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1.
Immunity ; 52(1): 14-16, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31951548

RESUMO

In the search for therapeutic combinations for the treatment of cancer, the pairing of targeted inhibitors of oncogenic driver pathways with immunotherapy has largely been overlooked. In Nature, Canon et al. (2019) describe how the novel KRAS-G12C inhibitor AMG 510 can potentiate immune rejection in combination with immune checkpoint blockade.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Imunoterapia , Proteínas Proto-Oncogênicas p21(ras) , Evasão Tumoral
2.
Expert Opin Ther Pat ; 30(2): 103-120, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31913776

RESUMO

Introduction: KRAS is one of the most important oncology drug targets, playing a pivotal role in the initiation and progression of many human tumors. It has long been held undruggable due to many previously failed attempts to both directly and indirectly target this challenging GTPase protein family.Areas covered: This review covers patent applications claiming inhibitors of the mutant GTPase KRASG12C that act via covalent modification of cysteine at codon 12 in the period of 2014 to the present. A total of 37 PCT applications from 9 applicants are evaluated, with the discussion organized alphabetically by assignee name.Expert opinion: The last 5 years have seen an explosion in interest around this important target with many companies aiming to capitalize on the breakthrough discovery of covalent allosteric inhibitors of the glycine to cysteine mutant form of the enzyme. The first agents from this effort have now entered clinical trials and preliminary data are encouraging with responses seen in both lung adenocarcinoma and colorectal cancer patients.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Progressão da Doença , Descoberta de Drogas , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Patentes como Assunto
3.
Anticancer Res ; 40(1): 427-433, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892597

RESUMO

BACKGROUND/AIM: The role of anti-PD1/PD-L1 therapy (IO) in NSCLC harboring driver mutations is questionable. This study aimed to examine the efficacy of IO in patients with non-small cell lung cancer (NSCLC) with a KRAS mutation (KRAS+). PATIENTS AND METHODS: We retrospectively identified NSCLC patients harboring KRAS mutation treated with IO in our Institution. We analyzed the results in comparison to non-KRAS patients. RESULTS: Among 328 consecutive KRAS+ NSCLC patients, 43 (13.1%) received IO in our Institution. In parallel 117 non-KRAS NSCLC patients treated with IO were selected for comparison. The baseline characteristics were similar between the two groups. No significant difference was observed between KRAS+ and non-KRAS patients in terms of mPFS (4.6 vs. 3.3 months, p=0.58) or OS (8.1 vs. 13.0 months, p=0.38). CONCLUSION: KRAS mutations seem to be irrelevant for selecting patients for IO that could be therefore considered an effective therapy for NSCLC patients, independently of KRAS status.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Idoso , Antígeno B7-H1/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
4.
J Photochem Photobiol B ; 202: 111672, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31778952

RESUMO

In highly proliferating cancer cells oncogenic mutations reprogram the metabolism and increase the production of reactive oxygen species (ROS). Cancer cells prevent ROS accumulation by upregulating antioxidant systems. Here we show that an increase of oxidative stress (ROS and singlet oxygen), generated by photoactivated TMPyP4, results in the upregulation of KRAS and Nrf2, the major regulator of the redox homeostasis. In agreement with a previous observation, the ectopic expression of KRAS G12D or G12 V is found to stimulate Nrf2. This suggests that ROS, KRAS and Nrf2 establish a molecular axis controlling the redox homeostasis in cancer cells. We found that this axis also modulates the function of the NF-kB/Snail/RKIP circuitry, regulating the survival and apoptosis pathways. Our data show that low ROS levels, obtained when Nrf2 is activated by KRAS, results in the upregulation of prosurvival Snail and simultaneous downregulation of proapoptotic RKIP: an expression pattern favouring cell proliferation. By contrast, high ROS levels, obtained when Nrf2 is inhibited by a small molecule (luteolin), favour apoptosis by upregulating proapoptotic RKIP and downregulating prosurvival Snail. The results of this study are useful to design efficient photodynamic therapy (PDT) against cancer. We hypothesize that cancer cells can be sensitized to PDT when the photosensitizer is used in the presence of an inhibitor of Nrf2 (adjuvant). To test this hypothesis, we used luteolin (3',4',5,7-tetrahydroflavone) as Nrf2 inhibitor, since it reduces the expression of Nrf2 and increases intracellular ROS. By means of colony formation and viability assays we found that when Nrf2 is inhibited, PDT shows an increase of efficiency up to 45%.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fator 2 Relacionado a NF-E2/genética , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Proteína de Ligação a Fosfatidiletanolamina/genética , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
5.
Acta Cytol ; 64(1-2): 124-135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31509835

