Combination therapies for treatment of cancer
Inventors
Bearss, David J. • Warner, Steven L. • Siddiqui-Jain, Adam • Whatcott, Clifford J. • Kim, Wontak
Assignees
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Publication Number
US-10568887-B2
Publication Date
2020-02-25
Expiration Date
Abstract
Combination therapies for treatment of cancer are provided. The disclosed methods comprise administration of a cyclin-dependent kinase inhibitor and a DNA methyltransferase inhibitor to a mammal in need thereof.
Core Innovation
The document describes a cancer treatment approach using combination therapy with a cyclin-dependent kinase (CDK) inhibitor and a DNA methyltransferase inhibitor. The CDK inhibitor includes alvocidib, also referred to as Flavopiridol, and the DNA methyltransferase inhibitor includes azacitidine and decitabine. The approach includes sequential administration, with one agent provided and then the other agent subsequently provided to a human.
The document links the therapeutic rationale to CDK9 inhibition of MCL-1. It states that alvocidib lowers MCL-1, and that sequential administration with a DNA methyltransferase inhibitor produces synergistic reductions in viability. The document further describes increased caspase 3/7 activity and apoptosis as part of the observed effects.
The document also describes kit/composition concepts in connection with the defined agents, and it reports examples using MV4-11 cells. In those examples, sequential administration of alvocidib with azacitidine or decitabine is reported to improve quantitative response metrics, including IC50/EC50, alongside the viability reduction and caspase 3/7 activity/apoptosis increase.
Claims Coverage
The partial content provides 1 independent claim. It contains 2 main inventive features: a specific sequential administration order and a treatment context for myelodysplastic syndrome (MDS) using decitabine followed by alvocidib.
Sequential treatment of MDS with decitabine then alvocidib
Treating myelodysplastic syndrome (MDS) by administering a therapeutically effective amount of decitabine to a human and subsequently administering a therapeutically effective amount of alvocidib.
Across the provided independent claim, the coverage is centered on treating MDS using sequential administration in which decitabine is given first and alvocidib is given subsequently, each in a therapeutically effective amount.
Stated Advantages
Reports synergistic reductions in viability with sequential alvocidib plus azacitidine or decitabine.
Reports increased caspase 3/7 activity and apoptosis with sequential alvocidib plus azacitidine or decitabine.
Reports improved IC50/EC50 metrics in the provided MV4-11 cell examples.
Documented Applications
Treating myelodysplastic syndrome (MDS) in a human using sequential administration of decitabine followed by alvocidib.
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