Cabeça e Pescoço/secundário , Recidiva Local de Neoplasia/patologia , Neoplasias de Tecido Muscular/metabolismo , Quinase do Linfoma Anaplásico/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Diagnóstico Diferencial , Feminino , Amplificação de Genes , Granuloma de Células Plasmáticas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Metástase Linfática , Mediastino/patologia , Pessoa de Meia-Idade , Miofibroblastos/patologia , Neoplasias de Tecido Muscular/patologia , Neoplasias de Tecido Muscular/radioterapia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(2): 120-125, 2020 Feb 12.
Artigo em Chinês | MEDLINE | ID: mdl-32062881

RESUMO

Objective: To study the prevalence of c-ros oncogene 1 fusion in lung adenocarcinoma and to evaluate its relationship with clinical characteristics. Methods: We retrospectively analyzed epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) fusion in 1 482 patients with adenocarcinoma from March 2014 to January 2017 in the first affiliated hospital of Zhejiang University. Furthermore, ROS1 fusion positive patients diagnosed between February 2017 and December 2017 were also included in ROS1 positive group. The data of age, sex, smoking history, TNM stage and chest computed tomography were collected by Electronic Medical Record (EMR). The clinical data were compared by the chi-squared test or Mann-Whitney test. Results: Of these 1 482 patients,54 cases were diagnosed with ROS1 rearrangement, including 19 males and 35 females, while 73 cases were diagnosed with ALK rearrangement, including 28 males and 45 females, and 679 cases diagnosed with EGFR mutation including 293 males and 386 females. And there were 676 patients without driven genes mutation. The mean age in ROS1 fusion group (54±12) was lower than EGFR mutation group (60±11, z=-3.982, P<0.001) and WT group (62±10, z=-4.944, P<0.001). Female proportion in ROS1 fusion group (64.8%, 35/54) was higher than WT group (28.4%, 192/676, χ(2)=30.94, P<0.001). Non-smoker percentages in ROS1 fusion group (72.2%, 39/54) was significantly higher than WT group (38.0%,257/676, χ(2)=24.27, P<0.001). ROS1 fusion group was similar to ALK fusion group in sex, age and smoking history, and there were no significant difference in TNM stage among these groups. On chest CT, adenocarcinomas with ROS1 fusion were found to be more peripheral in location (71.4%, 20/28) and solid in density (75%, 21/28), usually with lobulated margins (75.0%, 21/28) and spiculated in contour (57.1%,16/28). Conclusion: In our study lung adenocarcinoma with c-ROS oncogene 1 fusion was a rare subtype lung cancer and was usually detected in young, never smoking, and female patients.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Quinase do Linfoma Anaplásico/genética , Receptores ErbB/genética , Neoplasias Pulmonares/diagnóstico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Adenocarcinoma de Pulmão/epidemiologia , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Quinase do Linfoma Anaplásico/metabolismo , China/epidemiologia , Feminino , Fusão Gênica/genética , Genes erbB-1 , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Fusão Oncogênica , Prevalência , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio , Estudos Retrospectivos
3.
Nat Commun ; 11(1): 74, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900393

RESUMO

Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Quinase do Linfoma Anaplásico/genética , Apoptose/efeitos dos fármacos , Carbazóis/administração & dosagem , Rearranjo Gênico/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piperidinas/administração & dosagem , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Quinase do Linfoma Anaplásico/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/fisiopatologia , Inibidores de Proteínas Quinases/administração & dosagem , Fatores de Transcrição/genética
4.
Hematol Oncol ; 38(1): 59-66, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31834627

RESUMO

Galectin-1 (Gal-1) has been associated with adverse prognosis in several cancers including lymphoma entities with CD30 expression. However, Gal-1 expression has not been systematically assessed in peripheral T-cell lymphomas (PTCL). Specimens from 169 nodal PTCL were assessed for intratumoural Gal-1 expression by immunohistochemistry. Overall survival (OS) in groups exhibiting high and low Gal-1 expression was compared in the cohort and in a subset analysis of CD30-positive PTCL only. Gal-1 expression was also correlated with biomarkers of the tumour microenvironment. No significant difference in OS based on Gal-1 expression was observed in the entire PTCL cohort. However, in the CD30-positive cohort, patients with high Gal-1 levels had significantly poorer outcome (5 years OS 10%, 95% confidence interval CI, 1-36) than their low Gal-1 counterparts (5 years OS 48%, 95% CI, 30-64, P = .021). In univariate analyses age 60 or younger, non-elevated lactate dehydrogenase (LDH), and performance score less than 2 correlated with superior survival but high Gal-1 expression significantly predicted adverse outcome at both univariate (HR 2.5, 95% CI, 1.1-5.7, P = .026) and multivariate levels (HR 3.2, 95% CI, 1.2-8.5, P = .017). Tumours with high Gal-1 had few cytotoxic T cells in the tumour microenvironment. High intratumoural Gal-1 expression before therapeutic intervention correlates with adverse outcome in nodal CD30+ , ALK- PTCL patients.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Galectina 1/metabolismo , Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/mortalidade , Linfoma de Células T Periférico/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral , Adulto Jovem
5.
Nat Commun ; 10(1): 4343, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554817

RESUMO

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.


Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA , Epigenômica/métodos , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/metabolismo , Feminino , Glioma/classificação , Glioma/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Análise de Sobrevida , Sequenciamento Completo do Exoma/métodos
6.
Genet Test Mol Biomarkers ; 23(8): 589-597, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31373849

RESUMO

Objectives: Anaplastic lymphoma kinase (ALK) is one of the leading therapeutic targets in patients with non-small cell lung cancer (NSCLC). However, the clinical importance that the percentage of ALK-positive tumor cells has on NSCLC remains unclear. Methods: A total of 344 ALK-positive patients were enrolled in this study. The percentage of ALK-positive tumor cells was identified by fluorescence in situ hybridization. The discrimination and calibration analyses of the nomogram were estimated with Harrell's C-index. Results: Higher percentages (≥50%) of ALK-positive tumor cells were significantly correlated with male gender, poor differentiation, and normal levels of carbohydrate antigen 153 (CA153) and blood platelets (p < 0.05). A shorter first-line progression-free survival (PFS) was correlated with a lower percentage (15-49%) of ALK-positive tumor cells, chemotherapy, a poor performance state, non-adenocarcinoma, as well as abnormal CA153 and Cyfra21-1 levels; and an abnormal thrombin time (p < 0.05). A low percentage of ALK-positive tumor cells, crizotinib treatment, CA153 levels, and neutrophil count were independent risk factors for poor PFS in the multivariate analysis (p < 0.05). The nomogram showed a C-index of 0.76 for first-line PFS. Conclusion: A nomogram including the percentage of ALK-positive tumor cells may act as a crucial indicator for first-line PFS in ALK-positive NSCLC patients.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/enzimologia , Sobreviventes de Câncer , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Análise de Sobrevida
7.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412611

RESUMO

In 2011, the Vysis Break Apart ALK fluorescence in situ hybridization (FISH) assay was approved by the United States Food and Drug Administration as a companion diagnostic for detecting ALK rearrangement in lung cancer patients who may benefit from treatment of tyrosine kinase inhibitor therapy. This assay is the current "gold standard". According to updated ALK testing guidelines from the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology published in 2018, ALK immunohistochemistry is formally an alternative to ALK FISH, and simultaneous detection of multiple hot spots, including, at least, ALK, ROS1, RET, MET, ERBB2, BRAF and KRAS genes is also recommended while performing next generation sequencing (NGS)-based testing. Therefore, ALK status in a specimen can be tested by different methods and platforms, even in the same institution or laboratory. In this review, we discuss several clinically relevant technical aspects of ALK FISH, including pros and cons of the unique two-step (50- to 100-cell) analysis approach employed in the Vysis Break Apart ALK FISH assay, including: the preset cutoff value of ≥15% for a positive result; technical aspects and biology of discordant results obtained by different methods; and incidental findings, such as ALK copy number gain or amplification and co-existent driver mutations. These issues have practical implications for ALK testing in the clinical laboratory following the updated guidelines.


Assuntos
Quinase do Linfoma Anaplásico/genética , Rearranjo Gênico , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Algoritmos , Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores Tumorais , Amplificação de Genes , Dosagem de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Mutação
8.
Future Oncol ; 15(24): 2841-2855, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31364872

RESUMO

Aim: Patient-reported outcomes (PRO) can support clinically relevant primary end points. Materials & methods: The ALTA trial, an open-label, Phase II, randomized dose-comparison study, evaluated the safety and efficacy of brigatinib in ALK+ non-small-cell lung cancer. PRO data collection included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30). A linear mixed model for repeated measures was used to analyze change from baseline in the Global Health Status/Quality of Life subscale (GHS/QOL), with a change of greater than or equal to ten points deemed meaningful. Results: Improvement in mean GHS/QOL scores was statistically significant in the majority of treatment cycles; <10% of patients experienced a meaningful worsening of their GHS/QOL and symptom scores. Conclusion: PRO-measured benefits are consistent with objective response benefits associated with brigatinib.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organofosforados/efeitos adversos , Compostos Organofosforados/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida
9.
J Enzyme Inhib Med Chem ; 34(1): 1426-1438, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401883

