Compounds and methods useful for treating or preventing hematological cancers
The present invention includes methods of treating patients with acute myeloid leukemia across a range of genetic subtypes with DHODH inhibitors, such as 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid).
1. A method of treating a hematological cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a dihydroorotate dehydrogenase (DHODH) inhibitor, wherein the dihydroorotate inhibitor is selected from the group consisting of 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid; salts, or solvates thereof; wherein said DHODH inhibitor is administered to the subject with a frequency less than or equal to once every 48 hours; wherein said administration results in intermittent periods of nucleotide depletion that differentially starves malignant cells as compared to normal cells; and wherein the 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid is administered to the subject by injection.
2. The method according to claim 1 , wherein 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid or a salt or solvate thereof is administered to the subject with a frequency less than or equal to once every 72 hours.
3. The method according to claim 1 , wherein the hematological cancer comprises acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), mixed-lineage leukemia (MLL), myelodysplastic syndrome (MDS), and/or chronic myeloid leukemia (CML).
4. The method according to claim 3 , wherein the hematological cancer comprises AML.
5. The method according to claim 1 , wherein the subject has been treated or is being treated for a hematological cancer characterized by differentiation arrest.
6. The method according to claim 1 , wherein 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid is administered to the subject by an injection route selected from intravenous, intradermal, intramuscular, subcutaneous, intracutaneous, intrauterine, epidural and intracerebroventricular injections.
7. The method according to claim 1 , wherein at least one additional agent useful for treating a hematological cancer is further administered to the subject.
8. The method according to claim 7 , wherein the additional agent is arsenic trioxide.
9. The method according claim 1 , wherein the subject is not responsive to one or more anticancer agents.
10. The method according to claim 1 , wherein the method comprises administering to the subject a composition comprising a dihydroorotate dehydrogenase (DHODH) inhibitor in an amount and for a duration sufficient to increase levels of dihydroorotate and/or to reduce levels of uridine in a biological sample obtained from the subject, thereby treating the hematological cancer.