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-10682356-B2
Publication Date
2020-06-16
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 disclosed invention relates to cancer combination therapy that uses a cyclin-dependent kinase (CDK) inhibitor together with a DNA methyltransferase (DNMT) inhibitor. In particular, the combination uses a CDK inhibitor such as alvocidib (Flavopiridol) together with azacitidine or decitabine/azanucleosides, and is described as a method of treating cancer, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
Mechanistic rationale is described in which inhibition of CDK7/CDK9 lowers anti-apoptotic MCL-1, thereby complementing DNMT inhibition. DNMT inhibition is described as inducing DNA damage/apoptosis, and the combined approach is presented as producing enhanced anti-cancer activity compared with DNMT inhibition alone.
Experimental support described in the document includes that, in MV4-11 AML cells, alvocidib reduces MCL-1 in a time- and dose-dependent manner. The document further describes that combined alvocidib plus azacitidine shows synergistic growth inhibition, including a left-shifted IC50/EC50, and increased caspase-3/7 activity/apoptosis versus azacitidine alone. Additional support is described for alvocidib plus decitabine improving potency (IC50 reduction), with a stronger effect when alvocidib is administered prior to decitabine.
Claims Coverage
The relevant independent claim covers a sequential treatment regimen for MDS using two specified therapeutic agents. One inventive feature is expressed by the claim: the specific order of administration of azacitidine and alvocidib to a human in need thereof.
Sequential azacitidine then alvocidib treatment for MDS
Administering a therapeutically effective amount of azacitidine and subsequently a therapeutically effective amount of alvocidib to a human in need of treatment for myelodysplastic syndrome (MDS).
The claim coverage is directed to a single MDS treatment method in which azacitidine is administered first and alvocidib is administered subsequently, both in therapeutically effective amounts.
Stated Advantages
Synergistic growth inhibition with combined alvocidib plus azacitidine compared with azacitidine alone.
Increased caspase-3/7 activity and apoptosis versus azacitidine alone.
Improved potency with alvocidib plus decitabine, including IC50 reduction.
Stronger effect when alvocidib is administered prior to decitabine.
Documented Applications
Treating myelodysplastic syndrome (MDS) using sequential administration of azacitidine followed by alvocidib.
Cancer treatment including MDS and acute myeloid leukemia (AML), supported by experiments in MV4-11 AML cells.
Synergy evaluation in MV4-11 AML cells using alvocidib with azacitidine and using alvocidib with decitabine.
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