MET(MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand,...MET(MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor(HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, andmetastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of METtargeted cancer drugs and discuss the challenges in such development.展开更多
Growth factor gene transfer-induced therapeutic angiogenesis has become a novel approach for the treatment of myocardial ischemia. In order to provide a basis for the clinical application of an adeno- virus with hepat...Growth factor gene transfer-induced therapeutic angiogenesis has become a novel approach for the treatment of myocardial ischemia. In order to provide a basis for the clinical application of an adeno- virus with hepatocyte growth factor gene (Ad-HGF) in the treatment of myocardial ischemia, we estab- lished a minipig model of chronically ischemic myocardium in which an Ameroid constrictor was placed around the left circumflex branch of the coronary artery (LCX). A total of 18 minipigs were ran- domly divided into 3 groups: a surgery control group, a model group and an Ad-HGF treatment group implanted with Ameroid constrictor. Ad-HGF or the control agent was injected directly into the ischemic myocardium, and an improvement in heart function and blood supply were evaluated. The results showed that myocardial perfusion remarkably improved in the Ad-HGF group compared with that in both the control and model groups. Four weeks after the treatment, the density of newly formed blood vessels was higher and the number of collateral blood vessels was greater in the Ad-HGF group than in the model group. The area of myocardial ischemia reduced evidently and the left ventricular ejection fraction improved significantly in the Ad-HGF group. These results suggest that HGF gene therapy may become a novel approach in the treatment of chronically ischemic myocardium.展开更多
BACKGROUND Target therapy is licensed by United States Food and Drug Administration on certain cancers.Both sorafenib and lenvatinib are tyrosine kinase inhibitor and indicated on radioactive iodine(RAI)-refractory di...BACKGROUND Target therapy is licensed by United States Food and Drug Administration on certain cancers.Both sorafenib and lenvatinib are tyrosine kinase inhibitor and indicated on radioactive iodine(RAI)-refractory differentiated thyroid cancer(DTC).Lenvatinib is more effective in cancers'control than sorafenib,but causes more nephrotoxicity than sorafenib does.This case is the second published case about the serial adaptions from lenvatinib to sorafenib for improving the proteinuria and,meanwhile,achieving the therapeutic goal.CASE SUMMARY A 56-year-old man suffered from bilateral edematous lower extremities after 1-mo prescription of lenvatinib of 20 mg/d for RAI-refractory DTC.Aside from this symptom,he also developed hypertension.His laboratory showed grade-3 proteinuria(estimated 24-h urine protein:9993 mg),hypoalbuminemia and hypercholesterolemia.Anti-vascular endothelial growth factor(VEGF)therapyinduced nephrotic syndrome was impressed.After reduced dosage of lenvatinib of 10 mg/d and related symptomatic drugs,limited improvement was observed in both adverse effects and caner control.Under this condition,we substituted sorafenib of 400 mg/d for lenvatinib of 10 mg/d.After a 5-mo prescription,not only hypertension and peripheral edema were greatly improved,but also proteinuria was improved from grade three to grade one(estimated 24-h urine protein:962 mg).At the same time the cancer control was achieved,judged from computed tomography and laboratory evidence[thyroglobulin(Tg)before prescription of sorafenib:354.7 ng/m L;Tg after prescription of sorafenib:108.9 ng/m L].CONCLUSION Adaption from lenvatinib to sorafenib is a feasible method to improve the antiVEGF therapy-induced nephrotic syndrome and achieve the therapeutic goal at the same time.展开更多
文摘MET(MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor(HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, andmetastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of METtargeted cancer drugs and discuss the challenges in such development.
基金National "863" Programme (Grant Nos. 2003AA216080 and 2007AA021007)
文摘Growth factor gene transfer-induced therapeutic angiogenesis has become a novel approach for the treatment of myocardial ischemia. In order to provide a basis for the clinical application of an adeno- virus with hepatocyte growth factor gene (Ad-HGF) in the treatment of myocardial ischemia, we estab- lished a minipig model of chronically ischemic myocardium in which an Ameroid constrictor was placed around the left circumflex branch of the coronary artery (LCX). A total of 18 minipigs were ran- domly divided into 3 groups: a surgery control group, a model group and an Ad-HGF treatment group implanted with Ameroid constrictor. Ad-HGF or the control agent was injected directly into the ischemic myocardium, and an improvement in heart function and blood supply were evaluated. The results showed that myocardial perfusion remarkably improved in the Ad-HGF group compared with that in both the control and model groups. Four weeks after the treatment, the density of newly formed blood vessels was higher and the number of collateral blood vessels was greater in the Ad-HGF group than in the model group. The area of myocardial ischemia reduced evidently and the left ventricular ejection fraction improved significantly in the Ad-HGF group. These results suggest that HGF gene therapy may become a novel approach in the treatment of chronically ischemic myocardium.
文摘BACKGROUND Target therapy is licensed by United States Food and Drug Administration on certain cancers.Both sorafenib and lenvatinib are tyrosine kinase inhibitor and indicated on radioactive iodine(RAI)-refractory differentiated thyroid cancer(DTC).Lenvatinib is more effective in cancers'control than sorafenib,but causes more nephrotoxicity than sorafenib does.This case is the second published case about the serial adaptions from lenvatinib to sorafenib for improving the proteinuria and,meanwhile,achieving the therapeutic goal.CASE SUMMARY A 56-year-old man suffered from bilateral edematous lower extremities after 1-mo prescription of lenvatinib of 20 mg/d for RAI-refractory DTC.Aside from this symptom,he also developed hypertension.His laboratory showed grade-3 proteinuria(estimated 24-h urine protein:9993 mg),hypoalbuminemia and hypercholesterolemia.Anti-vascular endothelial growth factor(VEGF)therapyinduced nephrotic syndrome was impressed.After reduced dosage of lenvatinib of 10 mg/d and related symptomatic drugs,limited improvement was observed in both adverse effects and caner control.Under this condition,we substituted sorafenib of 400 mg/d for lenvatinib of 10 mg/d.After a 5-mo prescription,not only hypertension and peripheral edema were greatly improved,but also proteinuria was improved from grade three to grade one(estimated 24-h urine protein:962 mg).At the same time the cancer control was achieved,judged from computed tomography and laboratory evidence[thyroglobulin(Tg)before prescription of sorafenib:354.7 ng/m L;Tg after prescription of sorafenib:108.9 ng/m L].CONCLUSION Adaption from lenvatinib to sorafenib is a feasible method to improve the antiVEGF therapy-induced nephrotic syndrome and achieve the therapeutic goal at the same time.
