Methods and materials for determining the efficacy of prostate cancer therapies

Abstract

Methods for monitoring, and determining the efficacy of, a treatment for prostate cancer in a subject are provided, such methods including detecting the levels of expression of multiple polypeptide biomarkers in biological samples obtained from the subject prior to, and during, a course of treatment. Specific patterns of changes in the expression of the polypeptide biomarkers are indicative of the effectiveness of the treatment in the subject.

1 . A method for determining the efficacy of a treatment for prostate cancer in a subject, the method comprising:
 (a) detecting levels of expression of a plurality of biomarkers in biological samples obtained from the subject at different time intervals prior to and following administration of the treatment, wherein the plurality of polypeptide biomarkers comprises prostate specific antigen (PSA) and at least one biomarker selected from the group consisting of: C reactive protein (CRP), chromogranin A (CHGA), bone alkaline phosphatase (BAP), cysteine-rich secretory protein 3 (CRISP3), ERG, and prostatic acid phosphatase (PAP); and   (b) determining changes in the levels of expression of the plurality of biomarkers following administration of the treatment,   wherein a decrease in the level of expression of PSA and an increase in the level of expression of at least one biomarker selected from CRP, CHGA, BAP, CRISP3, ERG and PAP that is sustained for a period of at least two weeks indicates that the treatment is effective in treating prostate cancer in the subject.   
     
     
         2 . The method of  claim 1 , wherein the prostate cancer is a metastatic prostate cancer. 
     
     
         3 . The method of  claim 1 , wherein the biological samples are selected from the group consisting of: urine, blood and serum. 
     
     
         4 . The method of  claim 1 , wherein the levels of expression of the plurality of biomarkers are determined by immunoassay. 
     
     
         5 . The method of  claim 1 , wherein step (a) comprises:
 (a) contacting the biological samples with antibodies, or antigen binding fragments thereof, that selectively bind to the biomarkers; and   (b) detecting the binding of the antibodies, or antigen binding fragments thereof, to the biomarkers.   
     
     
         6 . A method for determining the efficacy of a treatment for prostate cancer in a subject, the method comprising:
 (a) detecting levels of expression of at least one biomarker in biological samples obtained from the subject at different time intervals prior to and following administration of the treatment, wherein the at least one biomarker is selected from the group consisting of: C reactive protein (CRP), bone alkaline phosphatase (BAP) and cysteine-rich secretory protein 3 (CRISP3); and   (b) determining changes in the level of expression of the at least one biomarker following administration of the treatment,   wherein a rapid increase in the level of expression of the at least one biomarker that is sustained for a period of less than four weeks indicates that the treatment is not effective in treating prostate cancer in the subject.   
     
     
         7 . The method of  claim 6 , wherein the prostate cancer is a metastatic prostate cancer. 
     
     
         8 . The method of  claim 6 , wherein the biological samples are selected from the group consisting of: urine, blood and serum. 
     
     
         9 . The method of  claim 6 , wherein step (a) comprises:
 (a) contacting the biological samples with antibodies, or antigen binding fragments thereof, that selectively bind to the biomarkers; and   (b) detecting the binding of the antibodies, or antigen binding fragments thereof, to the biomarkers.   
     
     
         10 . A method for determining the efficacy of a treatment for prostate cancer in a subject, the method comprising:
 (a) detecting levels of expression of a plurality of biomarkers in biological samples obtained from the subject at different time intervals prior to and following administration of the treatment, wherein the plurality of polypeptide biomarkers comprises chromogranin A (CHGA), cysteine-rich secretory protein 3 (CRISP3), C reactive protein (CRP), prostatic acid phosphatase (PAP), and bone alkaline phosphatase; and   (b) determining changes in the levels of expression of the plurality of biomarkers following administration of the treatment,   wherein an increase in the level of expression of at least one of the biomarkers of less than 5% indicates that the treatment is not effective in treating prostate cancer in the subject.   
     
     
         11 . The method of  claim 10 , wherein the prostate cancer is a metastatic prostate cancer. 
     
     
         12 . The method of  claim 10 , wherein the biological samples are selected from the group consisting of: urine, blood and serum. 
     
     
         13 . The method of  claim 10 , wherein step (a) comprises:
 (a) contacting the biological samples with antibodies, or antigen binding fragments thereof, that selectively bind to the biomarkers; and   (b) detecting the binding of the antibodies, or antigen binding fragments thereof, to the biomarkers.   
     
     
         14 . A method for determining the efficacy of a treatment for prostate cancer in a subject, the method comprising:
 (a) detecting levels of expression of a plurality of biomarkers in biological samples obtained from the subject at different time intervals prior to and following administration of the treatment, wherein the plurality of polypeptide biomarkers comprises cysteine-rich secretory protein 3 (CRISP3) and ERG; and   (b) determining changes in the levels of expression of the plurality of biomarkers following administration of the treatment,   wherein an increase in expression of at least one of the biomarkers indicates that the treatment is effective in treating prostate cancer in the subject.   
     
     
         15 . The method of  claim 14 , wherein the prostate cancer is a metastatic prostate cancer. 
     
     
         16 . A composition comprising a solid substrate and a plurality of binding agents immobilized on the substrate, wherein each of the binding agents is immobilized at a different, indexable, location on the substrate and the binding agents selectively bind to a plurality of polypeptide biomarkers, the plurality of polypeptide biomarkers comprising PSA, CRP, CHGA, BAP, CRISP3, ERG and PAP. 
     
     
         17 . A composition comprising a solid substrate and a plurality of polypeptide biomarkers immobilized on the substrate, wherein each of the polypeptide biomarkers is immobilized at a different, indexable, location on the substrate and wherein the plurality of polypeptide biomarkers comprises PSA, CRP, CHGA, bone alkaline phosphatase, CRISP3, ERG and PAP. 
     
     
         18 . A composition comprising a solid substrate and a plurality of oligonucleotides immobilized on the substrate, wherein each of the oligonucleotides is immobilized at a different, indexable, location on the substrate and the oligonucleotides are specific for a plurality of polynucleotide biomarkers comprising PSA, CRP, CHGA, bone alkaline phosphatase, CRISP3 and ERG. 
     
     
         19 . A method for determining the efficacy of a treatment for prostate cancer in a subject, the method comprising:
 (a) contacting a first biological sample obtained from the subject prior to administration of the treatment with a composition of  claim 17 ;   (b) contacting a plurality of subsequent biological samples obtained from the subject at a plurality of different time intervals following administration of the treatment with a plurality of compositions of  claim 18 ; and   (c) determining changes in the levels of expression of the plurality of biomarkers following administration of the treatment,   wherein:   (i) a decrease in the level of expression of PSA and an increase in the level of expression of at least one biomarker selected from CRP, CHGA, CRISP3, BAP, ERG and PAP that is sustained for a period of at least one week indicates that the treatment is effective in treating prostate cancer in the subject;   (ii) a rapid increase in the level of expression of at least one biomarker selected from the group consisting of: CRISP3, CRP and PAP that is sustained for a period of less than four weeks indicates that the treatment is not effective in treating prostate cancer in the subject; and   (iii) an increase in the level of expression of at least one biomarker selected from the group consisting of: CHGA, CRISPS, CRP, PAP and BAP of less than 5% indicates that the treatment is not effective in treating prostate cancer in the subject.   
     
     
         20 . The method of  claim 19 , wherein the biological samples are blood samples.