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11. 发明授权

US07754206B2 Method for treating cancer using a Notch4 ligand antagonist 有权
标题翻译：使用Notch4配体拮抗剂治疗癌症的方法
公开(公告)号：US07754206B2
公开(公告)日：2010-07-13
申请号：US11607780
申请日：2006-12-01
申请人： Michael F. Clarke , Max S. Wicha , Muhammad Al-Hajj
发明人： Michael F. Clarke , Max S. Wicha , Muhammad Al-Hajj
IPC分类号： A61K39/395 , C07K16/18
CPC分类号： C12N5/0695 , A01K67/0271 , A61K39/39558 , A61K2039/505 , A61K2039/5152 , A61K2039/5158 , C07K14/705 , C07K14/70585 , C07K14/71 , C07K16/28 , C07K16/2863 , C07K16/30 , C12N2501/42 , C12N2503/00 , C12N2503/02 , C12Q1/6886 , G01N33/5011 , G01N33/57492
摘要： The invention provides methods for treating cancer via administering to a patient having a solid tumor a therapeutically effective amount of an antibody against Delta-like ligand 4 (D114). The solid tumor may comprise solid tumor stem cells.
摘要翻译：本发明提供了通过向患有实体瘤的患者施用治疗有效量的针对Delta样配体4（D114）的抗体来治疗癌症的方法。实体瘤可包含实体肿瘤干细胞。

12. 发明申请

US20080260734A1 COMPOSITIONS AND METHODS FOR CHARACTERIZING, REGULATING, DIAGNOSING, AND TREATING CANCER 审中-公开
标题翻译：用于表征，调节，诊断和治疗癌症的组合物和方法
公开(公告)号：US20080260734A1
公开(公告)日：2008-10-23
申请号：US12131394
申请日：2008-06-02
申请人： Michael F. Clarke , Muhammad Al-Hajj
发明人： Michael F. Clarke , Muhammad Al-Hajj
IPC分类号： A61K39/395 , A61P31/00
CPC分类号： A61K39/39558 , A61K31/337 , A61K38/005 , A61K39/3955 , A61K45/06 , A61K2039/505 , C07K16/22 , C07K16/28 , C07K16/2863 , C07K16/3015 , C07K2317/76 , C12Q1/6886 , C12Q2600/106 , C12Q2600/118 , C12Q2600/136 , G01N33/57415 , G01N33/57484
摘要： The present invention relates to compositions and methods for characterizing, regulating, diagnosing, and treating cancer. For example, the present invention provides compositions and methods for inhibiting tumorigenesis of certain classes of cancer cells, including breast cancer cells and preventing metastasis. The present invention also provides systems and methods for identifying compounds that regulate tumorigenesis.
摘要翻译：本发明涉及用于表征，调节，诊断和治疗癌症的组合物和方法。例如，本发明提供抑制某些类型的癌细胞（包括乳腺癌细胞）和预防转移的肿瘤发生的组合物和方法。本发明还提供用于鉴定调节肿瘤发生的化合物的系统和方法。