RESUMO

Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the cyst type is important to provide appropriate care for the patients. It is also very clear that not one single modality can provide adequate diagnostic information. A multidisciplinary approach is the key to the diagnosis of pancreatic cysts. In this setting, the role of ancillary testing, which includes biochemical testing (carcinoembryonic antigen and amylase levels in the cyst), molecular testing (e.g., KRAS, GNAS, VHL, and CTNB1), and/or immunohistochemical tests are very important to obtain an accurate diagnosis. This review will discuss helpful ancillary tests in common pancreatic cyst neoplasms and how to approach the diagnosis of pancreatic cysts.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Cisto Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Antígeno Carcinoembrionário/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Análise Mutacional de DNA/métodos , Humanos , Imuno-Histoquímica/métodos , Mutação , Cisto Pancreático/genética , Cisto Pancreático/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética
6.
Gastroenterology ; 158(1): 226-237.e5, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31473224

RESUMO

BACKGROUND & AIMS: Long-term outcomes of patients with branch-duct intraductal papillary mucinous neoplasms (IPMNs), particularly those after 5 years of surveillance, have not been fully evaluated in large studies. We analyzed incidences of IPMN-derived carcinoma and concomitant ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]) over 20 years in a large population of patients. METHODS: We identified 1404 consecutive patients (52% women; mean age, 67.5 years) with a diagnosis of branch-duct IPMN, from 1994 through 2017, at the University of Tokyo in Japan. Using a competing risk analysis, we estimated cumulative incidence of pancreatic carcinoma, overall and by carcinoma type. We used competing risks proportional hazards models to estimate subdistribution hazard ratios (SHRs) for incidences of carcinomas. To differentiate IPMN-derived and concomitant carcinomas, we collected genomic DNA from available paired samples of IPMNs and carcinomas and detected mutations in GNAS and KRAS by polymerase chain reaction and pyrosequencing. RESULTS: During 9231 person-years of follow-up, we identified 68 patients with pancreatic carcinomas (38 patients with IPMN-derived carcinomas and 30 patients with concomitant PDACs); the overall incidence rates were 3.3%, 6.6%, and 15.0% at 5, 10, and 15 years, respectively. Among 804 patients followed more than 5 years, overall cumulative incidence rates of pancreatic carcinoma were 3.5% at 10 years and 12.0% at 15 years from the initial diagnosis. The size of the IPMN and the diameter of the main pancreatic duct associated with incidence of IPMN-derived carcinoma (SHR 1.85; 95% confidence interval 1.38-2.48 for a 10-mm increase in the IPMN size and SHR 1.56; 95% confidence interval 1.33-1.83 for a 1-mm increase in the main pancreatic duct diameter) but not with incidence of concomitant PDAC. CONCLUSIONS: In a large long-term study of patients with branch-duct IPMNs, we found the 5-year incidence rate of pancreatic malignancy to be 3.3%, reaching 15.0% at 15 years after IPMN diagnosis. We observed heterogeneous risk factor profiles between IPMN-derived and concomitant carcinomas.


Assuntos
Adenocarcinoma Mucinoso/epidemiologia , Carcinoma Ductal Pancreático/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/epidemiologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Cromograninas/genética , Progressão da Doença , Feminino , Seguimentos , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Risco
7.
J Enzyme Inhib Med Chem ; 35(1): 344-353, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31851852

RESUMO

Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01-TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC50 of 0.21 µM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-RasG12V protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Tioureia/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química
8.
APMIS ; 128(1): 3-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31628675

RESUMO

Biliary tract cancers (BTC) are a rare heterogeneous disease group with a dismal prognosis and limited treatment options. The mutational landscape consists of genetic aberrations both shared by and characteristic for anatomical location. Here, we present exome sequencing data on 22 genes from a phase 2 trial using a clinically validated panel used in patients with colorectal cancer. A total of 56 patients were included in a one-armed phase 2 trial investigating the treatment combination of capecitabine, gemcitabine, oxaliplatin, and cetuximab. Tissue DNA yield and quality allowed analysis of 30 patients on our panel including 22 genes. ARID1A (33%) and TP53 (33%) were found to be most frequently mutated followed by KRAS mutations found in 20% of the patients. Mutational aberrations in ARID1A were found more prevalent than expected, whereas TP53 and KRAS were in concordance with earlier reported data. Mutation in CTNNB1 was significantly associated with poor prognosis. Our panel is clinically validated and suitable for a high volume of samples to detect mutations in patients with BTC. However, it is reasonable to assume that the clinical utility could be optimized in this patient group by extending the panel to include BTC specific mutations with potential therapeutic consequences such as IDH1/2, FGFR fusions, ERBB3, and BRCA1/2.


