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PURPOSE: The KUNPENG study aimed to evaluate the efficacy and safety of vebreltinib (also known as bozitinib, APL-101, PLB-1001, and CBT-101), a potent and highly selective inhibitor of c-mesenchymal-epithelial transition (MET), in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring c-Met alterations. METHODS: This multicenter, multicohort, open-label, single-arm, phase II trial enrolled patients with c-Met dysregulated, locally advanced or metastatic NSCLC from January 2020 to August 2022 across 17 centers. Cohort 1 included patients with MET exon 14 skipping (METex14)-mutant NSCLC who had not previously received MET inhibitors. Participants were administered vebreltinib at a dosage of 200 mg twice a day in 28-day cycles. The primary end point was the objective response rate (ORR), and the key secondary end point was the duration of response (DoR), both evaluated by a blinded independent review committee according to the RECIST version 1.1. RESULTS: As of August 9, 2022, 52 patients had been enrolled in cohort 1, of whom 35 (67.3%) were treatment-naïve. The ORR reached 75% (95% CI, 61.1 to 86). Among treatment-naïve patients, the ORR was 77.1% (95% CI, 59.9 to 89.6), and in previously treated patients, it was 70.6% (95% CI, 44.0 to 89.7). The disease control rate was 96.2%, with a median DoR of 15.9 months, a median progression-free survival of 14.1 months, and a median overall survival of 20.7 months. The most common treatment-related adverse events were peripheral edema (82.7%), QT prolongation (30.8%), and elevated serum creatinine (28.8%). CONCLUSION: Vebreltinib has shown promising efficacy and a favorable safety profile in patients with METex14-mutant NSCLC.
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BACKGROUND: The present study analyzed the relationship between clinical features and the T790M mutation in non-small cell lung cancer (NSCLC) patients resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. METHODS: NSCLC patients with resistance to first-generation EGFR-TKIs in which the disease control time was more than 6 months after initial TKI treatment were enrolled. T790M mutation analysis was performed using one of the following methods according to each manufacturer's protocols: Cobas EGFR mutation test (41/105, 39.0%), digital PCR (42/105, 40.0%) or Scorpion amplification refractory mutation system (ARMS) (22/105, 21.0%). Sample type of T790M was from tissue only (53/105, 50.5%), plasma only (46/105, 43.8%), tissue and plasma (6/105, 5.7%). RESULTS: Of 105 patients, 57 were T790M-positive and 48 were T790M-negative. T790M-positive patients had longer progression-free survival (PFS) after initial EGFR-TKI treatment (p = 0.019). T790M positivity was more frequent in patients treated with gefitinib than in those treated with icotinib (65% vs 40.54%, p = 0.018). The rate of T790M positivity was lower in patients with EGFR L858R (44.44%, 12/27) before TKI treatment than in those with EGFR 19del (72.0%, 36/50, p = 0.036). Patients who achieved PR after initial EGFR-TKI treatment had a higher rate of T790M positivity than those with SD (75.76% vs 50%, p = 0.023). There was no relationship between T790M status and age, gender, primary site, metastasis site, or treatment before TKI. CONCLUSION: Progression-free survival (PFS), drug type, response to initial EGFR-TKI treatment, and EGFR status before initial EGFR treatment were associated with the frequency of T790M mutation.
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EphB3 is a member of the EPH family of receptors and has been found to play a role in the carcinogenesis of some human cancers. However, its expression and clinical significance in gastric cancer (GC) have not been well documented. In the present study, we detected the expression of EphB3 in GC and adjacent noncancerous tissues and explored its relationships with the clinicopathological features and prognosis of GC patients. It was found that EphB3 silenced GC cells epigenetically by direct transcriptional repression of GC cells via polycomb group protein EZH2 mediation. EphB3 was downregulated in GC cells and tissues, and EphB3 depletion promoted GC cell growth and invasion, while ectopic overexpression of EphB3 produced a significant anti-tumor effect. EphB3 was found to be involved in epithelial-mesenchymal transition by regulating E-cadherin and vimentin expression. In addition, patients with reduced EphB3 expression had shorter disease-free survival (DFS), indicating that EphB3 may prove to be a biomarker for prognosis of GC. These results demonstrated that EphB3 functioned as a tumor-suppressor and prognostic biomarker in GC.
