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-9427413-B2
Publication Date
2016-08-30
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 document describes treating hematologic cancers, including acute myeloid leukemia (AML), using hypoxia-inducible factor (HIF) inhibitors. It particularly focuses on echinomycin as a HIF inhibitor to target cancer stem cell (CSC) maintenance and survival function in hematologic cancers.
The problem addressed is that cancer stem cells maintain survival and self-renewal, including in post-remission AML, and that HIF activity is elevated in CSC subsets. The document states that HIF1α is elevated in CSC subsets through HIF1α overexpression and/or von Hippel-Lindau (VHL) downregulation, leading to HIF addiction.
In the described approach, administering echinomycin at serum concentrations described in the document abrogates CSC self-renewal and CSC-mediated tumor initiation while not adversely affecting hematopoietic stem cells (HSCs). The document further links HIF1α to regulation of the Notch/Hes1 pathway for CSC maintenance and survival, and it discusses pharmaceutical formulation and dosing frameworks for HIF inhibitors.
Claims Coverage
The relevant independent claim covers a method for reducing self-renewal of AML cancer stem cells in a subject with post-remission AML using echinomycin, with a defined serum concentration range, while avoiding adverse effect on hematopoietic stem cells (HSCs). Dependent claims further refine the leukemia cell phenotype and tighten a serum concentration sub-range.
Reduce AML CSC self-renewal without affecting HSCs
A method of reducing self-renewal of acute myeloid leukemia (AML) cancer stem cells in a subject with post-remission AML, without adverse effect on hematopoietic stem cells (HSCs).
Administer echinomycin with pharmaceutically acceptable carrier
Administering echinomycin and a pharmaceutically acceptable carrier to a subject in need thereof.
Serum echinomycin concentration between 0.01 nM and 5 nM
Wherein said administration results in a serum concentration of echinomycin ranging from 0.01 nM to 5 nM.
AML leukemia cells of CD38−/CD34+ phenotype
The method is carried out using a mammal that has leukemia cells with the phenotype CD38− CD34+.
Serum echinomycin concentration between 0.1 nM and 5 nM
The method is carried out with a serum concentration ranging from 0.1 nM to 5 nM.
Overall, the claim set centers on administering echinomycin to reduce self-renewal of post-remission AML cancer stem cells without adverse effect on HSCs, defined by achieving specific serum echinomycin concentrations, with further refinements to a CD38−/CD34+ phenotype and a tightened serum range.
Stated Advantages
reduces self-renewal of acute myeloid leukemia (AML) cancer stem cells
without adverse effect on hematopoietic stem cells (HSCs)
Documented Applications
No documented applications found
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