Methods to predict and prevent resistance to taxoid compounds

Abstract

Embodiments of the invention are directed to methods for predicting the resistance of cancer to members of the taxoid family by measuring the levels of prohibitin. Methods for treating cancer and taxoid family member resistant cancers using inhibitors of prohibitin, as well as therapeutic complexes that target prohibitin are also provided.

1 . A method for predicting the resistance of cancer to a member of the taxoid family in a subject, the method comprising:
 a. measuring a level of prohibitin in a biological sample obtained from a subject; and   b. comparing the level measured in step (a) to a standard level,   
       wherein an elevation of the measured level of prohibitin relative to the standard level is indicative of resistance to a member of the taxoid family. 
     
     
         2 . A method for predicting the resistance of cancer in a subject to a member of the taxoid family, the method comprising:
 a. measuring the level of prohibitin in multiple biological samples obtained from a subject periodically over a period time; and   b. measuring a change in the measured level of prohibitin in the biological samples,   
       wherein an elevation of the level of prohibitin is indicative of resistance to a member of the taxoid family. 
     
     
         3 . The method of  claim 1  or  2 , wherein the subject had been treated with the member of the taxoid family. 
     
     
         4 . The method of  claim 1  or  2 , wherein the member of the taxoid family is paclitaxel or docetaxel. 
     
     
         5 . The method of  claim 1  or  2 , wherein serial monitoring of the level of prohibitin is performed at least quarterly, at least bimonthly, at least biweekly, at least weekly, at least every three days or at least daily. 
     
     
         6 . The method of  claim 1  or  2 , wherein the level of prohibitin is measured by measuring the level of prohibitin on the cell surface of cancer cells in the biological sample. 
     
     
         7 . The method of  claim 1  or  2 , wherein the biological sample is selected from the group consisting of blood, tissue, serum, plasma, urine, stool, cerebrospinal fluid, nipple aspirates, tumor biopsy, and cell lysate. 
     
     
         8 . The method of  claim 7 , wherein the biological sample is a cell lysate and the level of prohibitin is measured by measuring the level of prohibitin in the microsomal fraction of the biological sample. 
     
     
         9 . The method of  claim 7 , wherein the biological sample is serum and the level of prohibitin is determined by measuring the level of prohibitin in the serum. 
     
     
         10 . The method of  claim 7 , wherein the biological sample is blood and the level of prohibitin is determined by measuring the level of prohibitin in platelets of the blood sample. 
     
     
         11 . The method of  claim 1  or  2 , wherein the level of prohibitin protein is measured using an antibody-based binding moiety which specifically binds prohibitin. 
     
     
         12 . The method according to  claim 11 , wherein the antibody-based binding moiety is labeled with a detectable label. 
     
     
         13 . The method according to  claim 12 , wherein the label is selected from the group consisting of a radioactive label, a hapten label, a fluorescent label, and an enzymatic label. 
     
     
         14 . The method according to  claim 11 , wherein the antibody-based binding moiety is an antibody. 
     
     
         15 . The method according to  claim 14 , wherein the antibody is a monoclonal antibody. 
     
     
         16 . The method of  claim 1  or  2 , wherein the level of prohibitin protein is measured using Western Blot analysis, Fluorescent activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, mass spectrometry, radio-immunoassy, surface plasmon resonance, or immunofluorescence. 
     
     
         17 . A method for improving the effectiveness of cancer treatment comprising measuring the level of prohibitin in a biological sample, wherein an elevated level of prohibitin as compared to a standard level indicates that the subject is resistant to treatment with a member of the taxoid family and is in need of alternative treatment so as to improve the effectiveness of cancer treatment. 
     
     
         18 . The method of  claim 17 , wherein the subject had been treated with the member of the taxoid family. 
     
     
         19 . The method of  claim 18 , wherein the member of the taxoid family is paclitaxel or docetaxel. 
     
     
         20 . The method of  claim 17 , wherein serial monitoring of the level of prohibitin is performed at least quarterly, at least bimonthly, at least biweekly, at least weekly, at least every three days or at least daily. 
     