Assuntos
Neoplasias dos Ductos Biliares/genética , Exoma , Mutação , Adulto , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Inclusão em Parafina , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , beta Catenina/genética
9.
Int J Cancer ; 146(1): 94-102, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199501

RESUMO

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , GTP Fosfo-Hidrolases/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/genética , Proteína Supressora de Tumor p53/genética , Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
10.
J Clin Pathol ; 73(1): 35-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31296605

RESUMO

AIMS: Precision medicine therapy is remodelling the diagnostic landscape of cancer. The success of these new therapies is often based on the presence or absence of a specific mutation in a tumour. The Idylla platform is designed to determine the mutational status of a tumour as quickly and accurately as possible, as a rapid, accurate diagnosis is of the utmost importance for the treatment of patients. This is the first complete prospective study to investigate the robustness of the Idylla platform for EGFR, KRAS and BRAF mutations in non-small cell lung cancer, metastatic colorectal cancer and metastatic melanoma, respectively. METHODS: We compared prospectively the Idylla platform with the results we obtained from parallel high-throughput next-generation sequencing, which is the current gold standard for mutational testing. Furthermore, we evaluated the benefits and disadvantages of the Idylla platform in clinical practice. Additionally, we reviewed all the published Idylla performance articles. RESULTS: There was an overall agreement of 100%, 94% and 94% between the next-generation panel and the Idylla BRAF, KRAS and EGFR mutation test. Two interesting discordant findings among 48 cases were observed and will be discussed together with the advantages and shortcoming of both techniques. CONCLUSION: Our observations demonstrate that the Idylla cartridge for the EGFR, KRAS and BRAF mutations is highly accurate, rapid and has a limited hands-on time compared with next-generation sequencing.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Melanoma/genética , Melanoma/secundário , Neoplasias/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fluxo de Trabalho
11.
Magy Onkol ; 63(4): 310-323, 2019 12 09.
Artigo em Húngaro | MEDLINE | ID: mdl-31821386

RESUMO

The RASopathy consortium was built from research groups of the Budapest University of Technology and Economics, Eötvös Loránd University, Semmelweis University and two startups: KINETO Lab Ltd. and Fototronic Ltd. The goal was to design and test novel covalent and allele-specific KRAS small molecular inhibitors. KRAS is the most frequently mutated human oncogene which was unsuccessfully targeted until recently. The consortium established G12C-expressing bacterial and human cancer cell models (homo- and heterozygous variants) of lung, colorectal and pancreatic tumors. Using covalent fragment and acrylamide warhead libraries we were able to select novel candidates of small molecular G12C-specific inhibitors which were compared to published best-in-class drug candidates.


Assuntos
Neoplasias , Alelos , Humanos , Mutação , Proteínas Proto-Oncogênicas p21(ras)
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 992-999, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31878995

