Methods and compositions relating to hematologic malignancies
Methods of treating a subject having, or at risk of having, a myeloproliferative disorder are provided according to embodiments of the present invention which include administering a therapeutically effective amount of an arachidonate 5-lipoxygenase (5-LO) inhibitor to the subject. Combinations of therapeutic agents are administered according to embodiments of the present invention. In some embodiments, two or more 5-LO inhibitors are administered to a subject to treat a myeloproliferative disorder. In further embodiments, at least one 5-LO inhibitor and at least one additional therapeutic agent are administered to a subject to treat a myeloproliferative disorder. Methods of inhibiting leukemia stem cells are provided according to embodiments of the present invention which include contacting leukemia stem cells with an effective amount of an arachidonate 5-lipoxygenase inhibitor.
1. A method of treating a subject having chronic phase BCR-ABL-induced myeloid leukemia characterized by oncogene-mediated elevated arachidonate 5-lipoxygenase, comprising:
administering a therapeutically effective amount of an arachidonate 5-lipoxygenase inhibitor to the subject; and
administering a therapeutically effective dose of a BCR-ABL tyrosine kinase inhibitor to the subject,
wherein leukemia stem cells are inhibited.
2. The method of claim 1 , wherein the arachidonate 5-lipoxygenase inhibitor is selected from the group consisting of: N-[1-(1-benzothien-2-yl)ethyl]-N-hydroxyurea (zileuton), atreleuton, BW-B 70C, darbufelone, licofelone, minocycline, tepoxalin, tebufelone, curcumin, DHDMBF, BF389, RJW63556, PGV20229, CI986, S2474, ZD2138, CJ-13,610, L-739,010, Wy-50295, TMK688, PEP03, GSK-2190915 and AZD-4407.
3. The method of claim 1 , wherein the kinase inhibitor is selected from the group consisting of: imatinib, dasatinib, nilotinib, bosutinib, AZD0530, NPB-001-05, AT9283, BAY 43-9006, bafetinib, AP24534, lestaurtinib, tozasertib, danusertib, XL228, KW-2449, AT-9283, VE-465, DCC-2036, PKC412, PF-03814735 and vatalanib.
4. The method of claim 1 , further comprising administering a therapeutically effective dose of a 5-lipoxygenase-activating protein inhibitor.
5. The method of claim 4 , wherein the 5-lipoxygenase-activating protein inhibitor is selected from the group consisting of: 1-[(4-chlorophenyl)methyl]3-[(1,1-dimethylethyl)thio]-α, α-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid (MK886), MK-0591, BAY-X-1005 and AM679.
6. The method of claim 1 , further comprising administering a therapeutically effective dose of a kinase inhibitor selected from the group consisting of: a dual specificity kinase inhibitor, a multi-specificity kinase inhibitor, a src kinase inhibitor and an aurora kinase inhibitor.
7. The method of claim 1 , further comprising administering a therapeutically effective dose of an Hsp90 inhibitor.
8. The method of claim 1 , further comprising administering a therapeutically effective dose of an anti-cancer agent selected from the group consisting of: a protein synthesis inhibitor, an anti-metabolite, an alkylating agent, a steroid, interferon alpha 2b; and a combination of any two or more thereof.
9. The method of claim 1 , wherein the subject is resistant to anti-cancer effects of a therapeutic agent selected from the group consisting of: imatinib, dasatinib and nilotinib.