Procaspase combination therapy for glioblastoma
Inventors
Hergenrother, Paul J. • Botham, Rachel C. • Fan, Timothy M. • Gilbert, Mark J. • Handley, Michael J. • 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-9421202-B2
Publication Date
2016-08-23
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 cancer therapy using a combination of PAC-1, a procaspase-3 activator, with a compound of Formula (I), where the compound of Formula (I) includes temozolomide (TMZ) or TMZ derivatives/prodrugs. The approach targets procaspase activation, including procaspase-3 activation and associated apoptosis, together with TMZ-driven DNA alkylation, and frames the combined mechanism as producing apoptosis in cancer cells and inhibiting cancer cell growth.
The problem addressed is cancer treatment in which apoptosis induction and cancer cell growth inhibition are desired, including brain and bone cancers. The background rationale is centered on the role of procaspase activation and DNA alkylation associated with TMZ, along with discussion of MGMT and related DNA repair elements as context for efficacy.
The disclosed therapy includes pharmaceutical compositions and methods that contact cancer cells or administer to a patient a therapeutically effective amount of the compound of Formula (I) and an effective amount of PAC-1. Administration is described as concurrent or sequential, including defined ordering between the compounds, and the target cancers explicitly include cancer of the brain and cancer of the bone, including glioblastoma/oligodendroglioma and osteosarcoma.
Claims Coverage
The independent claims cover three related inventive aspects: a pharmaceutical composition, a method of inducing apoptosis by contacting a cancer cell, and a patient method of treating cancer by administering the combination. Across these independent claims, the claims repeatedly use specified concentration ranges for the compound of Formula (I) and PAC-1, with “about” defined as a 20% variation.
Pharmaceutical composition of Formula I and PAC-1 with specified concentrations
A composition comprising a compound of Formula (I) and PAC-1, together with a pharmaceutically acceptable diluent, excipient, or carrier, where the concentration of the compound of Formula I is about 250 μM to about 750 μM and the concentration of PAC-1 is about 5 μM to about 30 μM, wherein about means a variation of 20% of the concentration.
Apoptosis induction by contacting cancer cells with Formula I and PAC-1 at specified concentrations
A method of inducing apoptosis in a cancer cell by contacting the cancer cell with an effective amount of a compound of Formula (I) and an effective amount of PAC-1, where apoptosis is thereby induced in the cancer cell, with the compound of Formula I at about 250 μM to about 750 μM and PAC-1 at about 5 μM to about 30 μM, and where the cancer is selected from cancer of the brain and cancer of bone.
Treating brain or bone cancer in patients by concurrent or sequential administration of Formula I and PAC-1
A method of treating a cancer in a patient in need thereof by administering, concurrently or sequentially, a therapeutically effective amount of a compound of Formula (I) and an effective amount of PAC-1, where the cancer is thereby treated, with the compound of Formula I at about 250 μM to about 750 μM and PAC-1 at about 5 μM to about 30 μM, and where the cancer is selected from cancer of the brain and cancer of bone.
Overall, the independent claims define a combined therapeutic pairing of PAC-1 with a compound of Formula (I) including TMZ using specified concentration ranges, and apply that pairing both to induce apoptosis in cancer cells and to treat brain or bone cancers in patients.
Stated Advantages
Reduced neurotoxicity potential.
Documented Applications
Cancer therapy targeting brain and bone cancers, including glioblastoma/oligodendroglioma and osteosarcoma, using PAC-1 together with a compound of Formula (I) such as TMZ.
In vivo survival benefit reported in a glioblastoma rat model for the PAC-1/TMZ combination.
Synergistic increase in cell death reported in glioblastoma and osteosarcoma cell culture.
Additional survival benefit reported in a metastatic osteosarcoma mouse model.
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