RESUMEN
PURPOSE: In a phase IIb trial of nimotuzumab plus gemcitabine, substantial clinical benefits were observed in patients with locally advanced or metastatic pancreatic cancer (PC). Therefore, we conducted a phase III clinical study to verify the efficacy and safety of this combination regimen in patients with K-Ras wild-type tumors (ClinicalTrials.gov identifier: NCT02395016). PATIENTS AND METHODS: Eligible patients were randomly assigned to receive nimotuzumab (400 mg once per week) or placebo followed by gemcitabine (1,000 mg/m2 on days 1, 8, and 15, once every 4 weeks) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, and safety. RESULTS: A total of 480 patients were screened; 92 patients were enrolled and 82 patients with K-Ras wild-type tumors were eligible. In the full analysis set, the median OS was 10.9 versus 8.5 months, while the restricted mean survival time (RMST) was 18.05 versus 11.14 months for the investigational versus control arm (ratio of control v investigation = 0.62 [0.40-0.97]; P = .036). Median PFS was 4.2 versus 3.6 months in the investigational versus control arm (log-rank P = .04; hazard ratio, 0.60 [0.37-0.99]) and the restricted mean PFS time was 8.08 versus 4.76 months (RMST ratio, 0.58 [0.38-0.90]; P = .036). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The objective response rates and disease control rates were 7% versus 10% and 68% versus 63% for the investigational and control groups, respectively. The incidence of adverse events were comparable between the two groups. CONCLUSION: In patients with locally advanced or metastatic K-Ras wild-type PC, nimotuzumab plus gemcitabine significantly improved OS and PFS with a good safety profile.
Asunto(s)
Gemcitabina , Neoplasias Pancreáticas , Humanos , Desoxicitidina , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Progresión de la Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
The pro-oncogene FBI-1, encoded by Zbtb7a, is a transcriptional repressor that belongs to the POK (POZ/BTB and Krüppel) protein family. In this study, we investigated a potential interaction between androgen receptor (AR) signaling and FBI-1 and demonstrated that overexpression of FBI-1 inhibited ligand-dependent AR activation. A protein-protein interaction was identified between FBI-1 and AR in a ligand-dependent manner. Furthermore, FBI-1, AR and SMRT formed a ternary complex and FBI-1 enhanced the recruitment of NCoR and SMRT to endogenous PSA upstream sequences. Our data also indicated that the FBI-1-mediated inhibition of AR transcriptional activity is partially dependent on HDAC. Interestingly, FBI-1 plays distinct roles in regulating LNCaP (androgen-dependent) and PC-3 cell (androgen-independent) proliferation.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Complejos Multiproteicos/metabolismo , Co-Represor 2 de Receptor Nuclear/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Cartilla de ADN/genética , Histona Desacetilasas/metabolismo , Humanos , Inmunoprecipitación , Luciferasas , Masculino , Plásmidos/genética , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
Nimotuzumab is a humanized anti-EGFR IgG1 monoclonal antibody and demonstrates a better safety profile than other anti-EGFR antibodies due to its intermediate affinity. Since it was approved in China for the treatment of nasopharyngeal cancer (NPC), it has been widely used in NPC and in many clinical trials for other cancer types. However, the optimal dose and administration frequency of nimotuzumab that should be used and which kind of cancer patients will be more benefited from nimotuzumab is still unknown. In this retrospective study, 205 advanced cancer patients with colorectal cancer, esophageal cancer, head and neck cancer, gastric cancer, non-small cell lung cancer, or other cancers from mainland China, treated with nimotuzumab in combination with chemotherapy, were enrolled. Over 60% of these patients received nimotuzumab > 6 doses and ≥ 400 mg/week as maintenance therapy. It was well tolerated in real-life patients. This report demonstrates that age, sex and previous treatment might be potential predictive factors for survival, and patients received nimotuzumab > 6 doses and > 200 mg/week might benefit more from nimotuzumab therapy. Using these factors for stratification analysis may form a predictive differential clinical strategy for nimotuzumab to maximize the benefit in patients with different epithelial tumors.