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Caderinas/biossíntese , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Receptor EphB3/biossíntese , Neoplasias Gástricas/metabolismo , Vimentina/biossíntese , Caderinas/genética , Linhagem Celular Tumoral , Intervalo Livre de Doença , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Transição Epitelial-Mesenquimal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Receptor EphB3/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Vimentina/genéticaRESUMO
Recently, long non-coding RNAs (lncRNAs) have been recognized as playing key roles in regulating cellular processes, such as proliferation, invasion, and metastasis. These lncRNAs have been shown to be abnormally expressed in tumorigenic processes. However, the role and clinical relevance of LUCAT1 in non-small-cell lung cancer (NSCLC) remain unclear. In this study, we found that the expression of LUCAT1 was significantly up-regulated in NSCLC tissues compared to non-tumor tissues, and its expression was associated with tumor size, tumor-node-metastasis (TNM) stage and overall survival (OS). Further experiments showed that LUCAT1 knockdown inhibited cell proliferation both in vitro and in vivo. Mechanistic investigations showed that LUCAT1 plays a key role in G0/G1 arrest. We further demonstrated that LUCAT1 was associated with polycomb repressor complexes (PRC2) and that this association was required for epigenetically repression of p21 and p57, thus contributing to the regulation of NSCLC cell cycle and proliferation. In summary, our results show that LUCAT1 could regulate tumorigenesis of NSCLC and be biomarker for poor prognosis in NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Epigênese Genética , Neoplasias Pulmonares/genética , Interferência de RNA , RNA Longo não Codificante/genética , Adulto , Idoso , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Biologia Computacional/métodos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Estadiamento de Neoplasias , PrognósticoRESUMO
AIM: To investigate the prognostic significance of perioperative leukopenia in patients with resected gastric cancer. METHODS: A total of 614 eligible gastric cancer patients who underwent curative D2 gastrectomy and adjuvant chemotherapy were enrolled in this study. The relationship between pre- and postoperative hematologic parameters and overall survival was assessed statistically, adjusted for known prognostic factors. RESULTS: The mean white blood cell count (WBC) significantly decreased after surgery, and 107/614 (17.4%) patients developed p-leukopenia, which was defined as a preoperative WBC ≥ 4.0 × 10(9)/L and postoperative WBC < 4.0 × 10(9)/L, with an absolute decrease ≥ 0.5 × 10(9)/L. The neutrophil count decreased significantly more than the lymphocyte count. P-leukopenia significantly correlated with poor tumor differentiation and preoperative WBC. A higher preoperative WBC and p-leukopenia were independent negative prognostic factors for survival [hazard ratio (HR) = 1.602, 95% confidence interval (CI): 1.185-2.165; P = 0.002, and HR = 1.478, 95%CI: 1.149-1.902; P = 0.002, respectively] after adjusting for histology, Borrmann type, pTNM stage, vascular or neural invasion, gastrectomy method, resection margins, chemotherapy regimens, and preoperative WBC count. The patients with both higher preoperative WBC and p-leukopenia had a worse prognosis compared to those with lower baseline WBC and no p-leukopenia (27.5 mo vs 57.3 mo, P < 0.001). CONCLUSION: Preoperative leukocytosis alone or in combination with postoperative leukopenia could be independent prognostic factors for survival in patients with resectable gastric cancer.
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Gastrectomia , Leucocitose/sangue , Leucopenia/sangue , Neoplasias Gástricas/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Feminino , Gastrectomia/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Leucocitose/diagnóstico , Leucocitose/mortalidade , Leucopenia/diagnóstico , Leucopenia/mortalidade , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Período Perioperatório , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/sangue , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Although ovarian metastasis secondary to gastric cancer (Krukenberg tumor) has been extensively described in the literature, gastric metastasis from ovarian carcinoma is rare. The present case report describes a patient with gastric metastasis from ovarian carcinoma. A 51-year-old female with previously treated ovarian carcinoma of stage III according to the International Federation of Gynecology and Obstetrics was admitted to the Department of Oncology, First Affiliated Hospital of Nanjing Medical University (Nanjing, China) with high serum carbohydrate antigen-125 levels. Endoscopic ultrasound and 18F-fluorodeoxyglucose positron emission tomography/computed tomography scanning revealed a lesion in the stomach with the typical appearance of a gastrointestinal stromal tumor. The histopathological examination revealed infiltration of the resected specimens by metastatic serous adenocarcinoma and a comparison with the previously resected ovarian specimen confirmed disease recurrence. Although isolated gastric recurrence from ovarian carcinoma is rare, when a patient has a history of ovarian carcinoma (particularly with a high CA-125 level) and when the imaging results show a mass in the stomach wall, metastasis from ovarian carcinoma should be considered.
