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 cancers associated with low level expression of nicotinic acid phosphoribosyltransferase 1 (Naprt1), comprising:
identifying a cancer associated with a low level of Naprt1 expression; and
administering to a subject in need thereof, a composition comprising 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.
2. The method of claim 1 , wherein identifying a cancer associated with a low level of Naprt1 expression comprises determining the level of expression of Naprt1 protein in cells of the cancer.
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 associated with a low level of Naprt1 expression comprises determining the level of expression of the mRNA transcript encoding the Naprt1 protein in cells of the cancer.
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 is associated with low expression levels of nicotinamide phosphoribosyltransferase (Nampt).
9. The method of claim 8 , further comprising determining whether said cancer expresses low levels of the Nampt.
10. The method of claim 1 , further comprising determining whether said cancer is associated with nicotinic acid (NA) Rescue Phenotype.
11. The method of claim 10 , wherein said cancer is associated with NA Rescue Phenotype.
12. The method of claim 1 , further comprising administering nicotinic acid to said subject.
13. A method of treating cancers associated with low level expression of nicotinic acid phosphoribosyltransferase 1 (Naprt1), comprising:
identifying a cancer associated with a low level of Naprt1 expression,
administering to a subject in need thereof, a composition comprising a therapeutically effective amount of: (i) nicotinic acid; (ii) 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 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 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 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 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.