Biomarkers of therapeutic responsiveness

Abstract

The present invention relates to methods of diagnosing a kidney disorder in a patient, as well as methods of monitoring the progression of a kidney disorder and/or methods of monitoring a treatment protocol of a therapeutic agent or a therapeutic regimen. The invention also relates to assay methods used in connection with the diagnostic methods described herein.

1 . A method for evaluating the efficacy of a treatment regimen in a patient diagnosed with renal cell carcinoma (RCC), said method comprising
 (a) measuring a level of a biomarker in a test sample obtained from a patient undergoing said treatment regimen for RCC, wherein said biomarker is selected from the group consisting of total Akt, total Erk1/2, total Met, total GSK3b, total Hif1a, total p21, total AMPKa1, total VEGF, total PlGF, total VEGFR-1/Flt-1, phosphorylated Akt, phosphorylated Erk1/2, phosphorylated. Met, phosphorylated STAT3, phosphorylated GSK3b, and phosphorylated AMPKa1; and   (b) evaluating from said level whether said patient is responsive to said treatment regimen.   
     
     
         2 . The method of  claim 1  wherein said method comprises measuring levels of two or more biomarkers. 
     
     
         3 . The method of  claim 2  wherein said measuring step comprises measuring levels of a first biomarker and an additional biomarker, wherein said first biomarker is a total form of a biomarker and said additional biomarker is a phosphorylated form of said biomarker. 
     
     
         4 . The method of  claim 3  wherein said measuring step comprises measuring levels of a pair of first and additional biomarkers selected from the group consisting of (a) total Akt and phosphorylated Akt; (b) total Erk1/2 and phosphorylated Erk1/2; (c) total Met and phosphorylated Met; (d) total GSK3b and phosphorylated GSK3b; and (e) total AMPKa1 and phosphorylated AMPKa1. 
     
     
         5 . A method of  claim 1  wherein said biomarker is selected from the group consisting of total Akt, phosphorylated. STAT3, total p21, total VEGF, total PlGF, total VEGFR-1/Flt-1, phosphorylated Erk1/2, p21 and phosphorylated AMPKa1. 
     
     
         6 . A method of  claim 5  wherein said phosphorylated AMPKa1 is phosphorylated at amino acid 174. 
     
     
         7 . A method of any one of  claims 2  to  5  wherein said level(s) reflect responsiveness or non-responsiveness to said treatment regimen. 
     
     
         8 . A method of  claim 1  wherein said treatment regimen comprises administration of a therapeutic agent that modulates one or more biological activities and/or one or more signaling pathways and the level(s) of said one or more biomarkers indicate modulation of said biological activities and/or said signaling pathways by said therapeutic agent. 
     
     
         9 . A method of  claim 8  wherein said signaling pathways are selected from the group consisting of the VEGF-signaling pathway and Raf/Ras/Erk/Mek signaling pathway. 
     
     
         10 . A method of  claim 9  wherein said therapeutic agent is an agonist of said signaling pathways. 
     
     
         11 . A method of  claim 9  wherein said therapeutic agent is an antagonist of said signaling pathways. 
     
     
         12 . A method of  claim 9  wherein said signaling pathway is the VEGF-signaling pathway. 
     
     
         13 . A method of  claim 9  wherein said therapeutic agent is a multi-kinase inhibitor. 
     
     
         14 . A method of  claim 13  wherein said therapeutic agent is selected from the group consisting of sorafenib, sunitinib, and cediranib. 
     
     
         15 . A method of  claim 14  wherein said therapeutic agent is sorafenib. 
     
     
         16 . A method of any one of  claims 14  to  15  wherein said therapeutic agent causes a reduction in tumor vasculature. 
     
     
         17 . A method of  claim 1  wherein said measuring and evaluating steps are carried out by a point of care device and said method further comprises providing a report to an end-user, by said device, whether said patient is responsive to said therapeutic regimen. 
     
     
         18 . A method of  claim 1  further comprising measuring a baseline level(s) of said biomarker before said therapeutic regimen is initiated, and said evaluating step further comprises comparing said level and said baseline level. 
     
     
         19 . A method of  claim 18  further comprising measuring an interim level of said biomarker during said therapeutic regimen and said evaluating step further comprises comparing said level, said interim level and said baseline level. 
     
     
         20 . The method of  claim 1 , wherein said evaluating step comprises comparing said level of said biomarker to a detection cut-off level, wherein said level above said detection cut-off level is indicative of RCC. 
     
     
         21 . The method of  claim 1 , wherein said evaluating step comprises comparing said level of said biomarker to a detection cut-off level, wherein said level below said detection cut-off level is indicative of RCC. 
     
     
         22 . The method of  claim 1  further comprising determining from said level of said biomarker the disease progression of RCC. 
     
     
         23 . The method of any one of the preceding claims wherein said measuring step(s) are conducted on a single sample. 
     
     
         24 . The method of any one of the preceding claims wherein said measuring step(s) employ a multiplexed assay. 
     
     
         25 . The method of any one of the preceding claims wherein said measuring step(s) are conducted in a single assay chamber. 
     
     
         26 . The method of  claim 25  wherein said assay chamber is a single well of an assay plate. 
     
     
         27 . The method of  claim 25  wherein said assay chamber is a cartridge. 
     
     
         28 . The method of any one of the preceding claims wherein said sample is selected from the group consisting of blood, peripheral blood mononuclear cells (PBMC), isolated blood cells, serum and plasma. 
     
     
         29 . The method of any one of the preceding claims wherein said sample is selected from a group consisting of biopsy tissue, intestinal mucosa, saliva, cerebral spinal fluid, and urine. 
     
     
         30 . The method of any one of the preceding claims wherein said level(s) are measured using an immunoassay.