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1. 发明授权

US09244058B2 Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors 有权
公开(公告)号：US09244058B2
公开(公告)日：2016-01-26
申请号：US13374132
申请日：2011-12-12
申请人： John D. Haley , Graeme Griffin , Lukas A. Amler , David A. Eberhard , Robert L. Yauch
发明人： John D. Haley , Graeme Griffin , Lukas A. Amler , David A. Eberhard , Robert L. Yauch
IPC分类号： G01N33/53 , G01N33/50 , G01N33/574
CPC分类号： A61K31/517 , G01N33/5011 , G01N33/57407 , G01N33/57484 , G01N2800/52
摘要： The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.

2. 发明申请

US20120157480A1 Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors 审中-公开
标题翻译：预测表皮生长因子受体激酶抑制剂的抗癌反应的生物标志物
公开(公告)号：US20120157480A1
公开(公告)日：2012-06-21
申请号：US13374132
申请日：2011-12-12
申请人： John D. Haley , Graeme Griffin , Lukas A. Amler , David A. Eberhard , Robert L. Yauch
发明人： John D. Haley , Graeme Griffin , Lukas A. Amler , David A. Eberhard , Robert L. Yauch
IPC分类号： A61K31/517 , A61P35/04 , A61P35/00
CPC分类号： A61K31/517 , G01N33/5011 , G01N33/57407 , G01N33/57484 , G01N2800/52
摘要： The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.
摘要翻译：本发明提供用于预测EGFR激酶抑制剂治疗癌症患者的有效性的诊断和预后方法。提供了用于预测肿瘤细胞生长对EGFR激酶抑制剂抑制的敏感性的方法，包括通过测定上皮和/或间质生物标志物的表达水平来评估肿瘤细胞是否经历了上皮与间质转化（EMT），其中已经经历EMT的肿瘤细胞对EGFR激酶抑制剂的抑制基本上较不敏感。还提供了用于治疗结合上述方法的EGFR激酶抑制剂的癌症患者的改进方法。另外，提供了用于鉴定预测肿瘤对EGFR激酶抑制剂的反应性的新生物标志物的方法。此外，还提供了用于鉴定恢复已经经历EMT的肿瘤细胞对EGFR激酶抑制剂抑制的敏感性的药剂的方法。

3. 发明申请

US20060211060A1 Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors 有权
公开(公告)号：US20060211060A1
公开(公告)日：2006-09-21
申请号：US11377530
申请日：2006-03-16
申请人： John Haley , Graeme Griffin , Lukas Amler , David Eberhard , Robert Yauch
发明人： John Haley , Graeme Griffin , Lukas Amler , David Eberhard , Robert Yauch
IPC分类号： G01N33/574
CPC分类号： A61K31/517 , G01N33/5011 , G01N33/57407 , G01N33/57484 , G01N2800/52
摘要： The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.

4. 发明授权

US07879566B2 Methods for the identification of modulators of OSGPR114 or OSGPR78 activity, and their use in the treatment of disease 有权
标题翻译：用于鉴定OSGPR114或OSGPR78活性调节剂的方法及其在治疗疾病中的应用
公开(公告)号：US07879566B2
公开(公告)日：2011-02-01
申请号：US12405402
申请日：2009-03-17
申请人： Graeme Griffin , Lambertus J. Oehlen
发明人： Graeme Griffin , Lambertus J. Oehlen
IPC分类号： G01N33/566 , C07K14/705
CPC分类号： G01N33/566 , C07K14/705 , G01N2333/726
摘要： This invention relates to the identification of LPA as a ligand for the G-protein coupled receptors OSGPR114 and OSGPR78. The invention is directed to new methods for screening candidate drugs for their ability to modulate the activity of OSGPR114 or OSGPR78, and new pharmaceutical agents identified by these methods. It is also directed to the use of such agents in the manufacture of medicaments for the treatment of OSGPR114 or OSGPR78 mediated diseases, and methods of treating diseases such as cancers by administering to an individual a therapeutic amount of a modulator of OSGPR114 or OSGPR78 identified by these methods.
摘要翻译：本发明涉及鉴定作为G蛋白偶联受体OSGPR114和OSGPR78的配体的LPA。本发明涉及用于筛选候选药物以调节OSGPR114或OSGPR78的活性的能力的新方法，以及通过这些方法鉴定的新药剂。还涉及这种药剂在制备用于治疗OSGPR114或OSGPR78介导的疾病的药物中的用途，以及通过向个体施用治疗量的OSGPR114或OSGPR78调节剂的方法来治疗疾病，例如癌症这些方法。

