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-11833147-B2
Publication Date
2023-12-05
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 based on administering PAC-1 and an effective amount of sunitinib to a subject in need thereof, where sunitinib is synergistic with PAC-1 in the treatment of the cancer. The therapy is directed to a carcinoid tumor, and PAC-1 is characterized as a procaspase-3 activator compound.
The disclosed approach emphasizes PAC-1 activation of procaspase-3 and caspase-3 mediated apoptosis as the mechanistic basis of the therapy. PAC-1 is also related to procaspase-7, and synergy with other therapeutic agents is described in the document.
The described cancer treatment further focuses on cellular synergy evidence, including apoptosis and reduced effective dosing and relative toxicity as discussed in the summary content. The document indicates that PAC-1 synergizes with multiple chemotherapeutic or targeted agents to induce apoptosis across several cancer cell lines.
Claims Coverage
The partial content identifies one independent claim. The claim centers on a synergistic combination therapy using PAC-1 and sunitinib for a carcinoid tumor, with specified concentration ranges for both agents.
Synergistic PAC-1 plus sunitinib for carcinoid tumor treatment
A method of treating cancer by administering to a subject an effective amount of PAC-1 and an effective amount of sunitinib, where sunitinib is synergistic with PAC-1 in the treatment of the cancer, and the cancer is a carcinoid tumor.
PAC-1 and sunitinib concentration ranges
The method specifies PAC-1 at a concentration of about 2.5 μM to about 10 μM and sunitinib at a concentration of about 100 nM to about 10 μM for the synergistic treatment of the carcinoid tumor.
Across the independent claim, the main inventive features are the synergistic combination of PAC-1 and sunitinib for treating a carcinoid tumor, together with specified concentration ranges for PAC-1 and sunitinib.
Stated Advantages
Synergizes with multiple chemotherapeutic or targeted agents to induce apoptosis.
Reduces effective dosing and relative toxicity as described in the provided summary content.
Documented Applications
Treating cancer, specifically a carcinoid tumor, using a combination of PAC-1 and sunitinib.
Cell-based synergy evidence in cancer cell lines including lymphoma U-937; osteosarcoma 143B/143B and HOS; triple-negative breast cancer BT20 and MDA MB 436; ovarian carcinoma IGROV-1; and associated apoptosis readouts described (e.g., Annexin V/PI).
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