MN/CA IX and EGFR Pathway Inhibition

Abstract

The invention is based upon the discovery that the EGFR pathway can stimulate a previously unknown tumorigenic function of CA IX, via phosphorylation of the sole tyrosine residue present in CA IX's intracellular domain. EGFR-phosphorylated CA IX then interacts with the p85 subunit of PI3K to activate Akt, which in turn is associated with anti-apototic function and increased cell survival. The latter finding indicates that there is a positive feedback loop for CA9 expression mediated by the PI3K pathway in preneoplastic/neoplastic diseases. Disclosed herein are novel therapeutic methods for treating preneoplastic/neoplastic diseases associated with abnormal MN/CA IX expression, using EGFR pathway inhibitors. Preferably, the EGFR pathway inhibitors are tyrosine kinase inhibitors or EGFR-specific antibodies. Further disclosed are methods for patient therapy selection for EGFR pathway inhibitors, preferably in combination with other cancer therapies, based on detection of abnormal MN/CA9 gene expression in preneoplastic/neoplastic tissues.

1 . A method of treating a mammal for a preneoplastic/neoplastic disease, wherein said disease is characterized by abnormal MN/CA9 gene expression, comprising administering to said mammal a therapeutically effective amount of a composition comprising an EGFR pathway inhibitor which is an anti-EGFR antibody. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein said anti-EGFR antibody is selected from cetuximab, panitumumab, nimotuzumab, matuzumab, and MDX-447. 
     
     
         5 . The method of  claim 1 , wherein said anti-EGFR antibody is conjugated to an antibody or biologically active antibody fragment which specifically binds MN/CA IX. 
     
     
         6 . The method of  claim 1 , wherein said anti-EGFR antibody is a bispecific antibody having a specificity for EGFR and a specificity for MN/CA IX. 
     
     
         7 . The method of  claim 1  further comprising administering to said mammal radiation and/or a therapeutically effective amount in a physiologically acceptable formulation of one or more of the following compounds selected from the group consisting of: conventional anticancer drugs, chemotherapeutic agents, different inhibitors of cancer-related pathways, bioreductive drugs, gene therapy vectors, CA IX-specific carbonic anhydrase inhibitors, CA IX-specific antibodies and CA IX-specific antibody fragments that are biologically active, and CA9 antisense therapies. 
     
     
         8 . The method of  claim 7 , wherein said inhibitors of cancer-related pathways are selected from HIF-1α targeted therapies, VEGF-R targeted therapies, IL-2 and interferon-α, inhibitors of the MAPK pathway, and inhibitors of the PI-3K pathway. 
     
     
         9 . The method of  claim 8 , wherein said inhibitor of the MAPK pathway is the bis aryl-urea Sorafenib (BAY 43-9006) or an omega-carboxypyridyl substituted urea. 
     
     
         10 . The method of  claim 7 , wherein said gene therapy vectors are targeted to hypoxic tumors. 
     
     
         11 . The method of  claim 1 , wherein said preneoplastic/neoplastic disease characterized by abnormal MN/CA9 gene expression is selected from the group consisting of mammary, urinary tract, bladder, kidney, urethra, ovarian, uterine, cervical, endometrial, squamous cell, adenosquamous cell, vaginal, vulval, prostate, liver, lung, skin, thyroid, pancreatic, testicular, brain, head and neck, mesodermal, sarcomal, stomach, spleen, gastrointestinal, esophageal, rectal, and colon preneoplastic/neoplastic diseases. 
     
     
         12 . The method of  claim 11 , wherein said preneoplastic/neoplastic disease characterized by abnormal MN/CA9 gene expression is kidney cancer. 
     
     
         13 . The method of  claim 11 , wherein said preneoplastic/neoplastic disease characterized by abnormal MN/CA9 gene expression is renal cell carcinoma. 
     
     
         14 . The method of  claim 1  wherein said disease is a normoxic tumor. 
     
     
         15 . The method of  claim 1  wherein said disease is a hypoxic tumor. 
     
     
         16 . The method of  claim 1 , wherein said mammal is a human. 
     
     
         17 - 26 . (canceled) 
     
     
         27 . The method of  claim 7  wherein said one or more compounds are selected from the group consisting of CA IX-specific carbonic anhydrase inhibitors, CA IX-specific antibodies and CA IX-specific antibody fragments that are biologically active. 
     
     
         28 . The method of  claim 27  wherein said one or more compounds are selected from the group consisting of CA IX-specific antibodies and CA IX-specific antibody fragments that are biologically active. 
     
     
         29 . The method of  claim 28  wherein said compound is a CA IX-specific antibody or a CA IX-specific antibody fragment that is biologically active. 
     
     
         30 . The method of  claim 29  wherein said CA IX-specific antibody or antibody fragment is either humanized or fully human. 
     
     
         31 . The method of  claim 29  wherein said CA IX-specific antibody or antibody fragment is conjugated to a cytotoxic entity. 
     
     
         32 . The method of  claim 30  wherein said humanized or fully human CA IX-specific antibody or antibody fragment is conjugated to a cytotoxic entity. 
     
     
         33 . The method of  claim 29  wherein said CA IX-specific antibody or antibody fragment is conjugated to an EGFR inhibitor. 
     
     
         34 . The method of  claim 30  wherein said humanized or fully human CA IX-specific antibody or antibody fragment is conjugated to an EGFR inhibitor.