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Colorectal cancer (CRC) remains an important public health problem in the world. Long noncoding RNA (lncRNA) is an RNA molecular that is longer than 200 nucleotides and cannot be translated into a protein. Recent studies have shown that lncRNAs play important roles in carcinogenesis and cancer metastasis. The aim of this study was to evaluate the expression and biological role of lncRNA maternally expressed gene 3 (MEG3) in colorectal cancer. Quantitative real-time-PCR (qRT-PCR) was performed to investigate the expression of MEG3 in tumor tissues and corresponding nontumor colorectal tissues from 62 patients. The lower expression of MEG3 was remarkably correlated with low histological grade, deep tumor invasion, and advanced tumor node metastasis (TNM) stage. Multivariate analyses revealed that MEG3 expression served as an independent predictor for overall survival. Further experiments revealed that overexpressed MEG3 significantly inhibited CRC cell proliferation both in vitro and in vivo. In conclusion, our study demonstrated that MEG3 is involved in the development and progression of colorectal cancer by regulating cell proliferation and shows that MEG3 may be a potential diagnostic and prognostic target in patients with colorectal cancer.
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Biomarcadores Tumorais/biossíntese , Proliferação de Células/genética , Neoplasias Colorretais/genética , RNA Longo não Codificante/biossíntese , Idoso , Apoptose/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante/genéticaRESUMO
Long non-coding RNAs (lncRNAs) are a novel class of RNA molecules defined as transcripts longer than 200 nucleotides that lack protein coding potential. LncRNA IRAIN has been verified that it is related to acute myeloid leukemia (AML) and breast cancer. However, there was no study to clarify whether it is involved in non-small cell lung cancer (NSCLC). Here, we demonstrated IRAIN as a tumor promoter in NSCLC. Its expression level was remarkably upregulated in NSCLC tissues and connected with tumor size and smoking status. Knockdown of IRAIN suppressed NSCLC cells proliferation in vitro. These data identify IRAIN as a novel promoting gene, which plays a vital role in tumorigenesis of NSCLC.
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Neoplasias da Mama/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
MicroRNAs are small endogenous RNAs that play important roles in the pathogenesis of human diseases, including malignancy. MicroRNA-1 (miR-1) is downregulated in non-small cell lung cancer (NSCLC); however, the underlying mechanisms by which it suppresses tumorigenesis in NSCLC are largely unknown. We investigated whether phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) was a novel target of miR-1 in the NSCLC cell line A549, and the mechanism of miR-1 inhibition of the tumorigenic properties of A549 cells is discussed. The influence of miR-1 on A549 cells was studied by transfection with miR-1 mimics or inhibitor. MiR-1 overexpression led to downregulation of PIK3CA protein, but not mRNA by western blot and quantitative real-time PCR, respectively. The dual-luciferase reporter assay confirmed that miR-1 targeted PIK3CA directly. PIK3CA downregulation by miR-1 mimics led to a significant reduction of phosphorylated Akt and survivin protein, the downstream targets of the PI3K/Akt pathway. Cell proliferation was studied using a cell counting kit. Migration and invasion were evaluated by Transwell and Matrigel assays, respectively. Cell cycle and apoptosis were detected by flow cytometry. The results were that miR-1 upregulation inhibited A549 cell proliferation, migration, and invasion. These findings indicate that miR-1 may play an important role in the pathogenesis of NSCLC by regulating PIK3CA through the PI3K/Akt pathway. Increasing miR-1 expression may provide a novel approach for NSCLC treatment.
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Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/genética , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Classe I de Fosfatidilinositol 3-Quinases , Regulação para Baixo , Citometria de Fluxo , Genes Reporter , Genes Supressores de Tumor , Humanos , Luciferases de Renilla/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Oncogenes , Inibidores de Fosfoinositídeo-3 Quinase , Plasmídeos , Reação em Cadeia da Polimerase em Tempo Real , TransfecçãoRESUMO
OBJECTIVE: To investigate the expression of forkhead box M1 (FOXM1) and its correlation with clinicopathological features and prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: The expression of FOXM1 in 68 cases of NSCLC was detected by immunohistochemistry. The FOXM1 expression in 6 tumor tissues (3 cases with negative and 3 cases with positive expression of FOXM1) was analyzed by Western blotting to confirm the immunohistochemical results. The correlation of the expression of FOXM1 with clinicopathalogical features and overall survival of the NSCLC patients was analyzed. RESULTS: The expression of FOXM1 protein was detected in the nuclei or cytoplasms of the tumor cells. The positive expression rate of FOXM1 was 36.8% (25/68). Western blotting confirmed the immunohistochemical results. The expression level of FOXM1 in advanced stage cancer was significantly higher than that in early stage NSCLC (P = 0.001). The median OS was 23.0 months in patients with negative expression of FOXM1 and 13.0 months in those with positive expression (P = 0.001). Univariate analysis revealed that histological grade, lymph nodes status, TNM stage and FOXM1 expression were significantly associated with prognosis in the NSCLC patients (P < 0.05). The Cox multivariate analysis demonstrated that lymph nodes status, TNM stage and FOXM1 expression were independent poor prognostic factors (P < 0.05). CONCLUSION: The expression status of FOXM1 in NSCLC is an independent prognostic factor and negatively correlated with prognosis.