5. 发明申请

US20070286864A1 Combined treatment with an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors 审中-公开
标题翻译：用EGFR激酶抑制剂和使肿瘤细胞对EGFR激酶抑制剂的作用敏感的药物的联合治疗
公开(公告)号：US20070286864A1
公开(公告)日：2007-12-13
申请号：US11811219
申请日：2007-06-08
申请人： Elizabeth A. Buck , Graeme Griffin
发明人： Elizabeth A. Buck , Graeme Griffin
IPC分类号： A61K39/395 , A61K31/517
CPC分类号： A61K31/517 , A61K39/39558 , A61K45/06 , A61K2300/00
摘要： The present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of a combination of an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors, wherein the agent is an PDK1 inhibitor, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy. A preferred example of an EGFR kinase inhibitor that can be used in practicing this invention is the compound erlotinib HCl (also known as TARCEVA®).
摘要翻译：本发明提供了一种治疗患者肿瘤或肿瘤转移的方法，其包括向患者同时或依次施用治疗有效量的EGFR激酶抑制剂和使肿瘤细胞对EGFR激酶抑制剂的作用敏感的药剂的组合其中所述试剂是PDK1抑制剂，其具有或不具有另外的试剂或治疗剂，例如其它抗癌药物或放射治疗剂。可用于实施本发明的EGFR激酶抑制剂的优选实例是化合物厄洛替尼HCl（也称为TARCEVA）。

6. 发明申请

US20060199229A1 Methods for identification of modulators of OSGPR116 activity, and their use in the treatment of disease 审中-公开
标题翻译：鉴定OSGPR116活性调节剂的方法及其在治疗疾病中的应用
公开(公告)号：US20060199229A1
公开(公告)日：2006-09-07
申请号：US11397181
申请日：2006-04-04
申请人： Graeme Griffin
发明人： Graeme Griffin
IPC分类号： G01N33/567 , A61K31/16
CPC分类号： C07K14/705 , G01N33/76 , G01N2333/726
摘要： This invention relates to the identification of fatty acid or lipid amides that decrease food intake in mammals, including fatty acid ethanolamides, as ligands for the G-protein coupled receptor OSGPR116, and describes the first demonstration of a specific G-protein coupled receptor that is activated by fatty acid ethanolamides that inhibit feeding. The invention is directed to new methods for screening candidate drugs for their ability to modulate the activity of OSGPR116, and new pharmaceutical agents identified by these methods. It is also directed to the use of such agents in the manufacture of medicaments for the treatment of OSGPR116 mediated diseases, and methods of treating diseases such as obesity and diabetes by administering to an individual a therapeutic amount of a modulator of OSGPR116 identified by these methods.
摘要翻译：本发明涉及在哺乳动物（包括脂肪酸乙醇酰胺）中降低食物摄取量的脂肪酸或脂质酰胺作为G蛋白偶联受体OSGPR116的配体，并且描述了特异性G蛋白偶联受体的第一次证明由脂肪酸乙醇酰胺激活，抑制喂养。本发明涉及用于筛选候选药物以调节OSGPR116的活性的能力的新方法，以及通过这些方法鉴定的新药物。还涉及这种药剂在制备用于治疗OSGPR116介导的疾病的药物中的用途，以及通过向个体施用治疗量的通过这些方法鉴定的OSGPR116调节剂的治疗疾病如肥胖症和糖尿病的方法。

7. 发明授权

US08586546B2 Combined treatment with an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors 有权
标题翻译：用EGFR激酶抑制剂和使肿瘤细胞对EGFR激酶抑制剂的作用敏感的药物的联合治疗
公开(公告)号：US08586546B2
公开(公告)日：2013-11-19
申请号：US13370682
申请日：2012-02-10
申请人： Elizabeth A. Buck , Graeme Griffin , Sharon M. Barr
发明人： Elizabeth A. Buck , Graeme Griffin , Sharon M. Barr
IPC分类号： A61K38/00
CPC分类号： A61K45/06 , A61K31/436 , A61K31/498 , A61K2300/00
摘要： The present invention provides a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of a combination of an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors, wherein said agent is an mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases. The present invention also provides a pharmaceutical composition comprising an EGFR kinase inhibitor and an mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases, in a pharmaceutically acceptable carrier. A preferred example of an EGFR kinase inhibitor that can be used in practicing the methods of this invention is the compound erlotinib HC1 (also known as TARCEVA®).
摘要翻译：本发明提供了一种治疗患者肿瘤或肿瘤转移的方法，其包括向所述患者同时或依次施用治疗有效量的EGFR激酶抑制剂与致敏肿瘤细胞对EGFR激酶抑制剂作用的药剂的组合其中所述试剂是结合并直接抑制mTORC1和mTORC2激酶两者的mTOR抑制剂。本发明还提供药物组合物，其包含在药学上可接受的载体中结合并直接抑制mTORC1和mTORC2激酶两者的EGFR激酶抑制剂和mTOR抑制剂。可用于实施本发明方法的EGFR激酶抑制剂的优选实例是化合物厄洛替尼HC1（也称为TARCEVA）。

8. 发明授权

US08093011B2 Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors 有权
公开(公告)号：US08093011B2
公开(公告)日：2012-01-10
申请号：US11377530
申请日：2006-03-16
申请人： John D. Haley , Graeme Griffin , Lukas A. Amler , David A. Eberhard , Robert L. Yauch
发明人： John D. Haley , Graeme Griffin , Lukas A. Amler , David A. Eberhard , Robert L. Yauch
IPC分类号： G01N33/574
CPC分类号： A61K31/517 , G01N33/5011 , G01N33/57407 , G01N33/57484 , G01N2800/52
摘要： The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.

