Targeting microRNAS for the treatment of liver cancer
Inventors
Bennett, C. Frank • Chajut, Ayelet • Esau, Christine • Marcusson, Eric • Yerushalmi, Noga
Assignees
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Publication Number
US-9845470-B2
Publication Date
2017-12-19
Expiration Date
Abstract
Provided herein are methods for the treatment of liver cancer. These methods encompass the administration of a compound comprising a modified oligonucleotide, wherein the modified oligonucleotide is targeted to a miRNA. Also provided herein are compositions for the treatment of liver cancer. Such compositions include compounds comprising a modified oligonucleotide, wherein the modified oligonucleotide is targeted to a miRNA. Certain miRNAs have been identified as overexpressed in liver cancer, such as, for example, hepatocellular carcinoma, and are thus selected for targeting by modified oligonucleotides. Further, certain miRNAs have been identified as overexpressed in hepatocellular carcinoma cells exposed to dioxin, and are thus selected for targeting by modified oligonucleotides. Antisense inhibition of certain of these miRNAs has been found to inhibit cell proliferation and induce apoptosis.
Core Innovation
The invention relates to treating liver cancer by administering to a subject in need thereof a compound comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides. The modified oligonucleotide includes a nucleobase sequence that is 100% identical over a region of 8 or more nucleobases to a sequence selected from SEQ ID NOs: 20 and 21.
The disclosed approach addresses liver cancer, including hepatocellular carcinoma and dioxin-induced HCC, by inhibiting overexpressed miRNAs through antisense inhibition. The targeting is directed to microRNA (miRNA) sequences or precursors, and the modified oligonucleotides are antisense modified oligonucleotides for miRNA inhibition.
The documentation includes experimental support showing miRNA expression profiling and anti-proliferative activity, including apoptosis induction measured by caspase 3/7. In preclinical contexts, the partial content reports xenograft tumor volume reduction and inhibitory effects on metastatic progression, along with clinical and biomarker-related readouts such as tumor size and tumor number, overall survival, progression-free survival, alpha-fetoprotein, and des-gamma-carboxyprothrombin.
Claims Coverage
The independent claim identified is clm-00001, covering a method for treating liver cancer using a modified oligonucleotide compound with specified length and nucleobase identity relative to sequences from SEQ ID NOs: 20 and 21. The coverage is further refined in dependent claims by narrowing oligonucleotide chemistry, target-binding constraints, subject selection biomarkers, and efficacy endpoints.
Modified oligonucleotide-based treatment of liver cancer with defined nucleobase identity
A method for treating liver cancer comprising administering to a subject in need thereof a compound comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence that is 100% identical over a region of 8 or more nucleobases of a sequence selected from SEQ ID NOs: 20 and 21.
Across the claim set reflected in the partial content, the core inventive coverage centers on administering a modified oligonucleotide (15 to 30 linked nucleosides) with a specified degree of 100% nucleobase identity over at least 8 nucleobases to sequences from SEQ ID NOs: 20 and 21, with dependent refinements further specifying oligonucleotide chemistry and connecting treatment to efficacy outcomes.
Stated Advantages
Reduced tumor size or tumor number, or prevention of an increase in tumor size or tumor number.
Inhibited metastatic progression.
Prolonged survival, including overall survival and progression-free survival.
Modulation of biomarkers including alpha-fetoprotein and des-gamma-carboxyprothrombin.
Documented Applications
Treating liver cancer, including hepatocellular carcinoma (HCC) and dioxin-induced HCC, by miRNA targeting using antisense modified oligonucleotides.
Using miRNA-related mechanisms linked to dioxin (TCDD/AhR) regulation of miRNAs, including validation involving AhR/Arnt binding to the miR-191 promoter.
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