Methods and compositions for treating malignant tumors associated with kras mutation

Patent metadata

Field	Value
Publication number	US-10792299-B2
Application number	US-201715434318-A
Country	US
Kind code	B2
Filing date	Feb 16, 2017
Priority date	Dec 26, 2014
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

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 malignant tumor, the composition comprising RNAi molecules and pharmaceutically acceptable excipients, wherein the RNAi molecules each comprise a sense strand having the nucleotide base sequence GAAGCCUUUUGAGACCCUANN (SEQ ID NO:133) and an antisense strand having the nucleotide base sequence UAGGGUCUCAAAAGGCUUCNN (SEQ ID NO:159), wherein upper case A, G, C and U refer to ribo-A, ribo-G, ribo-C and ribo-U, respectively, and wherein N is ribo-A, ribo-C, ribo-G, ribo-U, 2′-OMe-U, 2′-deoxy-A, 2′-deoxy-C, 2′-deoxy-G, 2′-deoxy-U, or deoxythymidine (dT=T=t), or an inverted, or chemically modified nucleotide.

2. The pharmaceutical composition of claim 1 , wherein the RNAi molecules are selected from

GAA GCCU U U U GAGACCC UAUU
(SEQ ID NO: 158)

and

fUAGgGuCu C A AA AGGC UU C UU ;
(SEQ ID NO: 184)

GAA GCCU U U U GAGACCC UAUU
(SEQ ID NO: 157)

and

U AGgGuCu C A AA AGGC UU C UU ;
(SEQ ID NO: 183)

GAA GCCU U U U GAGACCC U A UU
(SEQ ID NO: 156)

and

U AGgGuCu C A AA AGGCU U C UU ;
(SEQ ID NO: 182)

GAA GCCUUUUGAGACCCUA UU
(SEQ ID NO: 155)

and

U AGgGuCu C A AA AGGCU U C UU ;
(SEQ ID NO: 181)

GAA GCCU U U U GAGACCC U A UU
(SEQ ID NO: 154)

and

UAGgGuCuCAAAAGGCUUC UU ;
(SEQ ID NO: 180)

GAAGCCUUUUGAGACCCUA UU
(SEQ ID NO: 143)

and

UAGgGuCuCAAAAGGCUUC UU ;
(SEQ ID NO: 169)

and

GAAGCCUUUUGAGACCCUA UU
(SEQ ID NO: 141)

and

UAgGgUcUCAAAAGGCUUC UU .
(SEQ ID NO: 167)

wherein upper case A, G, C and U refer to ribo-A, ribo-G, ribo-C and ribo-U, respectively, lower case a, u, g, c, t refer to 2′-deoxy-A, 2′-deoxy-U, 2′-deoxy-G, 2′-deoxy-C, and deoxythymidine (dT=T=t), respectively, underlining refers to a 2′-OMe-substituted nucleotide, and lower case f refers to 2′-deoxy-2′-fluoro substitution.

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

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

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

6. A method for treating or ameliorating one or more symptoms of a lung cancer, colorectal cancer or pancreatic cancer tumor in a mammal in need thereof, the method comprising: 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;
wherein each of the RNAi molecules comprises a sense strand having the nucleotide base sequence GAAGCCUUUUGAGACCCUANN (SEQ ID NO:133) and an antisense strand having the nucleotide base sequence UAGGGUCUCAAAAGGCUUCNN (SEQ ID NO:159), wherein upper case A, G, C and U refer to ribo-A, ribo-G, ribo-C and ribo-U, respectively, and wherein N is ribo-A, ribo-C, ribo-G, ribo-U, 2′-OMe-U, 2′-deoxy-A, 2′-deoxy-C, 2′-deoxy-G, 2′-deoxy-U, or deoxythymidine (dT=T=t), or an inverted, or chemically modified nucleotide.

7. The method of claim 6 , wherein the RNAi molecules are selected from

GAA GCCU U U U GAGACCC UAUU
(SEQ ID NO: 158)

and

fUAGgGuCu C A AA AGGC UU C UU ;
(SEQ ID NO: 184)

GAA GCCU U U U GAGACCC UAUU
(SEQ ID NO: 157)

and

U AGgGuCu C A AA AGGC UU C UU ;
(SEQ ID NO: 183)

GAA GCCU U U U GAGACCC U A UU
(SEQ ID NO: 156)

and

U AGgGuCu C A AA AGGCU U C UU ;

Assignees

• Nitto Denko Corp

Inventors

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

Classifications

• C12Y205/01018

  Glutathione transferase (2.5.1.18) · CPC title

• C12N15/1135

  against oncogenes or tumor suppressor genes · 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

• C12N2310/344

  Position-specific modifications, e.g. on every purine, at the 3'-end · CPC title

• C12N2310/322

  2'-R Modification · CPC title