Methods and compositions for treating malignant tumors associated with KRAS mutation

Patent metadata

Field	Value
Publication number	US-RE49229-E
Application number	US-202016804696-A
Country	US
Kind code	E1
Filing date	Feb 28, 2020
Priority date	Dec 26, 2014
Publication date	Oct 4, 2022
Grant date	Oct 4, 2022

Abstract

This invention provides methods and compositions for preventing, treating or ameliorating one or more symptoms of a malignant tumor associated with KRAS mutation in a mammal in need thereof, by identifying a tumor cell in the mammal, the tumor cell comprising at least one of: (i) a mutation of the KRAS gene, and (ii) an aberrant expression level of KRAS protein; and administering to the mammal a therapeutically effective amount of a composition comprising one or more RNAi molecules that are active in reducing expression of GST-π.

First claim

What is claimed is:

1. A pharmaceutical composition for the treatment or therapy of a tumor associated with a mutation in the KRAS gene or overexpression of wild-type KRAS gene, the composition comprising RNAi molecules and pharmaceutically acceptable excipients, wherein the RNAi molecules comprise an antisense strand which comprises SEQ ID NO: 184 and a sense strand which comprises SEQ ID NO: 158.

2. The pharmaceutical composition of claim 1 , wherein the RNAi molecules are siRNAs or shRNAs.

3. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipients include one or more lipid compounds.

4. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipients include lipid nanoparticles.

5. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipients include lipid nanoparticles that encapsulate the RNAi molecules.

6. A method for preventing, treating or ameliorating one or more symptoms of a malignant tumor associated with KRAS mutation in a mammal in need thereof, the method comprising:
identifying a tumor cell in the mammal, the tumor cell comprising at least one of: (i) a mutation of the KRAS gene, and (ii) an aberrant expression level of KRAS protein; and
administering to the mammal a therapeutically effective amount of a composition comprising one or more RNAi molecules that are active in reducing expression of GST-π, and wherein the RNAi molecules comprise an antisense strand which comprises SEQ ID NO: 184 and a sense strand which comprises SEQ ID NO: 18.

7. The method of claim 6 , wherein the mammal is a human and the GST-π is a human GST-π.

8. The method of claim 6 , wherein the RNAi molecule is a siRNA or shRNA.

9. The method of claim 6 , wherein the RNAi molecule decreases expression of GST-π in the mammal.

10. The method of claim 6 , wherein the administration decreases expression of GST-π in the mammal by at least 5% for at least 5 days.

11. The method of claim 6 , wherein the administration decreases the volume of the malignant tumor in the mammal by at least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%.

12. The method of claim 6 , wherein the method reduces one or more symptoms of the malignant tumor, or delays or terminates the progression of the malignant tumor.

13. The method of claim 6 , wherein the administration reduces growth of malignant tumor cells in the subject.

14. The method of claim 6 , wherein the administration reduces growth for at least 2%, or at least 5%, or at least 10%, or at least 15%, or at least 20% of the malignant tumor cells in the subject.

15. The method of claim 6 , wherein the tumor cells comprise increased levels of expression of wild type KRAS protein compared to that in a normal cell.

16. The method of claim 6 , wherein the tumor cell over-expresses wild-type GST-π RNA or protein.

17. The method of claim 6 , wherein the tumor cell comprises mutations in the KRAS protein at one or more of residues 12, 13 and 61.

18. The method of claim 6 , wherein the tumor cell comprises mutations in the KRAS protein and the tumor is a cancer selected from lung cancer, colon cancer, and pancreatic cancer.

19. The method of claim 6 , wherein the tumor cell comprises mutations in the KRAS protein and the tumor is a sarcoma or carcinoma selected from the group consisting of lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, and colorectal carcinoma.

20. The method of claim 6 , wherein the malignant tumor is a sarcoma or carcinoma selected from the group of lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, colorectal carcinoma, breast cancer, and fibrosarcoma.

21. The method of claim 6 , wherein the malignant tumor is located in an anatomical region selected from the group of lung, colon, pancreas, gallbladder, liver, breast, and any combination thereof.

22. The method of claim 6 , wherein the administration is performed from 1 to 12 times per day.

23. The method of claim 6 , wherein the administration is performed for a duration of 1, 2, 3, 4, 5, 6 or 7 days.

24. The method of claim 6 , wherein the administration is performed for a duration of 1, 2, 3, 4, 5, 6, 8, 10 or 12 weeks.

25. The method of claim 6 , wherein the administration is a dose of from 0.01 to 2 mg/kg of the RNAi molecules at least once per day for a period up to twelve weeks.

26. The method of claim 6 , wherein the administration provides a mean AUC(0-last) of from 1 to 1000 ug*min/mL and a mean C max of from 0.1 to 50 ug/mL for the GST-π RNAi molecule.

27. The method of claim 6 , wherein the administration is intravenous injection, intradermal injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, oral, topical, infusion, or inhalation.

Assignees

• Nitto Denko Corp

Inventors

• Minomi Kenjirou
• Liu Jihua
• Wang Li
• Majeti Bharat
• Adami Roger
• Ying Wenbin

Classifications

• A61K31/713 Primary

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C12N15/113

  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 title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title

• A61K9/51

  Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)} · CPC title

• A61K49/0021

  the fluorescent group being a small organic molecule · CPC title