Treatment of Cancer WIth Dopamine Receptor Antagonists

Abstract

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/or 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.

1 . A method of treating acute myeloid leukemia (AML) in a subject comprising administering to the subject a dopamine receptor antagonist. 
     
     
         2 . The method of  claim 1 , wherein the dopamine receptor antagonist is a D 2  family dopamine receptor antagonist. 
     
     
         3 . The method of  claim 2 , wherein the dopamine receptor antagonist is a phenothiazine derivative or a compound listed in Table 1. 
     
     
         4 . The method of  claim 3 , wherein the phenothiazine derivative is thioridazine. 
     
     
         5 . The method of  claim 1 , wherein the acute myeloid leukemia comprises cells that express one or more dopamine receptors (DR) selected from DR1, DR2, DR3, DR4 and DR5. 
     
     
         6 . The method of  claim 5 , wherein the cells that express one or more dopamine receptors also express CD14. 
     
     
         7 . The method of  claim 1 , wherein the dopamine receptor antagonist preferentially induces the differentiation of cancer stem cells relative to hematopoietic or normal stem cells. 
     
     
         8 . The method of  claim 1 , wherein the subject is in remission. 
     
     
         9 . A method for reducing the proliferation of a cancer cell comprising contacting the cancer cell with a dopamine receptor antagonist. 
     
     
         10 . The method of  claim 9 , wherein the cancer cell is a cancer stem cell and contacting the cancer stem cell with the dopamine receptor antagonist induces differentiation of the cancer stem cell. 
     
     
         11 . The method of  claim 9 , wherein the cancer cell is an acute myeloid leukemia (AML) cell. 
     
     
         12 . The method of  claim 9 , wherein the cell is in vivo or in vitro. 
     
     
         13 . The method of  claim 9 , wherein the dopamine receptor antagonist is a D 2  family dopamine receptor antagonist. 
     
     
         14 . The method of  claim 9 , wherein the dopamine receptor antagonist is a phenothiazine derivative or a compound listed in Table 1. 
     
     
         15 . The method of  claim 14 , wherein the phenothiazine derivative is thioridazine. 
     
     
         16 . A method of identifying a subject with cancer suitable for treatment with a dopamine receptor antagonist, the method comprising determining the expression of one or more dopamine receptors in a sample of cancer cells from the subject, whereby subjects with cancer cells that express one or more dopamine receptors are identified as suitable for treatment with the dopamine receptor antagonist. 
     
     
         17 . The method of  claim 16 , wherein the step of determining the expression of one or more dopamine receptors in the sample comprises testing the sample for levels of polynucleotides or polypeptides that code for one or more dopamine receptors. 
     
     
         18 . The method of  claim 16 , wherein the one or more dopamine receptors are selected from DR1, DR2, DR3, DR4 and DR5. 
     
     
         19 . The method of  claim 18 , wherein the one or more dopamine receptors include D 2  family dopamine receptors. 
     
     
         20 . The method of  claim 16 , wherein the cancer is leukemia or breast cancer. 
     
     
         21 . The method of  claim 20 , wherein the cancer is acute myeloid leukemia or monocytic leukemia. 
     
     
         22 . A method of determining a prognosis for a subject with cancer, the method comprising:
 determining a level of expression of one or more biomarkers selected from dopamine receptor (DR) 1, DR2, DR3, DR4 and DR5 in a sample from the subject, and   comparing the level of expression of the one or more biomarkers to a control, wherein an increased level of expression of the one or more biomarkers relative to the control indicates that the subject has a more severe form of cancer.   
     
     
         23 . The method of  claim 22 , wherein the step of determining the expression of one or more biomarkers in the sample comprises testing the sample for levels of polynucleotides or polypeptides that code for the one or more biomarkers. 
     
     
         24 . The method of  claim 22 , wherein the biomarkers are DR3 and/or DR5. 
     
     
         25 . The method of  claim 22 , wherein the cancer is leukemia and an increased expression of one or more biomarkers compared to the control indicates a more severe form of leukemia. 
     
     
         26 . The method of  claim 25 , wherein the leukemia is acute myeloid leukemia or monocytic leukemia. 
     
     
         27 . A method for identifying a subject with leukemia comprising:
 determining a level of expression of one or more biomarkers selected from dopamine receptor (DR) 1, DR2, DR3, DR4 and DR5 in a sample of white blood cells from the subject, and   comparing the level of expression of the one or more biomarkers to a control.   
     
     
         28 . The method of  claim 27 , wherein an increased level of expression of one or more dopamine receptors compared to the control is indicative of a subject with leukemia. 
     
     
         29 . The method of  claim 28 , wherein the leukemia is acute myeloid leukemia or monocytic leukemia. 
     
     
         30 . A method of screening compounds for anti-cancer activity comprising:
 identifying compounds that antagonize one or more dopamine receptors, wherein compounds that antagonize dopamine receptors are identified as having anti-cancer activity.   
     
     
         31 . The method of  claim 30 , wherein the anti-cancer activity comprises reduced proliferation of breast cancer cells, AML cells or monocytic cells. 
     
     
         32 . A method for identifying a cancer stem cell from a population of cells, the method comprising:
 determining whether a cell expresses one or more biomarkers selected from dopamine receptor (DR) 1, DR2, DR3, DR4 and DR5;   wherein expression of the one or more biomarkers is indicative that the cell is a cancer stem cell.   
     
     
         33 . The method of  claim 32 , wherein the population of cells comprises cells isolated from a mammal or cells in tissue culture. 
     
     
         34 . The method of  claim 32 , wherein the population of cells comprises pluripotent stem cells. 
     
     
         35 . The method of  claim 32 , wherein the population of cells comprises cancer cells or pre-cancerous cells such as leukemic cells or breast cancer cells. 
     
     
         36 . The method of  claim 32 , wherein the population of cells comprises hematological cancer cells. 
     
     
         37 . The method of  claim 32 , wherein the step of determining whether the cell expresses one or biomarkers comprises testing the cell for the expression of polynucleotides or polypeptides that code for DR1, DR2, DR3, DR4 or DR5. 
     
     
         38 . The method of  claim 32 , wherein a cell that expresses DR1, DR2, DR3, DR4 and DR5 is identified as a cancer stem cell. 
     
     
         39 . The method of  claim 32 , further comprising isolating the cancer stem cells from the population of cells. 
     
     
         40 . The method of  claim 39 , wherein the step of isolating the cancer stem cells form the population of cells comprises flow cytometry, fluorescence activated cell sorting, panning, affinity column separation, or magnetic selection.