Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
Inventors
Owa, Takashi • Ozawa, Yoichi • Semba, Taro
Assignees
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Publication Number
US-8772269-B2
Publication Date
2014-07-08
Expiration Date
Abstract
The present invention relates to pharmaceutical compositions comprising a sulfonamide-including compound in combination with an angiogenesis inhibitor.
Core Innovation
The invention provides pharmaceutical compositions and kits that combine sulfonamide-including anti-tumor compounds with angiogenesis inhibitors, in particular VEGF inhibitors. The sulfonamide-including compounds include N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide and named examples such as E7070, E7820, LY186641, LY295501, LY-ASAP, LY573636, and CQS (2-sulfanylamido-5-chloroquinoxaline). The VEGF inhibitors include VEGF receptor kinase inhibitors and anti-VEGF antibodies such as bevacizumab.
The disclosure reports a high correlation between DNA microarray gene-expression change patterns and the E7070/E7820/related sulfonamide activities, suggesting similar mechanisms and cross-resistance among sulfonamides. It further describes unexpected synergistic effects when E7820 is combined with bevacizumab. The overall composition concept centers on angiogenesis inhibition and treatment of cancer.
The synergistic effects are described as occurring in vitro and in vivo. In vitro, synergy is reported using a vascular endothelial cell proliferation assay, and in vivo it is reported using a subcutaneous transplantation model with colon cancer cell lines and a human renal cancer cell line. The combination of E7820 with bevacizumab is described as exceeding bevacizumab alone and as outperforming E7820 combined with an anti-VEGF antibody from a prior reference.
Claims Coverage
The independent claims cover two main aspects: a pharmaceutical composition and methods of treating cancer and/or inhibiting angiogenesis. The central inventive feature is the combination of the specified sulfonamide-including compound with the specified VEGF receptor kinase inhibitor, with dependent refinements that specify pharmacologically acceptable salt forms and solvate forms.
Pharmaceutical composition comprising a sulfonamide-including compound and a VEGF receptor kinase inhibitor
A pharmaceutical composition comprising N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide, or a pharmacologically acceptable salt thereof or a solvate thereof, in combination with 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof or a solvate thereof.
Method for treating cancer and/or inhibiting angiogenesis by administering the sulfonamide-including compound with a VEGF receptor kinase inhibitor
A method for treating cancer and/or a method for inhibiting angiogenesis, comprising administering N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide, or a pharmacologically acceptable salt thereof or a solvate thereof, together with 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof or a solvate thereof, to a patient.
Claim coverage is centered on combining the specified indole sulfonamide with the specified VEGF receptor kinase inhibitor, or pharmacologically acceptable salt or solvate forms. The independent claims extend this combination to both a pharmaceutical composition and administration-based methods for treating cancer and/or inhibiting angiogenesis.
Stated Advantages
Synergistic effects of E7820 plus bevacizumab in vitro and in vivo are described as unexpected.
The combination of E7820 plus bevacizumab is described as exceeding bevacizumab alone.
The combination of E7820 plus bevacizumab is described as outperforming E7820 plus an anti-VEGF antibody from a prior reference.
Angiogenesis inhibition.
Cancer treatment.
Documented Applications
Use of sulfonamide-including compounds combined with VEGF inhibitors, including VEGF receptor kinase inhibitors and anti-VEGF antibodies such as bevacizumab, is described in the context of anti-tumor activity, including cancer treatment and angiogenesis inhibition.
In vitro assessment using a vascular endothelial cell proliferation assay to evaluate the E7820 plus bevacizumab combination is described.
In vivo assessment using a subcutaneous transplantation model with colon cancer cell line Colo320DM and a human renal cancer cell line 786-O to evaluate the E7820 plus bevacizumab combination is described.
Cancer treatment.
Inhibiting angiogenesis.
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