Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib
Inventors
Bearss, David J. • Siddiqui-Jain, Adam • Whatcott, Clifford J. • Warner, Steven L.
Assignees
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Publication Number
US-11497756-B2
Publication Date
2022-11-15
Expiration Date
Abstract
Methods for treating BCL-2 inhibitor-resistant cancer in subjects using an MCL-1 inhibitor as well as compositions associated with the same are disclosed.
Core Innovation
The invention relates to inhibiting a hematologic cancer that is BCL-2 inhibitor resistant in a subject. The method administers an effective amount of a therapy comprising alvocidib, a prodrug of alvocidib, or a pharmaceutically acceptable salt thereof for more than 21 days to a subject who is non-responsive or resistant to a prior therapy with a BCL-2 inhibitor.
The therapy is administered without venetoclax in combination during the course of the therapy. The disclosed rationale centers on BCL-2 inhibitor resistance and the use of MCL-1 inhibition, including concept-level discussion contrasting venetoclax and alvocidib in venetoclax-resistant settings. The disclosed therapy composition includes embodiments in which the therapy comprises an alvocidib phosphate prodrug, and embodiments in which the therapy further comprises additional agents.
To identify BCL-2 inhibitor resistance, the disclosure uses biomarker-based criteria involving BCL-2 and MCL-1. The hematologic cancer cell biomarker approach includes quantifying BCL-2 and MCL-1 protein expression, where an increase in MCL-1 relative to BCL-2 indicates resistance, and BH3 profiling using profiling peptides having SEQ ID NO:1 and SEQ ID NO:2, with examples that use an MCL-1 protein dependency percentage threshold in vitro.
The description provides supportive example results in BCL-2 inhibitor resistant models, including venetoclax-resistant AML models. The examples report MCL-1 downregulation and tumor growth reduction in vivo, and cell viability comparisons in additional resistant cell lines. The support aligns with the disclosed method by demonstrating activity of alvocidib in the context of BCL-2 inhibitor resistance.
Claims Coverage
The partial set includes one independent claim directed to a method for inhibiting a hematologic cancer that is BCL-2 inhibitor resistant. The independent claim contains multiple inventive concepts that are further refined by dependent claims using biomarker criteria, specific therapy forms, and co-therapeutic components.
Inhibiting BCL-2 inhibitor-resistant hematologic cancer with alvocidib for more than 21 days
A method for inhibiting a hematologic cancer that is BCL-2 inhibitor resistant in a subject by administering to the subject an effective amount of a therapy comprising alvocidib, a prodrug of alvocidib, or a pharmaceutically acceptable salt thereof for more than 21 days, wherein the subject is non-responsive or resistant to a prior therapy with a BCL-2 inhibitor.
Excluding venetoclax combination during alvocidib therapy
The method further specifies that venetoclax, or a pharmaceutically acceptable salt thereof, is not administered in combination with the alvocidib, or a prodrug thereof, or a pharmaceutically acceptable salt thereof during the course of the therapy.
Biomarker criterion based on relative MCL-1 and BCL-2 protein expression
A further determination that the hematologic cancer is BCL-2 inhibitor resistant by obtaining a hematologic cancer cell and quantifying BCL-2 and MCL-1 protein expression, where an increase in MCL-1 relative to BCL-2 indicates resistance.
MCL-1 protein dependency percentage threshold using profiling peptides (SEQ ID NO:1 and SEQ ID NO:2)
A further selection criterion in which the subject has an MCL-1 protein dependency percentage of at least 15%, obtained in vitro by contacting a first portion of a plurality of cancer cells with a profiling peptide having the sequence SEQ ID NO:1 or SEQ ID NO:2.
Higher MCL-1 protein dependency percentage threshold
A further selection criterion in which the subject has an MCL-1 protein dependency percentage of at least 40%.
Therapy includes alvocidib phosphate prodrug
The therapy comprises a phosphate prodrug of alvocidib, or a pharmaceutically acceptable salt thereof.
Therapy further comprises cytarabine and mitoxantrone
The therapy further comprises cytarabine and mitoxantrone.
Across the independent claim and its highlighted dependents in the provided material, the claim coverage centers on alvocidib (or alvocidib prodrug/salt) administered for more than 21 days to BCL-2 inhibitor-resistant hematologic cancer, with explicit exclusion of venetoclax during the therapy. Additional coverage specifies biomarker criteria using BCL-2 and MCL-1 protein expression and/or BH3 profiling with SEQ ID NO:1 and SEQ ID NO:2, including MCL-1 dependency thresholds, and specifies embodiments using an alvocidib phosphate prodrug and co-therapeutic agents.
Stated Advantages
Inhibiting a hematologic cancer that is BCL-2 inhibitor resistant in a subject.
Enabling a therapy regimen with alvocidib that is administered without combination with venetoclax during the course of therapy.
Identifying BCL-2 inhibitor resistance using quantification of BCL-2 and MCL-1 protein expression where increased MCL-1 relative to BCL-2 indicates resistance.
Identifying BCL-2 inhibitor resistance using BH3 profiling with profiling peptides having SEQ ID NO:1 or SEQ ID NO:2 and an MCL-1 protein dependency percentage threshold.
Supporting activity in venetoclax-resistant AML models with reported MCL-1 downregulation and tumor growth reduction in vivo.
Documented Applications
Treating a venetoclax-resistant AML model by inhibiting a hematologic cancer that is BCL-2 inhibitor resistant using alvocidib, including reported tumor growth reduction in vivo.
Treating BCL-2 inhibitor-resistant hematologic cancers by administering alvocidib (or prodrug/salt) for more than 21 days without combination with venetoclax during the course of therapy.
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