Uses of hypoxia-inducible factor inhibitors
Inventors
Liu, Yang • Wang, Yin • Liu, Yan • Malek, Sami N. • Zheng, Pan
Assignees
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Publication Number
US-9877998-B2
Publication Date
2018-01-30
Expiration Date
Abstract
The present invention relates to treating a hematologic cancer using a Hypoxia-Inducible Factor (HIF inhibitor). The invention also relates to inducing acute myeloid leukemia remission using the HIF inhibitor. The invention further relates to inhibiting a maintenance or survival function of a cancer stem cell (CSC) using the HIF inhibitor.
Core Innovation
The invention relates to treating hematologic cancers, including lymphoma and leukemia, by administering a hypoxia-inducible factor (HIF) inhibitor, with echinomycin described as a key example, to target cancer stem cells (CSCs). The problem addressed is that lymphoma CSCs are described as HIF-addicted, and the invention seeks to eliminate CSCs while avoiding adverse effects on normal hematopoiesis.
The disclosure describes that HIF1α is maintained in CSCs, and that HIF1α contributes to CSC maintenance through downregulation of VHL and functional cooperation with Notch signaling (Hes1). In this context, inhibiting HIF activity is shown to reduce CSC colony formation and tumor initiation, using in vitro and in vivo support.
The disclosure further describes treatment effects in models in which echinomycin eliminates human acute myeloid leukemia (AML) cells/AML-LSC (CD34+CD38−) and prevents relapse in secondary transplantation. The text also describes additional HIF inhibitors (2-methoxyestradiol and geldanamycin) and coadministration options, including combining with a Hedgehog pathway inhibitor (cyclopamine).
Claims Coverage
The partial claims provide coverage for two independent methods of treating lymphoma. Across the independent claims, the coverage is centered on administering echinomycin or a “chinomycin”/echinomycin-based regimen while maintaining a serum echinomycin concentration at or below a specified threshold, together with constraints intended to preserve a therapeutic window (killing cancer stem cells without adversely affecting normal hematopoiesis).
Maintaining serum echinomycin concentration at or below 5 nM with echinomycin-cancer stem cell killing
A method of treating a lymphoma by administering chinomycin as a sole active agent and a pharmaceutically acceptable carrier to a human, at a dose and interval to maintain a serum concentration of echinomycin that kills cancer stem cells without adversely affecting normal hematopoiesis, wherein the maintained serum concentration is less than or equal to 5 nM.
Administering echinomycin composition to maintain serum echinomycin concentration at or below 5 nM
A method of treating lymphoma, consisting of administering a composition consisting of echinomycin and a pharmaceutically acceptable carrier to a human, at a dose and interval to maintain a serum concentration of echinomycin of less than or equal to 5 nM.
Overall claim coverage is directed to lymphoma treatment regimens defined by maintaining a serum echinomycin concentration at or below 5 nM, with one independent claim further requiring that this maintained concentration kills cancer stem cells without adversely affecting normal hematopoiesis, and the other defining treatment with an echinomycin-containing composition under the same maintained-concentration threshold.
Stated Advantages
Kills cancer stem cells without adversely affecting normal hematopoiesis (as stated in the independent claim).
Documented Applications
Treating lymphoma in a human in need thereof (as specified in the independent claims).
Treating lymphoma and hematologic cancers by targeting cancer stem cells using a HIF inhibitor, with echinomycin described as effective in reducing CSC colony formation and tumor initiation (as described in the partial patent content).
Eliminating human AML cells/AML-LSC (CD34+CD38−) and preventing relapse in secondary transplantation using echinomycin (as described in the partial patent content).
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