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-10085978-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 invention relates to treating cancer by targeting the procaspase/caspase-3 pathway and inducing apoptosis in cells. Procaspase-3 is elevated in tumors, and downstream executioner signaling is directly required to induce apoptosis and treat the cancer. The disclosed strategy therefore focuses on activating caspase-3 signaling through procaspase-3 activation together with an additional cancer therapeutic agent.
A procaspase-3 activator, procaspase-activating compound-1 (PAC-1), is combined with temozolomide (TMZ) to synergistically induce apoptosis and thereby reduce tumor burden. The combination is described for brain cancer, including glioblastoma and glioblastoma multiforme (GBM), and for bone cancer, including osteosarcoma. The described effects include inducing apoptosis or programmed cell death and treating the corresponding cancers.
The invention further describes administering a therapeutically effective amount of a compound of Formula (I) together with a therapeutically effective amount of PAC-1, concurrently or sequentially, to induce apoptosis in cells of the cancer of the brain and treat the cancer of the brain. Concentration ranges are specified for the compound of Formula (I) and for PAC-1, and the administration includes concurrent administration and sequential administration. The document also states that reduced neurotoxicity is claimed with the combination approach.
Claims Coverage
The independent claims identified are clm-00001 and clm-00007. Each independent claim contains multiple inventive features, centered on concurrent or sequential administration of a compound of Formula (I) with PAC-1 to induce apoptosis in brain cancer cells under specified concentration ranges, and for one claim, oral administration.
Treating brain cancer by concurrent or sequential administration with apoptosis induction
A method of treating cancer of the brain by administering concurrently or sequentially a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of PAC-1, wherein apoptosis is induced in cells of the cancer of the brain and the cancer of the brain is thereby treated.
Specified concentration ranges for compound of Formula (I) and PAC-1 to induce apoptosis
The method specifies that 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, with apoptosis induced in cells of the cancer of the brain and treatment resulting.
Oral concurrent or sequential dosing of compound of Formula (I) and PAC-1
A method of treating brain cancer consisting essentially of orally administering concurrently or sequentially a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of PAC-1, wherein apoptosis is induced in cells of the cancer of the brain and the cancer of the brain is thereby treated.
Oral administration with specified concentration ranges and apoptosis induction
The method specifies that 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, with oral administration and apoptosis induced in cells of the cancer of the brain for treatment.
Across clm-00001 and clm-00007, the claim coverage is directed to inducing apoptosis in brain cancer cells by administering a therapeutically effective combination of a compound of Formula (I) with PAC-1, under specified concentration ranges, with administration either concurrent or sequential and, in clm-00007, orally.
Stated Advantages
Reduced neurotoxicity is claimed with the combination approach.
The disclosed combination approach is described as synergistically inducing apoptosis and reducing tumor burden.
The document describes extending survival in brain (glioblastoma) and bone (osteosarcoma) cancer models.
Documented Applications
Treatment of brain cancer, including glioblastoma and glioblastoma multiforme (GBM), using the disclosed PAC-1 and compound combination approach with apoptosis induction.
Treatment of bone cancer, including osteosarcoma, using the disclosed PAC-1 and compound combination approach with apoptosis induction.
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