Methods for identifying and validating selective anti-cancer stem cell agents

摘要

Described are methods of treating a cancer comprising administering to a subject in need thereof an effective amount of a dopamine receptor (DR) antagonist. The DR antagonist may be a phenothiazine derivative, such as thioridazine or chlorpromazine. Optionally, the cancer is acute myeloid leukemia. Also described are methods for identifying subjects with cancer, methods for providing a prognosis for a subjects with cancer and methods for identifying subjects likely to be responsive to therapy with DR receptor antagonists. Methods for identifying cancer stem cells and chemotherapeutic compounds that are DR receptor antagonists as also provided. Also described are methods for the identification and validation of agents that target cancer stem cells.

主权项

1. A method for identifying and validating a test agent as a selective anti-cancer stem cell agent, the method comprising:
i) contacting one or more variant neoplastic stem cells with the test agent and one or more normal stem cells with the test agent, wherein said variant neoplastic stem cells are transformed human Pluripotent Stem Cells or transformed induced Pluripotent Stem Cells characterized as having at least one property selected from
an ability to differentiate into more than one cell type without requiring Oct4 for self-renewal or survival,an ability to co-express FGFR1 and IGFR1,an ability to maintain an undifferentiated state in culture absent the presence of fibroblast growth factor (bFGF),an ability to maintain the expression of SSEA3 in the absence of bFGF, anda requirement of the presence of Nanog for self-renewal and cell survival; ii) detecting a change in cell count of the variant neoplastic stem cells in response to the test agent, and detecting a change in cell count of the normal stem cells in response to the test agent; and iii) identifying the test agent as a selective anti-cancer stem cell agent if contact with the test agent induces a decrease in cell count of the variant neoplastic stem cells without inducing a comparable decrease in the normal stem cells; wherein the variant neoplastic stem cells are seeded in a first receptacle at about 3000 to 7000 cells per receptacle and the normal stem cells are seeded in a second receptacle at about 8000 to 12000 cells per receptacle.