13. 发明申请

US20070231325A1 Prospective identification and characterization of breast cancer stem cells 有权
标题翻译：乳腺癌干细胞的前瞻性鉴定和表征
公开(公告)号：US20070231325A1
公开(公告)日：2007-10-04
申请号：US11607780
申请日：2006-12-01
申请人： Michael Clarke , Max Wicha , Muhammad Al-Hajj
发明人： Michael Clarke , Max Wicha , Muhammad Al-Hajj
IPC分类号： A61K39/395
CPC分类号： C12N5/0695 , A01K67/0271 , A61K39/39558 , A61K2039/505 , A61K2039/5152 , A61K2039/5158 , C07K14/705 , C07K14/70585 , C07K14/71 , C07K16/28 , C07K16/2863 , C07K16/30 , C12N2501/42 , C12N2503/00 , C12N2503/02 , C12Q1/6886 , G01N33/5011 , G01N33/57492
摘要： A small percentage of cells within an established solid tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. Thus, solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. We have developed a xenograft model in which we have been able to establish tumors from primary tumors via injection of tumors in the mammary gland of severely immunodeficient mice. These xenograft assay have allowed us to do biological and molecular assays to characterize clonogenic solid tumor stem cells. We have also developed evidence that strongly implicates the Notch pathway, especially Notch 4, as playing a central pathway in carcinogenesis. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells.
摘要翻译：建立的实体瘤内的一小部分细胞具有干细胞的特性。这些实体肿瘤干细胞产生更多的肿瘤干细胞和肿瘤中大部分已经失去广泛增殖能力的细胞和产生新肿瘤的能力。因此，实体肿瘤异质性反映了由固体肿瘤干细胞产生的肿瘤细胞后代的存在。我们已经开发了异种移植模型，其中我们已经能够通过在严重免疫缺陷小鼠的乳腺中注射肿瘤来从原发肿瘤中建立肿瘤。这些异种移植物测定使我们能够进行生物学和分子测定来表征克隆型实体瘤干细胞。我们还发现证据强烈地暗示Notch途径，特别是Notch 4，作为致癌过程的中心途径。该发现是实体肿瘤干细胞组合物的基础，区分功能不同的肿瘤细胞群体的方法，使用这些肿瘤细胞群体研究治疗剂对肿瘤生长的影响的方法，以及用于鉴定和测试新型抗癌剂的方法针对固体肿瘤干细胞的疗法。

14. 发明申请

US20060073125A1 Isolation and use of solid tumor stem cells 有权
标题翻译：实体肿瘤干细胞的分离和使用
公开(公告)号：US20060073125A1
公开(公告)日：2006-04-06
申请号：US11150524
申请日：2005-06-10
申请人： Michael Clarke , Sean Morrison , Max Wicha , Muhammad Al-Hajj
发明人： Michael Clarke , Sean Morrison , Max Wicha , Muhammad Al-Hajj
IPC分类号： A61K48/00 , A61K39/00 , C12N5/08
CPC分类号： C12N5/0695 , A01K67/0271 , A61K39/39558 , A61K2039/505 , A61K2039/5152 , A61K2039/5158 , C07K14/705 , C07K14/70585 , C07K14/71 , C07K16/28 , C07K16/2863 , C07K16/30 , C12N2501/42 , C12N2503/00 , C12N2503/02 , C12Q1/6886 , G01N33/5011 , G01N33/57492
摘要： A small percentage of cells within an established tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. The solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells.
摘要翻译：建立的肿瘤内的一小部分细胞具有干细胞的特性。这些实体肿瘤干细胞产生更多的肿瘤干细胞和肿瘤中大部分已经失去广泛增殖能力的细胞和产生新肿瘤的能力。实体肿瘤异质性反映了由实体肿瘤干细胞产生的肿瘤细胞后代的存在。该发现是实体肿瘤干细胞组合物的基础，区分功能不同的肿瘤细胞群体的方法，使用这些肿瘤细胞群体研究治疗剂对肿瘤生长的影响的方法，以及用于鉴定和测试新型抗癌剂的方法针对固体肿瘤干细胞的疗法。

15. 发明申请

US20070212737A1 Isolation and use of solid tumor stem cells 审中-公开
标题翻译：实体肿瘤干细胞的分离和使用
公开(公告)号：US20070212737A1
公开(公告)日：2007-09-13
申请号：US11647006
申请日：2006-12-28
申请人： Michael Clarke , Sean Morrison , Max Wicha , Muhammad Al-Hajj
发明人： Michael Clarke , Sean Morrison , Max Wicha , Muhammad Al-Hajj
IPC分类号： G01N33/574
CPC分类号： C12N5/0695 , A01K67/0271 , A61K39/39558 , A61K2039/505 , A61K2039/5152 , A61K2039/5158 , C07K14/705 , C07K14/70585 , C07K14/71 , C07K16/28 , C07K16/2863 , C07K16/30 , C12N2501/42 , C12N2503/00 , C12N2503/02 , C12Q1/6886 , G01N33/5011 , G01N33/57492
摘要： A small percentage of cells within an established tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. The solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells.
摘要翻译：建立的肿瘤内的一小部分细胞具有干细胞的特性。这些实体肿瘤干细胞产生更多的肿瘤干细胞和肿瘤中大部分已经失去广泛增殖能力的细胞和产生新肿瘤的能力。实体肿瘤异质性反映了由实体肿瘤干细胞产生的肿瘤细胞后代的存在。该发现是实体肿瘤干细胞组合物的基础，区分功能不同的肿瘤细胞群体的方法，使用这些肿瘤细胞群体研究治疗剂对肿瘤生长的影响的方法，以及用于鉴定和测试新型抗癌剂的方法针对固体肿瘤干细胞的疗法。