RESUMO

Objective To investigate the effect of microRNA let-7i on the drug-resistant cells of human breast cancer and its potential molecular mechanisms. Methods Reverse transcription PCR was performed to detect the relative levels of let-7i expressed in breast cancer cell line MCF-7 as well as MCF-7 resistant to both cisplatin (CDDP) and adriamycin (ADR) (MCF-7/CDDP, MCF-7/ADR) cells. CCK-8 assay was used to measure the varied sensitivity of cell MCF-7, MCF-7/CDDP and MCF-7/ADR to ADR following chemotherapy. CCK-8 assay and colony formation assay were carried out to observe the change of sensitivity to ADR after let-7i was over-expressed or inhibited, and flow cytometry was used to determine the induced apoptosis of breast cancer cells resistant to ADR following over-expression of let-7i. ELISA was conducted to measure the activity of caspase-3/9 against breast cancer drug. Reverse transcription-PCR was performed to detect the mRNA levels of Bcl2 and K-Ras, and Western blot analysis to examine the protein levels of Bcl2, BAX and K-Ras. Results Let-7i was down-regulated in drug-resistant breast cancer cells as compared with simple MCF-7 cell line, and negatively correlated with chemotherapy resistance. Compared with negative control group, over-expression of let-7i resulted in improved cell viability and colony formation of drug-resistant breast cancer cells, and facilitated the cancer cell apoptosis induced by ADR, yet raised caspase-3/9 activity. Bcl2 level decreased, whereas BAX increased with added ADR concentration. Over-expressed let-7i significantly inhibited Bcl2 and K-Ras expression in the drug-resistant cells. Conclusion Let-7i is down-regulated in drug-resistant breast cancer cells, and negatively correlated with chemotherapy resistance. The findings suggest that let-7i may inhibit the resistance of drug-resistant breast cancer cells via inhibiting the expression of K-Ras and Bcl2.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Apoptose , Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Regulação para Baixo , Doxorrubicina/farmacologia , Humanos , Células MCF-7
13.
Medicine (Baltimore) ; 98(50): e18423, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852167

RESUMO

RATIONALE: Vulvar metastasis of colorectal cancer (CRC) and acquired resistance to cetuximab is a very rare phenomenon. To our knowledge, few cases have been reported in the English literatures. PATIENT CONCERNS: A 55-year-old woman was diagnosed as adenocarcinoma of the rectum and the primary tumor was detected to be Kirsten-RAS (KRAS) wild type. DIAGNOSES: The patient was diagnosed with rectal adenocarcinoma by colonoscopy. Positron emission tomography/computed tomography (PET-CT) revealed multiple lymph node and bone metastases. INTERVENTIONS: The patient received a first-line course of palliative chemotherapy with FOLFOX combined with cetuximab. OUTCOMES: After an initial response, acquired resistance to cetuximab occurred and vulvar metastasis was established by a second biopsy. Further molecular analysis showed that the KRAS mutation was detected in plasma samples and tumor tissues. LESSONS: Vulvar metastasis from CRC is relatively rare and indicates a poor prognosis. Routine physical examinations of cutaneous and subcutaneous may facilitate early detection of metastases and timely intervention of medical technology. Moreover, combining serial tumor biopsy, liquid biopsy, and radiologic imaging could help to define mechanisms of drug resistance and to guide selection of therapeutic strategies.


Assuntos
Adenocarcinoma/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Retais/patologia , Neoplasias Vulvares/secundário , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Evolução Fatal , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Mutação , Compostos Organoplatínicos/uso terapêutico , Neoplasias Vulvares/patologia
14.
Bratisl Lek Listy ; 120(11): 832-838, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31747763

RESUMO

Head and neck squamous cell carcinomas (HNSCC) are a highly heterogenous disease which can be induced by two main carcinogens - tobacco and/or alcohol, or by HR HPV infection. This work examined 60 paraffin-embedded biopsies of head and neck carcinomas after histological verification. HPV infection, including its specific types in various HNSCC areas, was studied using multiplex qPCR. Expression levels of p16INK4A and p53 were detected by subsequent IHC analysis as being potential diagnostic markers. Based on the assumption that patients with HNSCC could benefit from anti-EGFR therapy (cetuximab), but the predictors are not yet defined, analyses of point mutations of ras genes (Kras, Nras) were carried out using multiplex qPCR and sequence analysis of the Braf gene. All statistical data were processed by Chí-x2 test.HPV infection was detected in 23.34 % of cases with HNSCC, of which 100 % were HPV 16, which is the most frequently infection found in the oropharyngeal region. Using IHC analysis, a positive expression of P16INK4A was detected in 100 % of HPV-positive HNSCC while this expression was discovered to be highly correlated with HPV infection. Furthermore, a correlation between p53 and HPV-negative HNSCC was proved. The mutation incidence was the highest in the Kras gene (codon 12 and codon 146), Nras (codon 12) and Braf. A correlation between tumor location in the oropharyngeal region and Kras mutations was proved. The HPV infection correlated with Kras mutations in case of codon 146 but on the grounds of low amount of output data, these figures could be irrelevant. In one case, c.1808 G>A, protein 603 Arg>Gln mutation was found in the Braf gene but its correlation with head and neck carcinomas has not been described yet (Tab. 2, Fig. 2, Ref. 24). Keywords: head and neck carcinomas, biopsy, HPV types, PCR, p16INK4A, p53, molecular predictors, Kras, Nras, Braf.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Infecções por Papillomavirus/complicações , Carcinoma de Células Escamosas/virologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , GTP Fosfo-Hidrolases/genética , Neoplasias de Cabeça e Pescoço/virologia , Papillomavirus Humano 16 , Humanos , Imuno-Histoquímica , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética
15.
Nat Med ; 25(11): 1783-1795, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700175

