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-9399035-B2
Publication Date
2016-07-26
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 invention relates to a cancer therapy that activates procaspase-3 to induce apoptosis by using PAC-1, described as a procaspase-activating compound that chelates inhibitory zinc ions. The disclosed rationale centers on cancer cells in which procaspase-3 levels are elevated, so that activation of procaspase-3 can promote programmed cell death through caspase-3 executioner caspases.
The approach is positioned as acting late in the apoptotic cascade by targeting a downstream effector, namely procaspase-3. The document further describes that PAC-1 can be combined with a second active agent to achieve synergy rather than merely additive effects, including treatment scenarios where the individual agents have minimal or no effect.
The document describes combination regimens for cancer treatment using PAC-1 with chemotherapeutic and targeted agents, including etoposide, bortezomib, staurosporine, doxorubicin, tamoxifen, cisplatin, carboplatin, and paclitaxel. The disclosed combination administration concepts include concurrent or sequential administration and support reduction of tumor burden while aiming to provide reduced neurotoxicity potential.
The document also describes pharmaceutical compositions and unitary dosage forms comprising PAC-1 in combination with additional components, including pharmaceutically acceptable diluents, excipients, or carriers. The disclosed examples and claimed formulations include the use of 2-hydroxypropyl-β-cyclodextrin as a carrier option.
Claims Coverage
The independent claim set has two main inventive elements: a specified PAC-1 concentration range together with a specified tamoxifen concentration range, formulated with a pharmaceutically acceptable diluent, excipient, or carrier. Dependent claims refine the carrier composition by adding specific carrier options and narrow the cyclodextrin identity, and they further constrain PAC-1 and tamoxifen concentration endpoints within the independent ranges.
Procaspase-activating PAC-1 and tamoxifen in a defined composition
A composition comprising about 15 μM to about 30 μM of PAC-1; about 10 μM to about 15 μM of tamoxifen; and a pharmaceutically acceptable diluent, excipient, or carrier.
Carrier specified with water, buffer, and/or cyclodextrin
The composition where the pharmaceutically acceptable diluent, excipient, or carrier includes water and optionally includes a buffer and/or a cyclodextrin.
Cyclodextrin specified as 2-hydroxypropyl-β-cyclodextrin
The composition where the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.
PAC-1 concentration endpoint at about 30 μM
The composition having a PAC-1 concentration of about 30 μM.
Tamoxifen concentration endpoint at about 10 μM
The composition characterized by having tamoxifen at an approximately 10 μM concentration.
Overall claim coverage focuses on a unitary pharmaceutical composition that combines PAC-1 with tamoxifen at defined concentration ranges, with dependent claims further narrowing carrier composition, including 2-hydroxypropyl-β-cyclodextrin, and fixing PAC-1 and tamoxifen concentration endpoints.
Stated Advantages
Enable synergy with a second active agent to reduce tumor burden, including when individual agents have minimal or no effect.
Reduced neurotoxicity potential.
Documented Applications
Treatment of cancer by activating procaspase-3 to induce apoptosis using PAC-1, including combination therapy with a second active agent.
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