THERAPEUTIC AND DIAGNOSTIC METHODS
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.
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.