Procaspase combination therapy for glioblastoma
Inventors
Hergenrother, Paul J. • Botham, Rachel C. • Fan, Timothy M. • Gilbert, Mark J. • HANDLEY, Michael K. • Joshi, Avadhut • Riggins, Gregory J. • Tarasow, Theodore M.
Assignees
VANQUISH ONCOLOGY Inc • Johns Hopkins University • University of Illinois System
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Publication Number
US-10874666-B2
Publication Date
2020-12-29
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 method of treating cancer in a subject in need thereof by administering a compound of Formula (I) concurrently or sequentially with PAC-1. The approach is directed to procaspase-3 activation, with PAC-1 used together with temozolomide (TMZ) as part of Formula (I). The combination is described as inducing apoptosis and inhibiting growth/proliferation of cancers.
The problem addressed is cancer that requires treatment, including glioblastoma multiforme (GBM) and meningioma, where therapeutic efficacy and safety are important. The disclosure emphasizes that the combination provides synergistic efficacy, including results described for glioblastoma and osteosarcoma, and reduced neurotoxicity in connection with the PAC-1 and TMZ combination.
The disclosed system includes a composition comprising the compound of Formula (I) and PAC-1, together with a pharmaceutically acceptable diluent/excipient/carrier such as 2-hydroxypropyl-β-cyclodextrin. Therapeutically effective amounts and concentration ranges are specified for the compound of Formula (I) and PAC-1, and administration may be concurrent or sequential, including sequential order permutations.
The disclosure supports the mechanism and efficacy with in vitro and in vivo data, including that PAC-1/TMZ synergy extends survival in a rat 9L intracranial glioblastoma model and induces death in glioblastoma/osteosarcoma cell cultures. Tumor outcomes are described, including non-hemorrhagic tumors suggesting an anti-angiogenic effect, and the biological rationale is related to procaspase-3 activation by PAC-1 via zinc chelation together with TMZ DNA alkylation.
Claims Coverage
The document contains one independent claim directed to a method of treating cancer by concurrently or sequentially administering a compound of Formula (I) together with PAC-1, with specified concentration ranges and cancer subtype limitations. Inventive features are further refined in dependent claims by specifying sequential order, synergistic concentration relationship, narrower PAC-1 concentration limits and discrete PAC-1 concentration selections, and administration routes.
Concurrent or sequential co-administration of Formula (I) and PAC-1
Administering to a subject in need of therapy for cancer concurrently or sequentially a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of PAC-1.
Concentration ranges for Formula (I) and PAC-1
Wherein the concentration of the compound of Formula I is about 250 μM to about 750 μM or about 50 mg/kg, and the concentration of PAC-1 is about 5 μM to about 30 μM or about 50 mg/kg.
GBM or meningioma treatment using the Formula (I) and PAC-1 combination
The cancer is glioblastoma multiforme (GBM) or meningioma and the cancer is thereby treated.
Sequential administration order of PAC-1 and Formula (I)
Administering the compound of Formula (I) and PAC-1 sequentially in either order.
Synergistic relative concentration relationship
The concentration of the Formula I compound relative to PAC-1 is synergistic.
PAC-1 concentration range
Performing the method with a PAC-1 concentration in the range of 5 μM to 30 μM.
Discrete PAC-1 concentration selections
Using a PAC-1 concentration selected from 5 μM, about 10 μM, about 12.5 μM, about 25 μM, or about 30 μM.
Administration route(s) for Formula (I) and PAC-1
Administering the compound of Formula (I) together with PAC-1 using infusion, injection, oral administration, or a combination of these routes.
Across the claim set, the core claimed inventive concept is co-administering a compound of Formula (I) with PAC-1 concurrently or sequentially at specified Formula (I) and PAC-1 concentration ranges, limited to treatment of GBM or meningioma. Dependent claims further specify sequential order, a synergistic concentration relationship, narrower PAC-1 ranges or discrete PAC-1 concentration values, and particular administration routes.
Stated Advantages
Synergistic efficacy with PAC-1 and TMZ, including described improvement in survival in a rat 9L intracranial glioblastoma model.
Inhibition of tumor growth/proliferation and induction of apoptosis.
Reduced neurotoxicity.
Tumor outcome described as non-hemorrhagic tumors, suggesting an anti-angiogenic effect.
Documented Applications
Treating glioblastoma multiforme (GBM).
Treating meningioma.
In vivo support in a rat 9L intracranial glioblastoma model, with survival extension described.
In vitro death in glioblastoma/osteosarcoma cell cultures described.
Osteosarcoma.
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