Therapeutic and diagnostic methods

Abstract

The invention relates to methods of treating diseases, particularly cancers, that respond favorably to the inhibition of Nicotinamide phosphoribosyltransferase (Nampt); it also relates to therapeutic methods that utilize Nampt inhibitors in combination with NAD biosynthesis precursors to intentionally kill cancer cells while limiting or minimizing toxicity to normal host cells; and it relates to methods of identifying cancers that will be most responsive to treatment with Nampt inhibitors, particularly when administered in combination with nicotinic acid.

What is claimed is: 
     
         1 . A method of treating selected cancers, comprising:
 identifying a cancer exhibiting a low level of Naprt expression; and   administering to a patient having said cancer exhibiting low levels of Naprt1 expression, a therapeutically effective dose of a compound of Formulae I-IVc or a compound of Tables 1 or 2, or a pharmaceutically-acceptable salt thereof.   
     
     
         2 . The method of  claim 1 , wherein identifying a cancer exhibiting a low level of Naprt1 expression comprises determining the level of expression of Naprt1 protein. 
     
     
         3 . The method of  claim 2 , wherein determining the level of expression of Naprt1 protein is by way of a Western Blot. 
     
     
         4 . The method of  claim 2 , wherein determining the level of expression of Naprt1 protein is by way of an Enzyme-Linked Immunosorbant Assay (ELISA). 
     
     
         5 . The method of  claim 1 , wherein identifying a cancer exhibiting a low level of Naprt1 expression comprises determining the level of expression of the mRNA transcript encoding the Naprt1 protein. 
     
     
         6 . The method of  claim 5 , wherein determining the level of expression of the mRNA transcript encoding the Naprt1 protein is by way of a Northern Blot. 
     
     
         7 . The method of  claim 5 , wherein determining the level of expression of the mRNA transcript encoding the Naprt1 protein is by way of quantitative RT-PCR. 
     
     
         8 . The method of  claim 1 , wherein said cancer exhibits low expression levels of the Nampt enzyme. 
     
     
         9 . The method of  claim 1 , further comprising determining whether said cancer expresses low levels of the Nampt enzyme. 
     
     
         10 . The method of  claim 1 , further comprising determining whether said cancer exhibits a NA Rescue Phenotype. 
     
     
         11 . The method of  claim 1 , wherein said cancer does not exhibit a NA Rescue Phenotype. 
     
     
         12 . The method of  claim 1 , further comprising administering nicotinic acid to said patient. 
     
     
         13 . A method of treating cancers exhibiting low levels of Naprt1 expression, comprising
 identifying a patient having a cancer exhibiting low levels of Naprt1 expression,   administering to said patient a protective amount of nicotinic acid,   administering to said patient a therapeutically effective amount of a compound of Formulae I-IVc or a compound of Tables 1 or 2, or a pharmaceutically-acceptable salt thereof.   
     
     
         14 . The method of  claim 13 , wherein said protective amount of nicotinic acid is administered prior to the therapeutically effective amount of a compound of Formulae I-Formulae I-IVc or a compound of Tables 1 or 2, or a pharmaceutically-acceptable salt thereof. 
     
     
         15 . The method of  claim 13 , wherein said protective amount of nicotinic acid is administered at the same time as the therapeutically effective amount of a compound of Formulae I-IVc or a compound of Tables 1 or 2, or a pharmaceutically-acceptable salt thereof. 
     
     
         16 . The method of  claim 13 , wherein said protective amount of nicotinic acid is administered after the therapeutically effective amount of a compound of Formulae I-IVc or a compound of Tables 1 or 2, or a pharmaceutically-acceptable salt thereof. 
     
     
         17 . The method of  claim 16 , wherein said protective amount of nicotinic acid is administered as part of the same dosage form comprising the therapeutically effective amount of a compound of Formulae I-IVc or a compound of Tables 1 or 2, or a pharmaceutically-acceptable salt thereof.