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-10301627-B2
Publication Date
2019-05-28
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 that comprises a modified oligonucleotide. The modified oligonucleotide consists of 15 to 30 linked nucleosides and includes a nucleobase sequence with sequence constraints relative to specified SEQ ID NOs.
The miRNA-targeted approach uses nucleobase sequences that are complementary to miRNAs or miRNA stem-loops, including sequence sets listed as SEQ ID NOs. The problem addressed is that microRNAs (miRNAs) are overexpressed in hepatocellular carcinoma, and regulating such miRNAs is used to inhibit cancer cell proliferation and promote apoptosis.
The invention further includes combining the modified oligonucleotide therapy with at least one additional therapy that is a chemotherapeutic agent. The described context includes miRNA inhibition in liver cancer, including hepatocellular carcinoma and dioxin-induced HCC, with the rationale supported by assays such as luciferase reporter and ChIP for AhR/Arnt regulation of miR-191 and related miRNAs.
Claims Coverage
The independent claim identified is clm-00001. It covers a method of treating liver cancer using a modified oligonucleotide defined by length and nucleobase sequence identity relative to SEQ ID NOs 18 and 19, administered together with at least one additional chemotherapeutic therapy. Dependent claims further refine the oligonucleotide sequence constraints, nucleobase/motif features, and specify example chemotherapeutic agent selections.
Modified oligonucleotide of 15 to 30 linked nucleosides with nucleobase sequence identity to SEQ ID NOs 18 and 19
A method where the compound comprises a modified oligonucleotide consisting of 15 to 30 linked nucleosides, with a nucleobase sequence that is 100% identical over a region of 8 or more nucleobases of a sequence selected from SEQ ID NOs: 18 and 19.
Combination with at least one additional therapy selected as a chemotherapeutic agent
A method where the modified oligonucleotide is administered along with at least one additional therapy, and the additional therapy is a chemotherapeutic agent.
Tightened contiguous nucleobase region length from SEQ ID NOs 18 and 19
In further refinement, the nucleobase sequence includes at least 17 to 21 contiguous nucleobases taken from a sequence selected from SEQ ID NOs: 18 and 19.
Zero-mismatch nucleobase sequence relative to SEQ ID NO: 10
In further refinement, the nucleobase sequence has no mismatches relative to the nucleobase sequence of SEQ ID NO: 10.
Modified sugar selection including 2′-O-methoxyethyl and other specified sugar moieties
In further refinement, each modified sugar is independently selected from 2′-O-methoxyethyl, 2′-fluoro, 2′-O-methyl, or a bicyclic sugar moiety.
Chemotherapeutic agent selection from a defined list of agents
In further refinement, the chemotherapeutic agent is selected from a defined group of listed agents that includes 5-fluorouracil, gemcitabine, doxorubicine, mitomycin C, sorafenib, etoposide, carboplatin, epirubicin, irinotecan, and oxaliplatin.
Overall claim coverage centers on treating liver cancer using a modified oligonucleotide defined by 15–30 linked nucleosides and nucleobase sequence identity to SEQ ID NOs 18 and 19 over an 8+ base region, administered with at least one additional chemotherapeutic agent. Dependent refinements further constrain contiguous nucleobase lengths, mismatch-free sequence relationships, allowable modified sugar types, and enumerate representative chemotherapeutic agents.
Stated Advantages
Inhibition of cancer cell proliferation.
Increase of apoptosis, including caspase 3/7-associated apoptosis.
Reduction of xenograft tumor volume using MOE/phosphorothioate anti-miR oligonucleotides.
AhR/Arnt-associated regulation of miR-191 and related miRNAs is supported by the described assays.
Documented Applications
Treating liver cancer, including hepatocellular carcinoma (HCC) and dioxin-induced HCC.
MiRNA-targeted antisense inhibition as an approach to inhibit proliferation and induce apoptosis in the described liver cancer context.
Combination therapy in which the modified oligonucleotide is administered together with at least one chemotherapeutic agent.
Use of dioxin/TCDD (AhR activation) related miRNA upregulation contexts to support the miRNA targeting rationale, including miR-191 regulation supported by luciferase reporter and ChIP.
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