RESUMEN
The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .
Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Benzofuranos , Unión Esofagogástrica , Paclitaxel , Neoplasias Gástricas , Humanos , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Unión Esofagogástrica/patología , Unión Esofagogástrica/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Benzofuranos/uso terapéutico , Benzofuranos/administración & dosificación , Benzofuranos/efectos adversos , Adulto , Método Doble Ciego , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Quinazolinas/uso terapéutico , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Supervivencia sin Progresión , Anciano de 80 o más AñosRESUMEN
Background: Although immunotherapy combined with targeted therapy can be effective for hepatocellular carcinoma (HCC), not all HCC patients respond to this treatment. Models for predicting tumour response in HCC patients receiving immunotherapy combined with targeted therapy are lacking. Methods: A total of 221 HCC patients from two independent prospective cohorts were retrospectively reviewed. The patients were randomly divided into training and validation cohorts at a ratio of 7:3. Standard clinical data were collected from each patient, including age, sex, hepatitis B infection status, laboratory tests, and immune target-related adverse events (itrAEs). Tumour responses were evaluated using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 guidelines. ItrAEs were assessed based on the Common Terminology Criteria for Adverse Events version 4.0. The nomogram for tumour response prediction was constructed based on the results of the multivariate logistic regression analysis, areas under the receiver operating characteristic curves (AUROCs) were used to determine the sensitivity and specificity of the model, and calibration plots and Hosmer-Lemeshow chi-square tests were performed to assess the calibration of the model. Results: In the multivariate logistic regression analysis, a solitary tumour (P=0.006), neutropenia (P=0.003) and hypertension (P=0.042) independently predicted objective response (OR). A nomogram for OR was established with AUROCs of 0.734, 0.675, 0.730, and 0.707 in the training, validation, first-line and second-line treatment sets, respectively. Tumour sizes less than 5 cm (P=0.005), a solitary tumour (P=0.037), prognostic nutritional indices greater than or equal to 54.3 (P=0.037), neutropenia (P=0.004) and fatigue (P=0.041) independently predicted disease control (DC). A nomogram for DC was established with AUROCs of 0.804, 0.667, and 0.768 in the training, first-line and second-line treatment sets, respectively. All the Hosmer-Lemeshow tests and calibration curves showed acceptable calibration. Conclusions: The current provides clinicians with new insights into selecting patients for immunotherapy combined with targeted therapy and contributes to the development of immunotherapy for HCC. It is necessary to expand the scale of our research and perform prospective studies to verify our findings.
RESUMEN
Diallyl disulfide (DADS) is characterized as an effective agent for the prevention and therapy of cancer, however, mechanisms regarding its anticancer effects are not fully clarified. In the present study, we compared the protein expression profile of gastric cancer MGC-803 cells subjected to DADS treatment with that of untreated control cells to explore potential molecules regulated by DADS. Using proteomic approaches, we identified 23 proteins showing statistically significant differences in expression, including 9 upregulated and 14 downregulated proteins. RT-PCR and western blot analysis confirmed that retinoid-related orphan nuclear receptor α (RORα) and nM23 were increased by DADS, whereas LIM kinase-1 (LIMK1), urokinase-type plasminogen activator receptor (uPAR) and cyclin-dependent kinase-1 (CDK1) were decreased. DADS treatment and knockdown of uPAR caused suppression of ERK/Fra-1 pathway, downregulation of urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9) and vimentin, and upregulation of tissue inhibitor of metalloproteinase-3 (TIMP-3) and E-cadherin, concomitant with inhibition of cell migration and invasion. Moreover, knockdown of uPAR potentiated the effects of DADS on MGC-803 cells. These data demonstrate that downregulation of uPAR may partially be responsible for DADS-induced inhibition of ERK/Fra-1 pathway, as well as cell migration and invasion. Thus, the discovery of DADS-induced differential expression proteins is conducive to reveal unknown mechanisms of DADS anti-gastric cancer.
Asunto(s)
Compuestos Alílicos/farmacología , Disulfuros/farmacología , Proteoma/metabolismo , Neoplasias Gástricas/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Proteómica/métodos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Transducción de Señal/efectos de los fármacos , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Vimentina/metabolismoRESUMEN
Diallyl disulfide (DADS) has been shown to cause G2/M phase cell cycle arrest in several human cancers. Here we demonstrate a mechanism by which DADS induces G2/M phase arrest in BGC823 human gastric cancer cells via Chk1. From cell cycle gene array results, we next confirmed that cyclin B1 expression was decreased by DADS, while the expression of p21, GADD45α and p53 were increased. Despite the lack of change in Chk1 gene expression in response to DADS according to the array analysis, intriguingly overexpression of Chk1, but not Chk2, exhibited increased accumulation in G2/M phase. Moreover, overexpression of Chk1 promoted the effect of DADS-induced G2/M arrest. Augmented phosphorylation of Chk1 by DADS was observed in Chk1-transfected cells, followed by downregulation of Cdc25C and cyclin B1 proteins. In contrast, phosphorylated Chk2 showed no obvious change in Chk2-transfected cells after DADS treatment. Furthermore, knockdown of Chk1 by siRNA partially abrogated DADS-induced downregulation of Cdc25C and cyclin B1 proteins and G2/M arrest. In contrast, knockdown of Chk2 did not show these effects. Therefore, these data indicate that DADS may specifically modulate Chk1 phosphorylation, and DADS-induced G2/M phase arrest in BGC823 cells could result in part from Chk1-mediated inhibition of the Cdc25C/cyclin B1 pathway.
Asunto(s)
Compuestos Alílicos/efectos adversos , Disulfuros/efectos adversos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Proteínas Quinasas/metabolismo , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Ciclina B1/genética , Ciclina B1/metabolismo , Regulación hacia Abajo , Humanos , Fosforilación , Proteínas Quinasas/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Fosfatasas cdc25/genética , Fosfatasas cdc25/metabolismoRESUMEN
miR-185 has been identified as an important factor in several cancers such as breast cancer, ovarial cancer, and prostate cancer. However, its effect and prognostic value in gastric cancer are still poorly known. In this study, we found that the expression levels of miR-185 were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Moreover, miR-185 might independently predict OS and RFS in gastric cancer. We further found that upregulation of miR-185 inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. Taken together, our findings demonstrate that the miR-185 is important for gastric cancer initiation and progression and holds promise as a prognostic biomarker to predict survival and relapse in gastric cancer. It is also a potential therapeutic tool to improve clinical outcomes in the above disease.