16. 发明申请

US20050232927A1 Compositions and methods for characterizing, regulating, diagnosing, and treating cancer 审中-公开
标题翻译：表征，调节，诊断和治疗癌症的组成和方法
公开(公告)号：US20050232927A1
公开(公告)日：2005-10-20
申请号：US11050282
申请日：2005-02-03
申请人： Michael Clarke , Muhammad Al-Hajj
发明人： Michael Clarke , Muhammad Al-Hajj
IPC分类号： A61K38/00 , A61K38/54 , A61K39/395 , C07K16/28 , G01N33/574
CPC分类号： A61K39/39558 , A61K31/337 , A61K38/005 , A61K39/3955 , A61K45/06 , A61K2039/505 , C07K16/22 , C07K16/28 , C07K16/2863 , C07K16/3015 , C07K2317/76 , C12Q1/6886 , C12Q2600/106 , C12Q2600/118 , C12Q2600/136 , G01N33/57415 , G01N33/57484
摘要： The present invention relates to compositions and methods for characterizing, regulating, diagnosing, and treating cancer. For example, the present invention provides compositions and methods for inhibiting tumorigenesis of certain classes of cancer cells, including breast cancer cells and preventing metastasis. The present invention also provides systems and methods for identifying compounds that regulate tumorigenesis.
摘要翻译：本发明涉及用于表征，调节，诊断和治疗癌症的组合物和方法。例如，本发明提供抑制某些类型的癌细胞（包括乳腺癌细胞）和预防转移的肿瘤发生的组合物和方法。本发明还提供用于鉴定调节肿瘤发生的化合物的系统和方法。

17. 发明申请

US20070259969A1 Isolation And Use Of Solid Tumor Stem Cells 有权
标题翻译：实体肿瘤干细胞的分离和使用
公开(公告)号：US20070259969A1
公开(公告)日：2007-11-08
申请号：US11753191
申请日：2007-05-24
申请人： Michael Clarke , Sean Morrison , Max Wicha , Muhammad Al-Hajj
发明人： Michael Clarke , Sean Morrison , Max Wicha , Muhammad Al-Hajj
IPC分类号： A61K31/00 , A61P35/00 , C12Q1/04 , G01N33/574
CPC分类号： C12N5/0695 , A01K67/0271 , A61K39/39558 , A61K2039/505 , A61K2039/5152 , A61K2039/5158 , C07K14/705 , C07K14/70585 , C07K14/71 , C07K16/28 , C07K16/2863 , C07K16/30 , C12N2501/42 , C12N2503/00 , C12N2503/02 , C12Q1/6886 , G01N33/5011 , G01N33/57492
摘要： A small percentage of cells within an established tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. The solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells.
摘要翻译：建立的肿瘤内的一小部分细胞具有干细胞的特性。这些实体肿瘤干细胞产生更多的肿瘤干细胞和肿瘤中大部分已经失去广泛增殖能力的细胞和产生新肿瘤的能力。实体肿瘤异质性反映了由实体肿瘤干细胞产生的肿瘤细胞后代的存在。该发现是实体肿瘤干细胞组合物的基础，区分功能不同的肿瘤细胞群体的方法，使用这些肿瘤细胞群体研究治疗剂对肿瘤生长的影响的方法，以及用于鉴定和测试新型抗癌剂的方法针对固体肿瘤干细胞的疗法。

