Procaspase 3 activation by combination therapy
Inventors
Hergenrother, Paul J. • Botham, Rachel C. • Fan, Timothy M. • Gilbert, Mark J. • HANDLEY, Michael K. • Roth, Howard S. • Tarasow, Theodore M.
Assignees
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Publication Number
US-10888560-B2
Publication Date
2021-01-12
Expiration Date
Abstract
The invention provides compositions and methods for the induction of cell death, for example, cancer cell death. Combinations of compounds and related methods of use are disclosed, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells. The disclosed drug combinations can have lower neurotoxicity effects than other compounds and combinations of compounds.
Core Innovation
The patent describes a method of treating cancer in a subject by administering the procaspase-3 activator compound PAC-1 concurrently or sequentially with an effective amount of a second active agent, wherein PAC-1 and the second active agent act synergistically upon administration and the cancer is thereby treated. PAC-1 is described in connection with chelation of inhibitory zinc ions and induction of apoptosis through procaspase-3 activation and caspase-3 activity.
The described combination includes PAC-1 together with a second active agent selected from tamoxifen, bortezomib, and staurosporine. The method specifies that the second active agent and PAC-1 are administered as a therapeutic combination, and the cancer treated is specific to the selected second active agent, including breast cancer with tamoxifen and lymphoma with bortezomib or staurosporine.
The described framework further includes specifying concentration ranges for PAC-1 and for the second active agent, and specifying concurrent or sequential contacting or administration. The document characterizes the combined action as synergistic and highlights reduced neurotoxicity as part of the overall approach.
Claims Coverage
One independent claim is identified. It includes synergy and cancer treatment using PAC-1 together with a second active agent, with constraints on administration timing, cancer type, and concentrations for each selected second active agent. The independent claim features are implemented across dependent claims by narrowing second-agent selection and concentration values and by constraining administration timing and routes.
Concurrent or sequential PAC-1 and second active agent for cancer treatment with synergy
A method of treating cancer in a subject in need thereof by administering PAC-1 concurrently or sequentially with an effective amount of a second active agent, wherein PAC-1 and the second active agent act synergistically upon administration and the cancer is thereby treated.
PAC-1 plus tamoxifen for breast cancer at defined concentrations and synergy
The method where the second active agent is tamoxifen, the concentration of tamoxifen is about 10 μM to about 15 μM, the cancer is breast cancer, and the concentration of PAC-1 is about 15 μM to about 30 μM, with synergistic action upon administration.
PAC-1 plus bortezomib for lymphoma at defined concentrations and synergy
The method where the second active agent is bortezomib, the concentration of bortezomib is about 100 nM to about 5 μM, the cancer is lymphoma, and the concentration of PAC-1 is about 15 μM to about 30 μM, with synergistic action upon administration.
PAC-1 plus staurosporine for lymphoma at defined concentrations and synergy
The method where the second active agent is staurosporine, the concentration of staurosporine is about 50 nM, the cancer is lymphoma, and the concentration of PAC-1 is about 15 μM to about 30 μM, with synergistic action upon administration.
Dependent narrowing of administration timing and selected concentrations
The dependent claims refine the independent method by specifying sequential administration, providing additional specific PAC-1 concentration options, and constraining second-agent selection to specified concentrations and routes for administering the second active agent and PAC-1.
Across the independent claim, the core inventive coverage is a synergistic cancer treatment combining PAC-1 with a selected second active agent, with specified cancer type and concentration constraints and with concurrent or sequential administration. Dependent claims further narrow timing, concentration options for PAC-1 and the second active agents, and route(s) of administration.
Stated Advantages
Reduced neurotoxicity.
Documented Applications
Treating breast cancer using PAC-1 administered with tamoxifen as the second active agent, with synergistic action upon administration.
Treating lymphoma using PAC-1 administered with bortezomib as the second active agent, with synergistic action upon administration.
Treating lymphoma using PAC-1 administered with staurosporine as the second active agent, with synergistic action upon administration.
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