Compositions and methods for the treatment of a beta-catenin-associated disease or disorder
Disclosed herein are methods for the treatment of cancer, comprising administering to a subject a β-catenin nucleic acid inhibitor molecule and a therapeutically effective amount of an MEK inhibitor or a c-Myc nucleic acid inhibitor molecule. Also disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a β-catenin nucleic acid inhibitor molecule; a therapeutically effective amount of an MEK inhibitor or a c-Myc nucleic acid inhibitor molecule and at least one pharmaceutical carrier.
1. A method of treating a β-catenin-associated cancer in a subject, comprising administering to the subject:
a therapeutically effective amount of a β-catenin nucleic acid inhibitor molecule; and
a therapeutically effective amount of a MEK inhibitor,
wherein the β-catenin nucleic acid inhibitor molecule is a dsRNAi inhibitor molecule,
wherein prior to administering the β-catenin nucleic acid inhibitor molecule, the subject has undergone at least two administrations of a prior treatment for the β-catenin-associated cancer, and
wherein the prior treatment is administration of a MEK inhibitor.
2. The method of claim 1 , wherein the MEK inhibitor is trametinib.
3. The method of claim 1 , wherein the β-catenin-associated cancer is colorectal cancer, hepatocellular carcinoma, or melanoma.
4. The method of claim 1 , wherein the subject is a human.
5. The method of claim 1 , wherein the double-stranded region of the dsRNAi inhibitor molecule is between 15 and 40 nucleotides in length.
6. The method of claim 1 , wherein the dsRNAi inhibitor molecule comprises a sense and an antisense strand and a duplex region of between 18 and 40 nucleotides, wherein the sense strand is 25-34 nucleotides in length and the antisense strand is 26-38 nucleotides in length and comprises 1-5 single-stranded nucleotides at its 3′ terminus.
7. The method of claim 6 , wherein the sense strand comprises the sequence of SEQ ID NO: 1 and the antisense strand comprises the sequence of SEQ ID NO: 2.
8. The method of claim 1 , wherein the β-catenin nucleic acid inhibitor molecule is formulated with a lipid nanoparticle.
9. The method of claim 8 , wherein the lipid nanoparticle comprises a cationic lipid and a pegylated lipid.
10. The method of claim 1 ,
wherein prior to administering the β-catenin nucleic acid inhibitor molecule, the subject has undergone prior treatment for the β-catenin-associated cancer and developed resistance to that treatment.
11. The method of claim 10 , wherein the MEK inhibitor of the prior treatment is trametinib.
12. The method of claim 10 , wherein the MEK inhibitor administered to the subject is trametinib.
13. The method of claim 11 , wherein the MEK inhibitor administered to the subject is trametinib.
14. The method of claim 1 , wherein the prior treatment is administration of a MEK inhibitor.
15. The method of claim 14 , wherein the MEK inhibitor of the prior treatment is trametinib.
16. The method of claim 14 , wherein the MEK inhibitor administered to the subject is trametinib.
17. The method of claim 15 , wherein the MEK inhibitor administered to the subject is trametinib.
18. The method of claim 1 , wherein prior to administering the β-catenin nucleic acid inhibitor molecule, the subject has undergone at least three, four, five, or six administrations of a prior treatment for the β-catenin-associated cancer.
19. The method of claim 1 , wherein the β-catenin-associated cancer has metastasized.
20. The method of claim 19 , wherein the β-catenin-associated cancer is colorectal cancer.
21. The method of claim 20 , wherein the colorectal cancer has metastasized to the liver.
22. The method of claim 19 , wherein the treatment reduces metastases in the subject.
23. A method of treating a β-catenin-associated cancer in a subject, comprising administering to the subject:
a therapeutically effective amount of a β-catenin nucleic acid inhibitor molecule; and
a therapeutically effective amount of a MEK inhibitor,
wherein the β-catenin nucleic acid inhibitor molecule is a dsRNAi inhibitor molecule comprising a sense and an antisense strand and a duplex region of between 18 and 40 nucleotides, wherein the sense strand is 25-34 nucleotides in length and the antisense strand is 26-38 nucleotides in length and comprises 1-5 single-stranded nucleotides at its 3′ terminus, and wherein the sense strand comprises the sequence of SEQ ID NO: 1 and the antisense strand comprises the sequence of SEQ ID NO: 2.