9. 发明申请

US20090274684A1 Methods for the Identification of Modulators of OSGPR114 or OSGPR78 Activity, and their use in the Treatment of Disease 有权
标题翻译： OSGPR114或OSGPR78活性调节剂鉴定方法及其在疾病治疗中的应用
公开(公告)号：US20090274684A1
公开(公告)日：2009-11-05
申请号：US12405402
申请日：2009-03-17
申请人： Graeme Griffin , Lambertus J. Oehlen
发明人： Graeme Griffin , Lambertus J. Oehlen
IPC分类号： A61K39/395 , G01N33/53 , G01N33/68 , G01N33/567 , C12Q1/68
CPC分类号： G01N33/566 , C07K14/705 , G01N2333/726
摘要： This invention relates to the identification of LPA as a ligand for the G-protein coupled receptors OSGPR 114 and OSGPR78. The invention is directed to new methods for screening candidate drugs for their ability to modulate the activity of OSGPR114 or OSGPR78, and new pharmaceutical agents identified by these methods. It is also directed to the use of such agents in the manufacture of medicaments for the treatment of OSGPR114 or OSGPR78 mediated diseases, and methods of treating diseases such as cancers by administering to an individual a therapeutic amount of a modulator of OSGPR114 or OSGPR78 identified by these methods.
摘要翻译：本发明涉及鉴定LPA作为G蛋白偶联受体OSGPR 114和OSGPR78的配体。本发明涉及用于筛选候选药物以调节OSGPR114或OSGPR78的活性的能力的新方法，以及通过这些方法鉴定的新药剂。还涉及这种药剂在制备用于治疗OSGPR114或OSGPR78介导的疾病的药物中的用途，以及通过向个体施用治疗量的OSGPR114或OSGPR78调节剂的方法来治疗疾病，例如癌症这些方法。

10. 发明申请

US20070280928A1 Combined treatment with an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors 有权
标题翻译：用EGFR激酶抑制剂和使肿瘤细胞对EGFR激酶抑制剂的作用敏感的药物的联合治疗
公开(公告)号：US20070280928A1
公开(公告)日：2007-12-06
申请号：US11717545
申请日：2007-03-13
申请人： Elizabeth Buck , Graeme Griffin , Sharon Barr
发明人： Elizabeth Buck , Graeme Griffin , Sharon Barr
IPC分类号： A61K31/517 , A61K39/395 , A61P35/00
CPC分类号： A61K45/06 , A61K31/436 , A61K31/498 , A61K2300/00
摘要： The present invention provides a method for treating NSCL, pancreatic, colon or breast cancer tumors or tumor metastases in a patient, comprising administering to the patient simultaneously or sequentially a therapeutically effective amount of a combination of an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors, wherein the agent is an mTOR inhibitor, with or without additional agents or treatments, such as other anti-cancer drugs or radiation therapy. The present invention also provides a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of a combination of an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors, wherein said agent is an mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases. The present invention also provides a pharmaceutical composition comprising an EGFR kinase inhibitor and an mTOR inhibitor that binds to and directly inhibits both mTORC1 and mTORC2 kinases, in a pharmaceutically acceptable carrier. A preferred example of an EGFR kinase inhibitor that can be used in practicing the methods of this invention is the compound erlotinib HCl (also known as TARCEVA®).
摘要翻译：本发明提供了一种治疗患者的NSCL，胰腺，结肠癌或乳腺癌肿瘤或肿瘤转移的方法，其包括向患者同时或依次施用治疗有效量的EGFR激酶抑制剂与致敏肿瘤的药剂的组合细胞对EGFR激酶抑制剂的作用，其中所述药剂是mTOR抑制剂，具有或不具有其它药物或治疗剂，例如其它抗癌药物或放射疗法。本发明还提供了一种用于治疗患者的肿瘤或肿瘤转移的方法，其包括向所述患者同时或依次施用治疗有效量的EGFR激酶抑制剂和致敏肿瘤细胞对EGFR激酶作用的药剂的组合抑制剂，其中所述药剂是结合并直接抑制mTORC1和mTORC2激酶两者的mTOR抑制剂。本发明还提供药物组合物，其包含在药学上可接受的载体中结合并直接抑制mTORC1和mTORC2激酶两者的EGFR激酶抑制剂和mTOR抑制剂。可用于实施本发明方法的EGFR激酶抑制剂的优选实例是化合物厄洛替尼HCl（也称为TARCEVA）。

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