RESUMO

Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Proliferação de Células/genética , Subunidade alfa do Receptor do Fator Neutrófico Ciliar/genética , Citocinas/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Subunidade alfa do Receptor do Fator Neutrófico Ciliar/química , Citocinas/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucinas/genética , Camundongos , Mutação/genética , Ligação Proteica , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cell Physiol Biochem ; 53(5): 820-831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31701729

RESUMO

BACKGROUND/AIMS: MLK4 (KIAA1804) is the second most frequently mutated kinase in microsatellite stable (MSS) colorectal carcinomas (CRC). This molecule is known to regulate different physiological cellular processes, including cell cycle, senescence and apoptosis, and mechanistic evidence has been provided that MLK4 plays a role in carcinogenesis. However, whether this kinase exerts a tumor suppressive role or an oncogenic function is still an object of debate. This study aims to elucidate the role of MLK4 in the pathogenesis of CRC by investigating human tumor specimens. METHODS: This study assessed MLK4 expression levels by immunohistochemistry in surgical tumor samples from 204 early-stage CRC patients and their correlation with various clinical-pathological features and patients' outcomes. In addition, MLK4 mRNA transcription was analysed in an independent cohort of 786 colon cancer samples. RESULTS: Loss of MLK4 staining was associated with poor overall (OS) and progression free survival (PFS) in CRC patients during a univariate analysis (OS:101 vs 164 months, p=0.0002; PFS:85 vs 125 months, p=0.0001), as well as in multivariate analysis (OS:HR=1.70; p=0.001; PFS:HR=1,61; p=0.001). This was confirmed by analysis of MLK4 mRNA in the second independent cohort. A subgroup analysis according to KRAS mutation status showed that MLK4 staining was associated with better OS and PFS in KRAS mutated cases (HR=2.77; p=0.0001 and HR=2.31; p=0.0003, respectively) and microsatellite stable tumors (HR=1.87; p=0.002 and HR=1.06; p=0.006) but not in KRAS wildtype and microsatellite unstable tumors. CONCLUSION: By providing the first report from clinical specimens on the prognostic significance of MLK4, we define an oncogenic loss-of-function of this kinase and suggest a possible role in the interaction with KRAS signaling in determining an aggressive phenotype of CRC. These findings warrant the further investigation of MLK4 in wider cohorts and various clinical settings.


Assuntos
Neoplasias Colorretais/patologia , MAP Quinase Quinase Quinases/metabolismo , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Idoso , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/genética , Masculino , Mutação , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras)/genética
17.
Anticancer Res ; 39(11): 6379-6387, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704871

RESUMO

BACKGROUND/AIM: In the present retrospective study, we assessed the molecular profile and clinicopathological correlations of Greek colorectal carcinoma (CRC) patients. PATIENTS AND METHODS: Data from 157 CRC patients were collected. High Resolution Melting Analysis and Pyrosequencing/Sanger sequencing were applied to identify KRAS, BRAF, NRAS mutations and microsatellite instability (MSI) status. Immunohistochemistry was performed to characterize the associated Mismatch Repair Protein loss. Statistical calculations were performed using the statistical package SPSS v21.0. RESULTS: KRAS mutations were detected in 39.3% of cases, BRAF in 10.9% and NRAS in 4.9%. MSI status was recognized in 11.5% of CRC patients and was associated with right colon tumors. MSI phenotype was inversely correlated with stage, N status and KRAS mutations and positively correlated with BRAF mutations. CONCLUSION: MSI positive CRCs in the Greek population are more often right-sided, free of metastasis, KRAS wild type and BRAF mutated. Providing more detailed clinicopathological and molecular data for specific populations will enable better clinical management and individualized therapy in the future.


