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181.
Christian Rolfo Elisa Giovannetti David S. Hong T. Bivona Luis E. Raez Giuseppe Bronte Lucio Buffoni Noemí Reguart Edgardo S. Santos Paul Germonpre Mìquel Taron Francesco Passiglia Jan P. Van Meerbeeck Antonio Russo Marc Peeters Ignacio Gil-Bazo Patrick Pauwels Rafael Rosell 《Cancer treatment reviews》2014
Introduction
Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs.Areas covered
This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal–epithelial transition factor (MET) amplification, epithelial–mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation.Conclusion
Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC. 相似文献182.
Background
It has been suggested that Alzheimer's disease (AD) is mediated by pathological angiogenesis. Vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), and tumor necrosis factor α (TNF -α) may play important roles in inflammation and angiogenesis through effects on inflammatory cell infiltration or neovascularization in AD pathogenesis. A few studies on the roles of VEGF in AD have been reported recently. But, the results were inconsistent. Angiogenin, which is suspected to have a similar function as VEGF, however, has not yet been studied in patients with AD.Objective
This study was performed to investigate the levels of angiogenin and vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptorI (VEGFR I), and vascular endothelial growth factor receptor II (VEGFR II) in serums of patients with AD, to compare their levels with control subjects, and to determine whether serum angiogenin, VEGF, VEGFR I, and VEGFR II levels are associated with Alzheimer's disease (AD).Methods
Serum angiogenin, VEGF, VEGFR I, and VEGFR II levels were quantified at the time of diagnosis in 20 patients with definite AD, and 18 healthy controls, using a commercial ELISA kit.Results
Patients with AD exhibited lower serum angiogenin (p = 0.003) and higher VEGF (p = 0.008) levels than control subjects. No difference in serum VEGFR I and VEGFR II concentrations was observed between AD patients and controls. There was a correlation between serum levels of angiogenin and cognitive function (MMSE-KC and CDR) in AD patients.Conclusion
The increased serum level of VEGF and decreased serum angiogenin level were founded. Cognitive function was correlated with serum levels of angiogenin. Angiogenin may be involved in the pathogenesis of AD. Further study should be needed to evaluate the possibility of serum angiogenin as a biomarker of AD and as a predictor of disease progression. 相似文献183.
184.
为了提高抗VEGFR2单链抗体AK404R的亲和力,本研究采用亲水突变法将AK404R的重链CDR3区进行突变,建立次级突变单链抗体库。利用噬菌体展示技术从次级突变库中筛选具有抗VEGFR2特异性、高亲和力抗体,获得的抗体突变株经大肠杆菌HB2151分泌表达,镍亲和色谱柱纯化,并采用竞争性ELISA法、生物信息学方法分别对其亲和力和结构进行了分析。本研究最终建立了6.4×105的次级突变单链抗体库,其中两株突变株的亲和力有明显提高,两株突变株经分离纯化得到电泳纯的蛋白,竞争性ELISA结果显示突变体WZ01和WZ02的亲和力比亲本提高了3倍;生物信息学方法分析突变体与抗原的作用面增大、契合紧密,这可能是亲和力提高的原因之一。研究结果表明,在重链CDR3区引入亲水性氨基酸构建抗体突变库,可有效提高scFv的亲和力。 相似文献
185.
Mangia A Malfettone A Saponaro C Tommasi S Simone G Paradiso A 《Human pathology》2011,42(11):1589-1595
The aim of this study is to evaluate the analysis of markers related with progression, to further characterize familial breast cancers. Here, we investigated the expression of breast cancer susceptibility gene-1, hypoxia-inducible factor-1α, vascular endothelial growth factor receptor 1, and Na+/H+ exchanger regulatory factor 1 in 187 microarrayed breast carcinomas from 94 familial and 93 sporadic breast cancer patients by immunohistochemical staining. Furthermore, the expression levels of these biomarkers were compared with triple-negative phenotype. Familiarity was significantly associated with younger age (P < .000), higher tumor grade (P = .038), negative estrogen receptor hormonal status (P = .036), and high proliferative activity (P = .029). The familial cancers were immunonegative for membranous Na+/H+ exchanger regulatory factor 1 expression compared with sporadic cancers (P = .001); notably, vascular endothelial growth factor receptor 1 staining correlated with cytoplasmic Na+/H+ exchanger regulatory factor 1 expression in familial tumors (P = .009). In multivariate analysis, the "new biomarkers," including negative human epidermal growth factor receptor 2 status (odds ratio, 4.538; 95% confidence interval, 1.756-11.728), negative membranous Na+/H+ exchanger regulatory factor 1 expression (odds ratio, 7.686; 95% confidence interval, 1.876-31.483) and positive nuclear breast cancer susceptibility gene-1 (odds ratio, 0.3982; 95% confidence interval, 0.169-0.936), significantly correlated with family history of breast cancer. We hypothesize that the evaluation of human epidermal growth factor receptor 2, Na+/H+ exchanger regulatory factor 1, and breast cancer susceptibility gene-1 could be clinically useful to identify familial breast tumors and to select patients candidate to breast cancer susceptibility genes 1/2 gene sequencing. 相似文献
186.
