PROSPECTIVE IDENTIFICATION AND CHARACTERIZATION OF BREAST CANCER STEM CELLS

• US 20110033481A1
• Filed: 04/12/2010
• Published: 02/10/2011
• Est. Priority Date: 08/03/2000
• Status: Abandoned Application

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Clarke, Michael F., Wicha, Max S., Al-Hajj, Muhammad
• Application Number:
  US12/758,540
• Publication Number:
  US 20110033481A1
• Time in Patent Office: Days
• US Class Current: 424/172.1
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/5152 Tumor cells
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/70585 CD44
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C12N 2501/42 Notch; Delta; Jagged; Serrate
• CPC Class Codes: C12N 2503/00 Use of cells in diagnostics
• CPC Class Codes: C12N 2503/02 Drug screening
• CPC Class Codes: C12N 5/0695 Stem cells; Progenitor cells; Precursor cells
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/57492 involving compounds localized on the membrane of tumor or cancer cells

Abstract

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 glad of severely immunodeficient mice. These xenograft assays 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.

Claims

1-31. -31. (canceled)

32-55. -55. (canceled)

56. A method of killing or inhibiting the proliferation of solid tumor stem cells in a solid tumor comprising solid tumor stem cells, said method comprising contacting the solid tumor stem cells with an effective amount of an inhibitor of Notch signaling, wherein the inhibitor is an antibody against a Notch receptor.

57. The method of claim 56, wherein the effective amount is an amount sufficient to kill the solid tumor stem cells.

58. The method of claim 56, wherein the effective amount is an amount sufficient to cause cell death of cells in the solid tumor.

59. The method of claim 56, wherein the Notch receptor is Notch4.

60. The method of claim 56, wherein the Notch receptor is Notch1.

61. The method of claim 56, wherein the Notch receptor is Notch2.

62. The method of claim 56, wherein the solid tumor stem cells express the cell surface marker CD44.

63. The method of claim 56, wherein the solid tumor stem cells do not express CD24 or express low levels of CD24.

64. The method of claim 56, wherein the solid tumor is an epithelial cancer.

65. The method of claim 64, wherein the epithelial cancer is a breast cancer.

66. The method of claim 64, wherein the epithelial cancer is an ovarian cancer.

67. The method of claim 56, wherein the solid tumor is a sarcoma.

68. The method of claim 56, further comprising determining the death or inhibition of proliferation of solid tumor stem cells in the solid tumor following contact with the antibody.

69. A method of targeting solid tumor stem cells in a solid tumor comprising solid tumor stem cells, said method comprising contacting the solid tumor stem cells with an antibody against a Notch receptor.

70. The method of claim 69, wherein the Notch receptor is Notch4.

71. The method of claim 69, wherein the Notch receptor is Notch1.

72. The method of claim 69, wherein the Notch receptor is Notch2.