18. 发明申请

US20060051325A1 Isolation and use of solid tumor stem cells 审中-公开
公开(公告)号：US20060051325A1
公开(公告)日：2006-03-09
申请号：US11150073
申请日：2005-06-10
申请人： Michael Clarke , Sean Morrison , Max Wicha , Muhammad Al-Hajj
发明人： Michael Clarke , Sean Morrison , Max Wicha , Muhammad Al-Hajj
IPC分类号： C12N5/08
CPC分类号： C12N5/0695 , A01K67/0271 , A61K39/39558 , A61K2039/505 , A61K2039/5152 , A61K2039/5158 , C07K14/705 , C07K14/70585 , C07K14/71 , C07K16/28 , C07K16/2863 , C07K16/30 , C12N2501/42 , C12N2503/00 , C12N2503/02 , C12Q1/6886 , G01N33/5011 , G01N33/57492
摘要： A small percentage of cells within an established tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. The solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells.

19. 发明申请

US20050089518A1 Prospective identification and characterization of breast cancer stem cells 审中-公开
标题翻译：乳腺癌干细胞的前瞻性鉴定和表征
公开(公告)号：US20050089518A1
公开(公告)日：2005-04-28
申请号：US10497791
申请日：2002-12-06
申请人： Michael Clarke , Max Wicha , Muhammad Al-Hajj
发明人： Michael Clarke , Max Wicha , Muhammad Al-Hajj
IPC分类号： G01N33/574 , A01K67/027 , A61K31/00 , A61K35/76 , A61K38/00 , A61K38/17 , A61K39/00 , A61K39/395 , A61K45/00 , A61K47/48 , A61P15/00 , A61P35/00 , C07K16/18 , C07K16/28 , C07K16/30
CPC分类号： C07K16/28 , A61K38/1703 , A61K47/6897 , A61K47/6901 , A61K2039/505 , B82Y5/00 , C07K16/3015 , C12N5/0695
摘要： Human breast tumors contain hetrogeneous cancer cells. using an animal xenograft model in which human breast cancer cells were grown in immunocompromised mice we found that only a small minority of breast cancer cells had capacity to form new tumors. The ability to form new tumors was not a slochastic property, rather certain populations of cancer cells were depleted for the ability to form new tumors, while other populations were enriched for the ability to form new tumors. Tumorigenic cells could be distinguished from non-tumorigenic cancer cells based on surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD4430CD24−/lowLINEAGE A few as 100 cells from this population were able to form tumors the animal xenograft model, while tens of thousands of cells from non-tumorigenic populations failed to form tumors. The tumorigenic cells could be serially passaged, each time generating new tumors containing and expanded numbers of CD44+CD24 Lineage tumorigenic cells as well as phenotypically mixed populations of non-tumorigenic cancer cells. This is reminiscent of the ability of normal stem cells to self-renew and differentiate. The expression of potential therapeutic targets also differed between the tumorigenic and non-tumorigenic populations. Notch activation promoted the survival of the tumorigenic cells, and a blocking antibody against Notch 4 induced tumorigenic breast cancer cells to undergo apoptosis.
摘要翻译：人乳腺肿瘤包含巨噬细胞癌细胞。使用动物异种移植模型，其中人类乳腺癌细胞在免疫受损的小鼠中生长，我们发现只有少数乳腺癌细胞具有形成新肿瘤的能力。形成新肿瘤的能力不是一个稀疏性，而是某些癌细胞群能够形成新的肿瘤，而其他的群体却能够形成新的肿瘤。基于表面标志物表达，致瘤细胞可以与非致瘤性癌细胞区分开。我们前瞻性地鉴定并分离了致瘤细胞作为CD44细胞系CD24 - /低序列，从该群体的100个细胞能够形成动物异种移植模型的肿瘤，而数十个来自非致瘤性群体的数千个细胞未能形成肿瘤。致瘤细胞可以连续传代，每次产生含有和扩增数量的CD44 + CD24序列致瘤细胞的新肿瘤以及非致瘤性癌细胞的表型混合群体。这让人想起正常干细胞自我更新和分化的能力。潜在的治疗靶点的表达也在致瘤性和非致瘤性群体之间不同。 Notch激活促进致瘤细胞的存活，并且针对Notch4的阻断抗体诱导致瘤性乳腺癌细胞进行细胞凋亡。

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