《Expert opinion on pharmacotherapy》2013,14(18):3091-3102
Pazopanib (Votrient, GW786034) is a potent pan-VEGF inhibitor in advanced clinical development. Like other orally available VEGFR inhibitors, pazopanib is clinically efficacious and well tolerated. The recently reported Phase III clinical trial in metastatic renal cell carcinoma showed activity similar to approved agents with variations in toxicity which has led to its recent FDA approval. Given the growing number of agents in this category, differences not only in single-agent activity but also toxicity and combinatorial potency will probably distinguish pazopanib from other similar agents. 相似文献
187.
《Expert opinion on emerging drugs》2013,18(4):605-618
For decades, options for the treatment for metastatic renal cancer have been limited and mostly ineffective. During this time, immunotherapy agents, such as IFN-α and IL-2, have represented the major treatment options. Over the last 3 years, advances in cancer biology have characterized important signaling pathways that regulate blood vessel growth and cell proliferation. These studies have identified a number of novel ‘druggable’ targets. Since 2004, this has resulted in regulatory approval of four additional agents that are active against renal cancer (bevacizumab, sorafenib, sunitinib and temsirolimus). A large number of additional candidate molecules that block the vascular endothelial growth factor and mTOR pathways have subsequently been identified. These agents are rapidly progressing through clinical testing in renal cancer and in other malignancies. This paper overviews the status of these investigational agents and anticipates areas of future research and development. 相似文献
188.
《Expert opinion on emerging drugs》2013,18(3):435-448
Although chemotherapy has improved the treatment of metastatic bladder cancer, resection and continual surveillance remain the modalities used for treatment of organ-confined disease. More targeted therapies are needed to address the shortcomings of existing treatments. The authors recently became aware of the overexpression of tyrosine kinase growth factor receptors in a variety of malignancies. These receptor tyrosine kinases are coupled to several proliferative and antiapoptotic pathways that drive cancer cell growth. Targeted small-molecule therapies, including monoclonal antibodies and tyrosine kinase inhibitors, directed at these receptors have proven effective against a variety of tumor models. In this report, the authors summarize the results of several such studies and discuss the rationale and potential use of novel targeted drugs in the treatment of bladder cancer. 相似文献
189.
目的 探讨益气活血方对胃溃疡愈合部位新血管的生成及促血管生成因子表达的作用.方法 胃溃疡模型大鼠随机分为模型组、奥美拉唑组、益气活血方组、奥美拉唑加益气活血方组.HE染色观察新生血管数量,免疫组化测定胃组织中VEGF和VEGFR表达水平.结果 奥美拉唑组溃疡指数与模型组相比,均有显著性下降(P<0.01);益气活血方加奥美拉唑组溃疡指数与奥美拉唑组相比有明显下降(P<0.05).益气活血方组、益气活血方加奥美拉唑组与模型组、奥美拉唑组相比,14 d和21 d时微血管数量明显增多(P<0.05).实验各组VEGF表达与VEGFR表达,均随胃溃疡愈合进程而增强,愈合后表达降低.模型组,直到28 d时表达增加.结论 益气活血方主要通过增加胃溃疡黏膜组织中VEGF和VEGFR表达,促进新血管的生成,从而提高溃疡愈合质量,中西药合用具有协同增效作用. 相似文献
190.
血管生成是肿瘤转移的基础,新生血管形成是肿瘤复发转移不可或缺的条件。血管内皮生长因子(VEGF)及其受体(VEGFR)是肿瘤血管形成过程中的重要调节因子。VEGF/VEGFR信号通路抑制剂已经成功进入临床应用阶段,但只有一部分患者能够从中获益。探索能够可靠预测VEGF/VEGFR信号通路抑制剂疗效的评价指标,将会给肿瘤患者带来更大的临床获益。本文将对VEGF/VEGFR信号通路抑制剂疗效预测指标的研究进展作一综述。 相似文献