Methods of identifying respondents to hypoxia inducible factor 1-alpha inhibitors

Abstract

This invention relates to methods of measuring HIF expression and activity, as well as measuring inhibition of HIF following administration of an HIF inhibitor useful in treating HIF related diseases. The present invention further relates to methods of identifying individuals who will respond to HIF inhibitors. The invention also relates to methods of monitoring a patient response to a given dosage of an HIF inhibitor. The invention also includes assays and kits for performing the methods described herein.

1 . A method of determining efficacy of a HIF-1α inhibitor therapy comprising:
 obtaining a first blood sample from said individual;   exposing said first blood sample to a first leukocyte stimulating agent;   measuring a level of HIF in said first blood sample;   identifying said individual susceptible to treatment, wherein elevated levels of HIF indicate said individual's susceptibility to said treatment with said HIF-1α inhibitor;   administering a HIF-1α inhibitor to said individual;   obtaining a second blood sample from said individual;   exposing said second blood sample to a second leukocyte stimulating agent;   measuring a second level of HIF expression in said second blood sample, wherein decreased levels of HIF indicates effective HIF-1α inhibitor therapy.   
   
   
       2 . The method of  claim 1 , wherein said leukocyte stimulating agent is a T cell stimulating agent. 
   
   
       3 . The method of  claim 1 , wherein said leukocyte stimulating agent is selected from phorbol myristate acetate, calcium ionophore, concanavalin A, anti-CD3 antibody, anti-CD28 antibody, PHA, SEA, SEB, and combinations thereof. 
   
   
       4 . The method of  claim 1 , wherein said HIF-1α inhibitor is selected from PX-478, PX-12, 2-ME2, topotecan, camptothecin and combinations thereof. 
   
   
       5 . A method of determining efficacy of a HIF-1α inhibitor therapy in an individual comprising:
 obtaining a first blood sample from said individual;   measuring a first level of HIF in said blood sample;   administering a HIF-1α inhibitor to said individual;   obtaining a second blood sample from said individual;   exposing said blood sample to a leukocyte stimulating agent and hypoxic conditions; and   measuring a second level of HIF in said second blood sample, wherein decreased levels of HIF indicates effective HIF-1α inhibitor therapy.   
   
   
       6 . The method of  claim 5 , wherein said leukocyte stimulating agent is a T cell stimulating agent. 
   
   
       7 . The method of  claim 5 , wherein said leukocyte stimulating agent is selected from phorbol myristate acetate, calcium ionophore, concanavalin A, anti-CD3 antibody, anti-CD28 antibody, PHA, SEA, SEB, and combinations thereof. 
   
   
       8 . The method of  claim 5 , wherein said HIF-1α inhibitor is selected from PX-478, PX-12, 2-ME2, topotecan, camptothecin and combinations thereof.