Method for treating or sensitizing interferon beta resistant cancer comprising cFLIP siRNA
Inventors
Shin, Young Kee • Kim, Tae Eun • HONG, SUNG YOUL • Choi, Jun Young • Kim, Na Young
Assignees
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Publication Number
US-12377132-B2
Publication Date
2025-08-05
Expiration Date
Abstract
The present invention relates to a composition for treating or sensitizing interferon beta resistant cancer disease comprising cFLIP siRNA, and, more specifically, to a pharmaceutical composition for treating interferon beta resistant cancer disease, comprising, as an active ingredient: (a) an siRNA complementarily binding to mRNA of a cFLIP gene; and (b) a human interferon beta variant which comprises glycine-asparagine-isoleucine-threonine-valine sequence (GNITV) at C-terminus in a human natural interferon beta amino acid sequence shown in SEQ ID NO: 1, or has replaced the 27th arginine amino acid with threonine or serine.
Core Innovation
The invention provides a method for treating an interferon-beta-resistant cancer disease by administering an effective amount comprising siRNA that binds to mRNA of the cFLIP gene in a complementary manner, together with a human interferon-beta mutant defined within a wild-type human interferon-beta amino acid sequence defined by SEQ ID NO: 1. The interferon-beta mutant comprises a glycine-asparagine-isoleucine-threonine-valine (GNITV) sequence at the C-terminus and/or includes a threonine or serine substitution for arginine at the 27th amino acid, and is selected from SEQ ID NO: 2 to SEQ ID NO: 6 and SEQ ID NO: 18 to SEQ ID NO: 21. The siRNA is selected from nucleotide sequences SEQ ID NO: 9 to SEQ ID NO: 13.
A second aspect provides a method for sensitizing interferon-beta-resistant cancer cells through administration of an siRNA and an interferon-beta mutant. The siRNA binds to mRNA of the cFLIP gene in a complementary manner and the interferon-beta mutant comprises an amino acid sequence selected from SEQ ID NO: 2 to SEQ ID NO: 6 and SEQ ID NO: 18 to SEQ ID NO: 21. The approach targets cFLIP mRNA and combines it with the defined interferon-beta mutant sequences.
The background problem is that cancers can be interferon-beta-resistant or interferon-beta-nonresponsive, meaning an interferon-beta-based approach does not achieve adequate therapeutic effect. The invention addresses this by combining cFLIP gene targeting siRNA with a specific human interferon-beta mutant. The cFLIP inhibition is described as promoting death-receptor/apoptosis signaling and enabling improved anticancer effects of the interferon-beta mutant in interferon-beta-resistant/nonresponsive cells.
Claims Coverage
The document includes two independent claims. Across these claims, the coverage focuses on an siRNA that binds cFLIP mRNA combined with a human interferon-beta mutant carrying defined sequence changes, for treatment of interferon-beta-resistant cancer disease and for sensitizing interferon-beta-resistant cancer cells.
Treating an interferon-beta-resistant cancer disease with cFLIP-targeting siRNA and a GNITV C-terminus or R27T/R27S IFN-beta mutant
Administering to a subject an effective amount comprising siRNA that binds to mRNA of a cFLIP gene in a complementary manner, together with a human interferon-beta mutant comprising a GNITV sequence at the C-terminus or a threonine or serine substitution for arginine at the 27th amino acid, with the interferon-beta mutant selected from SEQ ID NO: 2 to SEQ ID NO: 6 and SEQ ID NO: 18 to SEQ ID NO: 21, and the siRNA selected from SEQ ID NO: 9 to SEQ ID NO: 13.
Sensitizing interferon-beta-resistant cancer cells with cFLIP-targeting siRNA and defined IFN-beta mutant sequences
Administering to interferon-beta-resistant cancer cells an siRNA that binds to mRNA of a cFLIP gene in a complementary manner, wherein the siRNA comprises any one nucleotide sequence selected from SEQ ID NO: 9 to SEQ ID NO: 13, and an interferon-beta mutant comprising any one amino acid sequence selected from SEQ ID NO: 2 to SEQ ID NO: 6 and SEQ ID NO: 18 to SEQ ID NO: 21.
The claim set covers combination administration of defined cFLIP-binding siRNAs (SEQ ID NO: 9-13) with specific human interferon-beta mutants (SEQ ID NO: 2-6 and SEQ ID NO: 18-21), for treating interferon-beta-resistant cancer disease and for sensitizing interferon-beta-resistant cancer cells.
Stated Advantages
Enables improved anticancer effects of the interferon-beta mutant in interferon-beta-resistant/nonresponsive cells.
Promotes death-receptor/apoptosis signaling in the interferon-beta-resistant context.
Reduces viability of interferon-beta-resistant cancer cells.
Activates apoptosis-associated signaling including caspase-8.
Documented Applications
Treating an interferon-beta-resistant cancer disease in a subject in need thereof.
Sensitizing interferon-beta-resistant cancer cells by administering an siRNA targeting cFLIP mRNA and a defined human interferon-beta mutant.
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