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Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Proteína Forkhead Box M1 , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos ProporcionaisRESUMO
OBJECTIVE: To investigate the influence of the recombinant human endostatin and gemcitabine combined with HIFU on the mouse xenograft model of pancreatic cancer. METHODS: Use human pancreatic cancer cell line PANC-1 to set up the mouse xenograft model, then randomized into four arms. Each arm was treated with gemcitabine, endostatin, gemcitabine combined with endostatin and normal saline respectively. Observe the volume of the tumor, the serum VEGF level and MVD in the tumor tissue among the different arms. All mice were treated with HIFU, then pathological examination was done. RESULTS: The tumor volume, serum VEGF level and MVD in the combined-therapy arm are all lower than the monotherapy arms and the control arm. The coagulation necrosis occurred in tumors after HIFU treatment. CONCLUSION: Endostatin and gemcitabine has better effect than gemcitabine or endostatin monotherapy on the animal xenograft model of human pancreatic cancer. HIFU combined with chemotherapy and/or targeted therapy may enhance the effect for pancreatic cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/terapia , Terapia por Ultrassom/métodos , Animais , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Sistemas de Liberação de Medicamentos , Endostatinas/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microvasos/metabolismo , Neoplasias Pancreáticas/patologia , Distribuição Aleatória , Fator A de Crescimento do Endotélio Vascular/sangue , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
OBJECTIVE: The aim of this study was to investigate the changes in mTOR activity and survivin expression in liver cancer cell line HepG2 cells treated with tamoxifen. METHODS: Survivin transcription level and p70S6K was demonstrated by PCR, dual-luciferase reporter assay and Western blot analysis, respectively, and the apoptosis in the HepG2 cells was detected by flow cytometry. RESULTS: Tamoxifen leads to apoptosis of the cells and reduction in survivin expression, as well as a dramatic reduction in the activated form of p70S6K. Treating HepG2 cells with rapamycin, a specific mTOR inhibitor, significantly reduced the survivin protein level but not affected the survivin transcription, indicating that tamoxifen and rapamycin were synergistic in regards to down-regulation of survivin expression in hepatocellular carcinoma cells. CONCLUSIONS: Our results suggest that tamoxifen down-regulates survivin expression in HepG2 cells and it is mediated by transcriptional and post-transcriptional level via PI3K/Akt/mTOR pathway to induce apoptosis.
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Apoptose/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Tamoxifeno/farmacologia , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Hormonais/farmacologia , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Células Hep G2 , Humanos , Proteínas Inibidoras de Apoptose/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Survivina , Serina-Treonina Quinases TOR/antagonistas & inibidoresAssuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacologia , Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Proteínas Inibidoras de Apoptose , SurvivinaRESUMO
OBJECTIVE: To determine the expression level changes of survivin, a inhibitor of apoptosis protein, followed by activation of insulin receptors in human hepatocellular carcinoma HepG2 cell line, and to investigate the signalling pathway involved in the regulation. METHODS: Human hepatocellular carcinoma HepG2 cells were treated with insulin alone or pre-treated with LY294002, a specific inhibitor of PI3K signalling pathway, to determine whether blocking PI3K signaling can attenuate the up-regulation of survivin expression. Real time RT-PCR and Western blot analysis were used to measure survivin mRNA and protein changes before and after treatment, respectively. RESULTS: Without serum supplement, HepG2 cells expressed a small amount of survivin. Insulin induced survivin expression in a dose- and time-dependent fashion. Survivin expression was blocked if cells were pre-treated with LY294002 prior to insulin stimulation. CONCLUSION: Insulin induces survivin expression via PI3K signalling pathway, suggesting that to interfere the key gene in this signalling pathway may block survivin expression, therefore, promoting apoptosis in hepatocellular carcinoma cells.