RESUMO

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/química , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
10.
Zhongguo Fei Ai Za Zhi ; 22(8): 488-493, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31451138

RESUMO

BACKGROUND: Anaplastic lymphoma kinase (ALK) positive in non-small cell lung cancer (NSCLC) was about 5%-7% and ALK tyrosine kinase inhibitor (TKI) was the standard treatment in NSCLC. The aim of this study is to evaluate the efficacy and safety of crizotinib in patients with advanced ALK gene-positive or recurrent NSCLC. METHODS: Three methods were used to screen patients with advanced or recurrent NSCLC harboring ALK gene fusion/translocation. The patients with ALK positive tested by flourescence in situ hybridization (FISH) was given orally crizotinib, 250 mg, bid. The objective response rate (ORR), progression-free survival (PFS) and safety were evaluated. RESULTS: A total of 226 patients were screened, 39 of whom had ALK fusion or translocation, and 37 were enrolled in the study. 35 patients were evaluated for objective response, ORR was 70.3%, and disease control rate (DCR) was 94.6%, and median PFS was 11.8 mon. The main adverse reactions were elevated transaminase (Grade 1, 91.7%), elevated transaminases (Grade 2, 23.4%), nausea (Grade 1, 75.6%), anemia (Grade 1-2, 62.3%), visual impairment (Grade 1, 21.8%), weight loss (Grade 1, 31.4%), pneumonia (Grade 2, 3.5%). CONCLUSIONS: Crizotinib can be used for the treatment of advanced NSCLC with ALK fusion/translocation. It is highly effective and well tolerated.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Crizotinibe/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do Tratamento , Adulto Jovem
11.
Zhongguo Fei Ai Za Zhi ; 22(8): 507-511, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31451141

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) with neuroendocrine differentiation (NED) was a new pathologic type and uncommon in clinics. The aim of this study is to observe the relationship between clinical pathologic characteristics, imagination, biological behavior and prognosis in NSCLC-NED. METHODS: The clinical data of 47 patients with NSCLC-NED admitted from January 2009 to November 2017 in the Fifth Medical Center of General Hospital of People's Liberation Army were collected. The demographic data and imaging characteristics were summarized. Pathological features, treatment and prognosis, analysis of the correlation between different factors and prognosis. RESULTS: Of the 47 patients with NSCLC-NED, the median age was 61 years (45 years-78 years), 38 males and 9 females; 37 were poorly differentiated cancer with NED, and 10 were middle differentiated cancer with NED; 2 cases of driving gene positive (1 case of EGFR sensitive mutation, 1 case of ALK fusion), objective response rate (ORR) of first-line chemotherapy was 34.5%, and median progression-free survival (PFS) was 4 months; the median overall survival (OS) was 11 months, and only 2 cases (4.2%, 2/47) of OS were over 2 years. CONCLUSIONS: NSCLC-NED is different from simple NSCLC or pulmonary neuroendocrine tumors. Males, ≤70 years old, severely smoking, and patients with lower tumor differentiation often have NED, and most of them are stage IV. This type of patient-driven gene positive proportion is lower than the general adenocarcinoma population, less sensitive to chemotherapy, and the overall survival is shorter, indicating a poor prognosis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Tumores Neuroendócrinos/patologia , Idoso , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/mortalidade , Estudos Retrospectivos
12.
Eur J Med Chem ; 182: 111571, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425908

RESUMO

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/síntese química , Crizotinibe/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Radioisótopos de Flúor , Humanos , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Cintilografia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Distribuição Tecidual
13.
Medicine (Baltimore) ; 98(32): e16702, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393373

RESUMO

CD30 is a member of the tumor necrosis factor family of cell surface receptors normally expressed in lymphocytes, as well as some lymphomas, but has been described in other malignancies. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that belongs to the insulin receptor superfamily, and is normally expressed in neural cells, but has been detected in several malignancies. There is conflicting data in the literature that describes the expression of these receptors in breast cancer, and the aim of this study is to test the expression of CD30 and ALK in a cohort of Middle Eastern patients with breast carcinoma.Cases of invasive breast cancer from the archives of AUBMC were reviewed over a period of 9 years, and the blocks that were used for immunohistochemical staining for ER, PR, Her-2/neu were selected. Immunohistochemical staining for CD30 (JCM182) and ALK (5A4 and D5F3) was performed.Two hundred eighty-four cases were identified (2 cases were male), with a mean age of 55 ±â€Š12. CD30 and ALK expression was not seen in any of the cases.Our cohort showed complete negativity to both CD30 and ALK, adding to the conflicting data available in the literature, and more studies are needed to reliably identify a trend of expression of CD30 and ALK in breast carcinoma, especially in the Middle East.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Neoplasias da Mama/metabolismo , Antígeno Ki-1/metabolismo , Adulto , Idoso , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Medicine (Baltimore) ; 98(32): e16754, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393391

