Compounds that target MYC microRNA responsive elements for the treatment of MYC-associated cancer

• US 10,443,055 B2
• Filed: 12/18/2017
• Issued: 10/15/2019
• Est. Priority Date: 12/22/2016
• Status: Active Grant

• Current Assignee: BETH Israel Deaconess Medical Center (Caregroup Incorporated)
• Original Assignee: BETH Israel Deaconess Medical Center (Caregroup Incorporated)
• Inventors: Pandolfi, Pier Paolo, Bester, Assaf C., Tay, Yvonne
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US15/845,573
• Publication Number:
  US 20180195067A1
• Time in Patent Office: 666 Days
• Field of Search: None
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2750/14143 viral genome or elements thereof as genetic vector

Abstract

Novel mIR-330 agents and their methods of use are provided. Methods of treating MYC-associated cancers are provided.

Claims

1. A method of treating a MYC-associated cancer in a subject in need thereof, the method comprising:

selecting a subject that overexpresses MYC; and

administering to the subject a pharmaceutical composition comprising a nucleic acid sequence having at least 80% complementarity to a micro RNA (miR) Responsive Element (MRE) sequence set forth as SEQ ID NO;

1, thereby treating cancer in the subject, wherein the MYC-associated cancer is further characterized by downregulation of hsa-miR-330-5p.

2. The method of claim 1, wherein the nucleic acid sequence has at least 90% complementarity, 95% complementarity, or 98% complementarity to the MRE sequence set forth as SEQ ID NO:

1.

3. The method of claim 1, wherein the nucleic acid sequence is further perfectly complementary to an MRE seed sequence set forth as SEQ ID NO:

2.

4. The method of claim 1, wherein the nucleic acid sequence comprises a miRNA or an siRNA, optionally wherein the miRNA is a miR-330-5p compound.

5. The method of claim 4, wherein the miRNA or siRNA is between 20 and 24 nucleotides in length.

6. The method of claim 1, wherein the MRE is a MYC MRE.

7. The method of claim 1, wherein MYC expression is downregulated in the subject after administering the pharmaceutical composition to the subject.

8. The method of claim 1, wherein MYC mRNA cleavage is mediated or translation of MYC mRNA is inhibited.

9. The method of claim 1, wherein the MYC-associated cancer is liver cancer or colorectal cancer.

10. The method of claim 1, wherein the nucleic acid sequence is administered using a recombinant Adeno-Associated virus (AAV).

11. The method of claim 1, wherein the nucleic acid sequence is a double-stranded nucleic acid sequence having a sense strand and an antisense strand, wherein the antisense strand has at least 80% complementarity to the MRE sequence.

12. A method of targeting MYC overexpression in a cancer cell characterized by overexpression of MYC, comprising contacting the cell with a nucleic acid sequence having at least 80% complementarity to an MRE sequence set forth as SEQ ID NO:

1 to inhibit translation of the MYC mRNA, wherein the cancer cell is further characterized by downregulation of hsa-miR-330-5p.

13. The method of claim 12, wherein the nucleic acid sequence comprises a miRNA or an siRNA, optionally wherein the miRNA is a miR-330-5p compound.