Combination therapy for MDS
Disclosed are compositions and methods for the treatment of disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The disclosed methods include administering to an individual in need of such treatment a composition that may include an IRAK1/4 inhibitor. In other aspects, the method may include administration of a BLC2 inhibitor.
1. A method of treating myelodysplastic syndrome (MDS) characterized by increased NFκB activity in an individual comprising the step of administering to said individual a composition comprising an IRAK1/4 inhibitor.
2. The method of claim 1 wherein said IRAK1/4 inhibitor is selected from N-acyl-2-aminobenzimidazoles, imidazo[1,2-a]pyridino-pyrimidine, imidazo[1,2-a]pyridino-pyridine, benzimidazolo- pyridine, N-(2-morpholinylethyl)-2-(3-nitrobenzoylamido)-benzimidazole,
or combinations thereof.
3. The method of claim 1 wherein said IRAK1/4 inhibitor comprises an RNAi sufficient to inhibit IRAK1 expression.
4. The method of claim 1 , further comprising the step of administering to said individual an apoptotic modulator.
5. The method of claim 1 , further comprising the step of administering to said individual an apoptotic modulator, wherein said apoptotic modulator comprises a BCL2 inhibitor.
6. The method of claim 1 , comprising the step of administering to said individual an apoptotic modulator, wherein said apoptotic modulator comprises a BCL2 inhibitor selected from
combinations thereof.
7. The method of claim 1 wherein said myelodysplastic syndrome is selected from Fanconi Anemia, refractory anemia, refractory neutropenia, refractory thrombocytopenia, refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia with excess blasts I and II (RAEB), 5q- syndrome, myelodysplasia unclassifiable, refractory cytopenia of childhood, or a combination thereof.
8. The method of claim 1 wherein said administering step is selected from orally, rectally, nasally, topically, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, or a combination thereof.
9. The method of claim 1 wherein said administration decreases the incidence of marrow failure, immune dysfunction, transformation to overt leukemia, or combinations thereof in said individual, as compared to an individual not receiving said composition.
10. The method of claim 1 wherein said method decreases a marker of viability of MDS cells.
11. The method of claim 1 , wherein said treatment decreases a marker of viability of MDS cells.
12. The method of claim 1 , wherein said treatment decreases a marker of viability of MDS and/or AML cells, wherein marker is selected from survival over time, proliferation, growth, migration, formation of colonies, chromatic assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof.
13. A method of treating myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), wherein said MDS or AML is characterized by increased NFκB activity, in an individual comprising the step of administering to said individual
a) an IRAK1/4 inhibitor; and
b) an agent selected from an apoptotic agent, an immune modulating agent, an epigenetic modifying agent, and combinations thereof.
14. The method of claim 13 wherein said IRAK1/4 inhibitor is selected from N-acyl-2-aminobenzimidazoles, imidazo[1,2-a]pyridino-pyrimidine, imidazo[1,2-a]pyridino-pyridine, benzimidazolo- pyridine, N-(2-morpholinylethyl)-2-(3-nitrobenzoylamido)-benzimidazole,
or combinations thereof.
15. The method of claim 13 wherein said IRAK1 inhibitor comprises an RNAi sufficient to inhibit IRAK1 expression.
16. The method of claim 13 wherein said administration step includes administration of an apoptotic modulator.
17. The method of claim 13 wherein said administration step includes administration of an apoptotic modulator comprising a BCL2 inhibitor.
18. The method of claim 13 wherein said administration step includes administration of an apoptotic modulator selected from
combinations thereof.
19. The method of claim 13 wherein said administration step includes administration of an immune modulator.
20. The method of claim 13 wherein said administration step includes administration of an immune modulator, wherein said immune modulator comprises lenalidomide.