RESUMO

RATIONALE: Pulmonary sarcomatoid carcinoma (PSC) represents <1% of all lung cancers and is characterized by a very poor prognosis. The optimal therapeutic regimen remains unclear. We describe a rare case of PSC with both anaplastic lymphoma kinase (ALK)-arranged and high levels of programmed death ligand 1 (PD-L1) expression. PATIENT CONCERNS: A 46-year-old woman, nonsmoker, came to our attention due to uncontrolled pain in the lower left limb. DIAGNOSIS: PSC with both ALK rearrangement and high levels of PD-L1 expression. INTERVENTIONS: The patient started first-line systemic treatment with pembrolizumab reporting stable disease; at progression, she received second-line treatment with crizotinib. The treatment was not well-tolerated, and the patient then underwent 5 cycles of ceritinib treatment. OUTCOMES: The patient showed a partial response to targeted therapy. At progression, brigatinib was initiated, but the patients reported liver progression soon after the initiation of this therapy. LESSONS: Molecular-driven investigation is necessary in PSC for treatment selection.


Assuntos
Carcinossarcoma/patologia , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinossarcoma/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade
15.
Acta Med Acad ; 48(1): 116-120, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31264439

RESUMO

OBJECTIVE: We report a female patient diagnosed with a leiomyosarcoma and who harbored a druggable target as identified by comprehensive genomic profiling in the course of clinical care. CASE REPORT: The patient progressed five years after curative intent surgery and adjuvant treatment. After failure of multiple lines of chemotherapy,she was enrolled in a trial of an ALK inhibitor based on comprehensive genomic profiling (CGP) identifying an TNS1-ALK fusion. CONCLUSION: In this case, identification of the ALK kinase fusion permitted enrollment in a matched mechanism driven clinical trial after exhausting standard of care treatment options. CGP raises the possibility of uterine inflammatory myofibroblastic tumor as an alternative diagnosisto leiomyosarcoma, highlighting the complementary role of CGP beyond immunohistochemical analyses.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Genômica , Leiomiossarcoma/diagnóstico , Neoplasias de Tecido Muscular/diagnóstico , Tensinas/metabolismo , Neoplasias Uterinas/patologia , Adulto , Biomarcadores Tumorais/metabolismo , Feminino , Testes Genéticos , Humanos , Leiomiossarcoma/genética , Neoplasias de Tecido Muscular/genética , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética
16.
Eur J Med Chem ; 179: 358-375, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260890

RESUMO

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC50 = 6.27 µM and 10.71 µM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALKL1196M with an IC50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC50: 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1G2032R. Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Células A549 , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/química , Relação Estrutura-Atividade
17.
Pathol Int ; 69(6): 366-371, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31215130

RESUMO

A 35-year-old Japanese man who had experienced hoarseness for 10 years presented with a vocal cord lesion. A gross examination revealed a left vocal cord polyp occupying two-thirds of the vocal space. The endoscopically resected lesion contained scattered atypical fibroblastic, stellate, or ganglion-like cells with mucoid stroma. Vacuolated cells were also seen. Lymphoplasmacytic infiltrate was largely undetectable. A vocal cord polyp was first suspected, but well-differentiated liposarcoma and inflammatory myofibroblastic tumor (IMT) were included in the differential diagnoses. The tumor cells were positive for anaplastic lymphoma kinase (ALK), calponin, and vimentin, and negative for other smooth muscle markers by immunohistochemistry. Structures resembling myofibroblasts were not observed by electron microscopy, which confirmed abundant rough endoplasmic reticulum in the tumor cells and accumulated lipid droplets in some tumor cells. ALK gene rearrangement was detected by fluorescence in situ hybridization, and TIMP3-ALK fusion was confirmed by 5' rapid amplification of cDNA ends. We diagnosed the lesion as an IMT, and an ALK-rearranged stellate cell tumor may be postulated. This is the first report of a fusion partner gene of ALK in a case of laryngeal IMT.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Granuloma de Células Plasmáticas/patologia , Miofibroblastos/patologia , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Adulto , Biomarcadores Tumorais/genética , Granuloma de Células Plasmáticas/diagnóstico , Humanos , Masculino , Receptores Proteína Tirosina Quinases/genética , Prega Vocal/metabolismo
18.
Zhongguo Fei Ai Za Zhi ; 22(6): 329-335, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31196365