     
         21 . The method of  claim 17 , wherein the level of prohibitin is measured by measuring the level of prohibitin on the cell surface of cancer cells in the biological sample. 
     
     
         22 . The method of  claim 17 , wherein the biological sample is selected from the group consisting of blood, tissue, serum, urine, stool, plasma, cerebrospinal fluid, nipple aspirates, tumor biopsy, and cell lysate. 
     
     
         23 . The method of  claim 22 , wherein the biological sample is a cell lysate and the level of prohibitin is measured by measuring the level of prohibitin in the microsomal fraction of the biological sample. 
     
     
         24 . The method of  claim 22 , wherein the biological sample is serum and the level of prohibitin is determined by measuring the level of prohibitin in the serum. 
     
     
         25 . The method of  claim 22 , wherein the biological sample is blood and the level of prohibitin is determined by measuring the level of prohibitin in platelets of the blood sample. 
     
     
         26 . The method of  claim 17 , wherein the level of prohibitin protein is measured using an antibody based binding moiety which specifically binds prohibitin. 
     
     
         27 . The method according to  claim 26 , wherein the antibody-based binding moiety is labeled with a detectable label. 
     
     
         28 . The method according to  claim 27 , wherein the label is selected from the group consisting of a radioactive label, a hapten label, a fluorescent label, and an enzymatic label. 
     
     
         29 . The method according to  claim 28 , wherein the antibody-based binding moiety is an antibody. 
     
     
         30 . The method according to  claim 29 , wherein the antibody is a monoclonal antibody. 
     
     
         31 . The method of  claim 17 , wherein the level of prohibitin protein is measured using Western Blot analysis, Fluorescent activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, immunohistochemistry, mass spectrometry, radio-immunoassay or immunofluorescence. 
     
     
         32 . A method of treating cancer comprising administering to a subject an inhibitor of prohibitin. 
     
     
         33 . The method of  claim 32 , wherein the cancer is resistant to a taxoid family member. 
     
     
         34 . The method of  claim 32 , further comprising administering a taxoid family member. 
     
     
         35 . The method of  claim 34 , wherein the taxoid family member is paclitaxel. 
     
     
         36 . The method of  claim 32 , wherein the inhibitor inhibits translocation of prohibitin to the cell surface. 
     
     
         37 . The method of  claim 32 , wherein the inhibitor of prohibitin inhibits transcription or expression of prohibitin. 
     
     
         38 . The method of  claim 32 , wherein the inhibitor of prohibitin is selected from the group consisting of siRNA, antibody, small molecule, or peptide. 
     
     
         39 . The method of  claim 32 , further comprising administering glutathione-S-transferase π. 
     
     
         40 . A method of treating a cancer in a subject that is resistant to a taxoid family member comprising administering to the subject a compound comprising an agent that selectively binds prohibitin and a therapeutic agent. 
     
     
         41 . The method of  claim 40 , wherein the agent that selectively binds prohibitin is a peptide having the amino acid sequence of SEQ ID NO:2. 
     
     
         42 . The method of  claim 40 , wherein agent that selectively binds prohibitin is an antibody-based binding moiety. 
     
     
         43 . The method of  claim 40 , wherein the therapeutic agent is a drug, a chemotherapeutic agent, a radioisotope, a pro-apoptosis agent, an anti-angiogenic agent, a hormone, a cytokine, a cytotoxic agent, a cytocidal agent, a peptide, a protein, an antibiotic, an antibody, a Fab fragment of an antibody, a hormone antagonist, and an antigen. 
     
     
         44 . A method to direct treatment of a subject which comprises having a subject tested for the level of prohibitin in a biological sample from the subject, wherein a clinician reviews the results as compared to a standard level of prohibitin, and if the biological sample has an elevated level of prohibitin as compared to a standard level the clinician directs the subject to be treated with an inhibitor of prohibitin. 
     
     
         45 . A method to direct treatment of a subject which comprises having a subject tested for the level of prohibitin in a biological sample from the subject, wherein a clinician reviews the results as compared to a standard level of prohibitin, and if the biological sample has an elevated level of prohibitin as compared to a standard level the clinician directs the subject to be treated with a compound comprising an agent that selectively binds prohibitin and a therapeutic agent.