Assuntos
Neoplasias do Colo/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Feminino , Grécia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Neoplasias do Colo Sigmoide/genética , Neoplasias do Colo Sigmoide/patologia
19.
Zhonghua Wai Ke Za Zhi ; 57(11): 840-847, 2019 Nov 01.
Artigo em Chinês | MEDLINE | ID: mdl-31694133

RESUMO

Objective: To examine the prognostic value of four important driver gene mutations in patients with radical resection of pancreatic cancer. Methods: The clinical data and follow-up data of pancreatic cancer patients undergoing radical pancreatectomy and targeted sequencing from January 2016 to March 2018 at Department of Hepato-Biliary-Pancreatic Surgery, Changhai Hospital were retrospectively analyzed.There were 159 males and 88 females,aged of (60.8±8.7)years(range:33-83 years) and preoperative CA19-9 of (492.4±496.6)kU/L(range: 2-1 200 kU/L). One hundred and fifty nine cases of tumors were located in the head and 88 cases in the body and tail of the pancreas. After univariate analysis of clinical pathological factors (including gender, age, preoperative CA19-9, tumor location, tumor differentiation, pathological T and N stage, Micr. perineural invasion, Micr. lympho-vascular invasion, resection margin), the variable whose P<0.1 was included in COX regression model with four important driver gene mutations to find which mutation was related to prognosis independently. The number of gene mutations and KRAS subgroups were analyzed by Kaplan-Meier curve. Results: Among 247 patients,the number of KRAS,TP53, SMAD4 and CDKN2A mutations was 212 cases(85.8%), 160 cases(64.8%), 66 cases(26.7%) and 44 cases(17.8%),respectively.KRAS mutation was correlated with the tumor differentiation and pathological T stage (χ(2)=24.570/6.690, P=0.000/0.035), TP53 mutation was correlated with the tumor differentiation and the resected margin(χ(2)=5.500/4.620, P=0.019/0.032), and CDKN2A mutation was correlated with gender(χ(2)=16.574, P=0.000).COX regression model analysis showed that only KRAS mutation was an independent risk factor for disease free survival and overall survival(HR=1.776, 95%CI: 1.079-2.923, P=0.024; HR=1.923, 95%CI: 1.016-3.639, P=0.045); KRAS(G12D) mutation was associated with shorter OS(P=0.007). Conclusion: KRAS and its subgroup KRAS(G12D) mutation can be used as a prognostic index for patients with radical resection of pancreatic cancer.


Assuntos
Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/sangue , Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pancreatectomia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , Proteína Smad4/genética , Proteína Supressora de Tumor p53/genética
20.
J Surg Oncol ; 120(8): 1427-1435, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31729037

RESUMO

BACKGROUND AND OBJECTIVES: Mucinous adenocarcinoma is a distinct subtype of colorectal cancer (CRC) with a worse prognosis when compared with non-mucinous adenocarcinoma. The aim of this study was to compare somatic mutations and copy number alteration (CNA) between mucinous and non-mucinous CRC. METHODS: Data from The Cancer Genome Atlas-colon adenocarcinoma and rectum adenocarcinoma projects were utilized. Mucinous and non-mucinous CRC were compared with regard to microsatellite status, overall mutation rate, the most frequently mutated genes, mutations in genes coding for mismatch repair (MMR) proteins and genes coding for mucin glycoproteins. CNA analysis and pathway analysis was undertaken. RESULTS: Mucinous CRC was more likely to be microsatellite instability-high (MSI-H) and hypermutated. When corrected for microsatellite status the single-nucleotide variation and insertion-deletion rate was similar between the two cohorts. Mucinous adenocarcinoma was more likely to have mutations in genes coding for MMR proteins and mucin glycoproteins. Pathway analysis revealed further differences between the two histological subtypes in the cell cycle, RTK-RAS, transforming growth factor-ß, and TP53 pathways. CONCLUSIONS: Mucinous CRC has some distinct genomic aberrations when compared with non-mucinous adenocarcinoma, many of which are driven by the increased frequency of MSI-H tumors. These genomic aberrations may play an important part in the difference seen in response to treatment and prognosis in mucinous adenocarcinoma.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma/genética , Neoplasias do Colo/genética , Genômica , Neoplasias Retais/genética , Adenocarcinoma/patologia , Adenocarcinoma Mucinoso/patologia , Estudos de Coortes , Neoplasias do Colo/patologia , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/genética , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação INDEL , Instabilidade de Microssatélites , Mucinas/genética , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/patologia , Proteína Smad4/genética , Fator de Crescimento Transformador beta/genética , Proteína Supressora de Tumor p53/genética
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