RESUMO

BACKGROUND: Pneumonic-type lung carcinoma is a special type of lung cancer both clinically and radiologically. Here we present our experience on pneumonic-type lung carcinoma in an attempt to investigate the clinical, radiological and pathological features, diagnostic procedures, treatment, and prognosis of this type of tumor. METHODS: Pathologically confirmed lung cancer with a chest CT characterized by ground glass opacity or consolidation was defined as pneumonic-type lung carcinoma. Cases with advanced pneumonic-type lung carcinoma admitted to Peking Union Medical College Hospital (PUMCH) from January 1, 2013 to August 30, 2018 were enrolled. Retrospective analysis of clinical data and survival follow-up of these patients was conducted. RESULTS: A total of 46 cases were enrolled, all of which were adenocarcinoma. Cough (41/46, 89.1%) and expectoration (35/46, 76.1%) were the most prominent symptoms. The most frequent chest CT findings were ground glass attenuation (87.0%), patchy consolidation (84.8%), and multiple ground-glass nodules (84.8%). Multiple cystic changes (40%) and cavitation (13%) were also quite frequent. Ipsilateral and contralateral intrapulmonary metastasis were noted in 95.3% and 84.8% of cases respectively. The median duration from symptom onset to diagnosis was 214 days (95%CI: 129-298). Both surgical lung biopsy and CT-guided percutaneous lung biopsy had a diagnostic yield of 100%. Transbronchial lung biopsy (TBLB) combined with bronchoalveolar lavage (BAL) had a diagnostic yield of 80.9% (17/21). Sputum cytology had a diagnostic yield of 45% (9/20). Twenty-six cases were invasive mucinous adenocarcinoma (26/46, 56.5%) and the remainder were unable to identify pathological subtypes due to lack of adequate biopsy sample size. EGFR mutation was detected in 15.8% (6/38) of patients and ALK rearrangement was detected in 3.0% (1/33) of patients. The median overall survival for these patients was 522 d (95%CI: 424-619). In patients without EGFR mutation or ALK rearrangement, chemotherapy significantly improved survival (HR=0.155, P=0.002,2). The median overall survival was 547 d (95%CI: 492-602 d) with chemotherapy and 331 d (95%CI: 22-919) without chemotherapy. CONCLUSIONS: Diagnosis of pneumonic-type carcinoma is usually delayed due to clinical and radiological features mimicking pulmonary infection. TBLB combined with BAL has a quite high diagnostic yield. The most frequent histological type is invasive mucinous adenocarcinoma. The incidence of EGFR mutation or ALK rearrangement is low in pneumonic-type carcinoma. For patients without cancer driver genes, chemotherapy is recommended to improve overall survival.


Assuntos
Carcinoma/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Idoso , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/genética , Carcinoma/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios X
19.
Blood ; 134(2): 171-185, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31151983

RESUMO

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.


Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica/fisiologia , Linfoma Anaplásico de Células Grandes/metabolismo , Transdução de Sinais/fisiologia , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Linfoma Anaplásico de Células Grandes/genética , Regulação para Cima
20.
Cancer Radiother ; 23(4): 346-354, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31130373

RESUMO

While the prognosis of metastatic non-small-cell lung cancer has shown significant progress these last years, notably with the discovery of oncogen-driven subtypes and the development of targeted therapies, significant improvements are still needed. More recently, numerous authors studied the oligo-metastasis concept, where the metastasis are limited in number and sites involved, and that could benefit from an aggressive approach of these lesions, for instance with the help of stereotactic radiotherapy. Nevertheless, there is no clear consensus existing for the time being for the treatment of these tumors. Three main clinical situations can be distinguished: oligo-metastasis state de novo at diagnosis (synchronous) or as first metastatic event of an initially locally limited affection (metachronous); oligo-progression during systemic treatment of a pluri-metastatic disease; and finally oligo-persistence of some remaining metastatic lesions at the nadir of the systemic therapy effect. In this review, we will discuss the place of stereotactic radiotherapy in the treatment of non-small-cell oligo-metastatic oncogene-addicted cancers treated with targeted therapies, differentiating these three main clinical situations. In all these indications, this technique could provide a benefit in terms of local control, possibly even in specific survival, when associated with targeted therapy continuation, related to local control of the oligo-metastatic cerebral or extracerebral lesions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Metástase Neoplásica/terapia , Radiocirurgia , Quinase do Linfoma Anaplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico
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