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-11844798-B2
Publication Date
2023-12-19
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 combination therapy for inducing apoptosis in cancer by administering a procaspase-activating compound PAC-1 together with the DNA-alkylating agent temozolomide (TMZ). The described approach includes treating cancers using compositions and methods that contact cancer cells with both compounds to produce apoptosis and inhibit growth and proliferation.
The disclosure describes administering therapeutically effective amounts of TMZ and PAC-1 to a subject with osteosarcoma, with concurrent or sequential administration. The combination is stated to be a synergistic anticancer combination therapy that is about 20% to about 93% more effective than an additive anticancer effect of TMZ and PAC-1.
The document further describes compositions comprising Formula (I) corresponding to TMZ or TMZ derivatives/prodrugs, formulated with PAC-1 and pharmaceutically acceptable carriers or excipients. It also describes assessment of tumor procaspase-3/caspase-3 levels and reduction of tumor burden as part of the reported preclinical evaluation.
Claims Coverage
The provided independent claim covers treating osteosarcoma by administering TMZ and a first procaspase activating compound (PAC-1) concurrently or sequentially as a synergistic anticancer combination. The dependent claims further define dose or concentration ranges, specified synergy improvement percentages, oral and/or intravenous administration, and formation in vivo or in vitro.
Concurrent or sequential TMZ and PAC-1 treatment of osteosarcoma with synergy
A method of treating osteosarcoma in a subject by administering a therapeutically effective amount of temozolomide (TMZ) and a first procaspase activating compound (PAC-1) concurrently or sequentially, wherein the TMZ and PAC-1 form a synergistic anticancer combination that is about 20% to about 93% more effective than an additive anticancer effect of TMZ and PAC-1.
Therapeutically effective PAC-1 range
The method includes using a therapeutically effective concentration of PAC-1 in the range of about 5 μM to about 30 μM, or about 50 mg/kg.
Therapeutically effective TMZ range
The method includes administering TMZ at a therapeutically effective concentration of about 250 μM to about 750 μM, or about 50 mg/kg.
Specified magnitude of synergistic anticancer improvement
The method provides that the synergistic anticancer combination is more effective than the additive anticancer effect of TMZ and PAC-1 by specified synergy improvement values including about 20.34%, about 26.95%, about 37.72%, about 39.3%, about 39.96%, about 41.06%, about 45.3%, about 55.68%, about 62.57%, about 65.65%, about 69.3%, about 75.36%, about 79.42%, and about 93.49%.
Oral and/or intravenous administration of TMZ and PAC-1
The method includes administering TMZ and PAC-1 orally, intravenously, or both in combination.
Synergistic combination formed in vivo or in vitro
The method provides that the synergistic anticancer combination is formed in vivo or in vitro.
Across the independent and dependent claims, the patent’s claim coverage centers on osteosarcoma treatment using concurrent or sequential administration of TMZ with PAC-1 as a synergistic anticancer combination, with dependent claims specifying PAC-1 and TMZ concentration or dose ranges, discrete synergy improvement percentages, oral and/or intravenous administration, and a formation context of the synergistic combination in vivo or in vitro.
Stated Advantages
Synergistic anticancer efficacy that is about 20% to about 93% more effective than an additive anticancer effect of TMZ and PAC-1.
Reduced neurotoxicity.
Selective killing associated with elevated procaspase-3 levels.
Documented Applications
Treating bone cancer in a subject, specifically osteosarcoma, by administering TMZ and PAC-1 concurrently or sequentially.
Preclinical use in rat glioblastoma models, including a survival benefit associated with PAC-1/TMZ synergy.
Preclinical use in glioblastoma and osteosarcoma cell culture, including inducing increased death.
Preclinical use in a mouse metastatic osteosarcoma model, including a survival benefit.
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