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-10085977-B2
Publication Date
2018-10-02
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 cancer therapy strategy that uses the compound PAC-1 in combination with an additional anticancer agent, with PAC-1 and the second active agent contacted with an effective amount to inhibit the growth or proliferation of cancer cells or to induce apoptosis in a cancer cell. The second active agent is selected as a topoisomerase inhibitor, a DNA intercalating agent, or a mitotic inhibitor. The approach further specifies that the cancer cells are osteosarcoma cells or ovarian carcinoma cells.
The patent indicates that procaspase-3 is elevated in various cancers and that PAC-1 is an activator that acts late in the apoptotic cascade, including through chelation of inhibitory zinc ions. By positioning PAC-1 as a procaspase-3 activator in the later stages of apoptosis, the combination is described as enabling synergy with second active agents that act earlier or through disparate mechanisms. The documented examples and drawings include synergy or additive effects for specific agent pairs.
The described compositions and treatment regimens include PAC-1 together with a second active agent and pharmaceutically acceptable carrier, diluent, or excipient, including embodiments featuring 2-hydroxypropyl-β-cyclodextrin. The patent supports in vitro or in vivo contacting and states that administration can be concurrent or sequential. The patent also expands the scope by listing representative second active agents spanning multiple chemotherapeutic classes.
Claims Coverage
The independent claims cover (i) inhibition of growth or proliferation, (ii) induction of apoptosis, and (iii) treatment of osteosarcoma or ovarian cancer in a patient, each via contacting or administering PAC-1 together with an effective amount of a second active agent selected from topoisomerase inhibitors, DNA intercalating agents, or mitotic inhibitors, with cancer cell type limitations in some claims. Across the independent claims, the core inventive features relate to PAC-1 combination therapy, second-agent class selection, and the osteosarcoma/ovarian carcinoma target scope; one dependent set specifies concurrent or sequential administration timing.
PAC-1 plus a topoisomerase, DNA intercalating, or mitotic second active agent for inhibiting cancer cell growth
Contacting cancer cells with an effective amount of the compound PAC-1 and an effective amount of a second active agent, where the second active agent is a topoisomerase inhibitor, a DNA intercalating agent, or a mitotic inhibitor, thereby inhibiting growth or proliferation, wherein the cancer cells are osteosarcoma cells or ovarian carcinoma cells.
PAC-1 plus a topoisomerase, DNA intercalating, or mitotic second active agent to induce apoptosis
Contacting a cancer cell in vitro or in vivo with an effective amount of the compound PAC-1 and an effective amount of a second active agent, where the second active agent is a topoisomerase inhibitor, a DNA intercalating agent, or a mitotic inhibitor, thereby inducing apoptosis, wherein the cancer cell is an osteosarcoma cell or ovarian carcinoma cell.
Concurrent or sequential administration of PAC-1 and a class-selected second active agent for treating osteosarcoma or ovarian cancer
Administering to a patient, concurrently or sequentially, a therapeutically effective amount of the compound PAC-1 and an effective amount of a second active agent, where the second active agent is a topoisomerase inhibitor, a DNA intercalating agent, or a mitotic inhibitor, thereby treating the osteosarcoma or ovarian cancer.
Concurrent or sequential administration of PAC-1 and a class-selected second active agent for treating osteosarcoma
Administering to a patient, concurrently or sequentially, a therapeutically effective amount of the compound PAC-1 and an effective amount of a second active agent, where the second active agent is a topoisomerase inhibitor, a DNA intercalating agent, or a mitotic inhibitor, thereby treating the osteosarcoma.
Across the independent claims, the patent centers on PAC-1 combination therapy with a second active agent selected from topoisomerase inhibitors, DNA intercalating agents, or mitotic inhibitors, with effects directed to inhibition of cancer cell growth or to inducing apoptosis, and with patient treatment claims focused on osteosarcoma and/or ovarian cancer using concurrent or sequential administration.
Stated Advantages
Synergy or additive effect is described for combinations of PAC-1 with specific anticancer agent pairs.
Aiming to reduce neurotoxicity is described.
Documented Applications
In vitro or in vivo contacting of osteosarcoma cells or ovarian carcinoma cells to inhibit growth or proliferation or to induce apoptosis.
Treatment of osteosarcoma or ovarian cancer in a patient in need thereof by administering PAC-1 concurrently or sequentially with a second active agent selected from topoisomerase inhibitors, DNA intercalating agents, or mitotic inhibitors.
Treatment of osteosarcoma in a patient in need thereof by administering PAC-1 concurrently or sequentially with a second active agent selected from topoisomerase inhibitors, DNA intercalating agents, or mitotic inhibitors.
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