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Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-11660280-B2
Publication Date
2023-05-30
Expiration Date
Abstract
The present disclosure describes the use of 2,4-disulfonyl phenyl tert-butyl nitron (2,4-ds-PBN) in the treatment of temozolomide drug resistant gliomas. The 2,4-ds-PBN may be used combined with other chemo- and radiotherapies and surgery, including temozolomide, to reduce glioma occurrence, recurrence, spread, growth, metastasis, and vascularization, and to inhibit development of temozolomide resistance.
Core Innovation
The invention provides therapeutic methods using 2,4-disulfonyl phenyl tert-butyl nitrone (2,4-ds-PBN; OKN-007) alone and in combination with temozolomide to treat temozolomide-resistant gliomas. The disclosure describes routes of administration, pharmaceutical forms, salts and synthetic routes for 2,4-ds-PBN, and identifies lipopolysaccharide binding protein (LBP) as a diagnostic, prognostic and monitoring biomarker and as a targeting and imaging handle. Experimental efficacy data are reported [procedural detail omitted for safety].
The background problem addresses temozolomide resistance in gliomas and the need to inhibit tumor vascularization, growth and spread. The invention further describes combinations with standard glioma therapies and presents mechanism-of-action evidence implicating downregulation of TGF-β1 and extracellular matrix and angiogenesis pathways. Analytical and imaging methods are provided to assess therapeutic effect and target engagement [procedural detail omitted for safety].
Claims Coverage
The claims include one independent method claim directed to treating temozolomide-resistant glioma by administering 2,4-ds-PBN together with temozolomide to inhibit vascularization, growth or spread.
Combination administration of 2,4-ds-PBN and temozolomide
Treating a temozolomide-resistant glioma in a subject by administering 2,4-disulfonyl phenyl tert-butyl nitrone (2,4-ds-PBN) together with temozolomide to inhibit the vascularization, growth or spread of the glioma.
The independent claim centers on treating temozolomide-resistant glioma by combined administration of 2,4-ds-PBN and temozolomide with the intended effect of inhibiting tumor vascularization, growth or spread.
Stated Advantages
Combined OKN-007 (2,4-ds-PBN) plus temozolomide increases survival.
Combined therapy reduces tumor volume and alters tumor vascular perfusion.
2,4-ds-PBN sensitizes temozolomide-resistant cell lines to temozolomide.
2,4-ds-PBN monotherapy shows efficacy with reduced toxicity.
Potential for lower-than-standard temozolomide dosing when combined with 2,4-ds-PBN.
Documented Applications
Treatment of temozolomide-resistant gliomas, including glioblastoma, astrocytoma and oligodendroglioma.
Use of 2,4-ds-PBN as monotherapy or in combination with temozolomide and with standard glioma therapies such as radiation, PCV, BCNU/CCNU and DFMO.
Use of lipopolysaccharide binding protein (LBP) as a diagnostic, prognostic and monitoring biomarker and as a targeting and imaging handle, including LBP-linked therapeutic and imaging conjugates.
Administration via multiple routes and pharmaceutical formats including enteral (including dietary supplementation), intravenous and intra-arterial delivery, and use of salts and pharmaceutical formulations of 2,4-ds-PBN.
Selection or application to tumor forms expressing markers such as TGF-β1, MGMT and APGN.
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