Antisense modulation of focal adhesion kinase expression

Abstract

Compounds, compositions and methods are provided for inhibiting FAK mediated signaling. The compositions comprise antisense compounds targeted to nucleic acids encoding FAK. Methods of using these antisense compounds for inhibition of FAK expression and for treatment of diseases, particularly cancers, associated with overexpression or constitutive activation of FAK are provided.

What is claimed is:  
     
         1 . An antisense compound 8 to 30 nucleobases in length targeted to the 5′-untranslated region, translational termination region or 3′ untranslated region of a nucleic acid molecule encoding focal adhesion kinase, wherein said antisense compound inhibits the expression of said focal adhesion kinase.  
     
     
         2 . The antisense compound of  claim 1  which is an antisense oligonucleotide.  
     
     
         3 . The antisense compound of  claim 2  wherein the antisense oligonucleotide has a sequence comprising SEQ ID NO: 3, 4, 6, 7, 8, 9, 16, 17, 18, 20 or 23.  
     
     
         4 . The antisense compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.  
     
     
         5 . The antisense compound of  claim 4  wherein the modified internucleoside linkage is a phosphorothioate linkage.  
     
     
         6 . The antisense compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified sugar moiety.  
     
     
         7 . The antisense compound of  claim 6  wherein the modified sugar moiety is a 2′-O-methoxyethyl moiety.  
     
     
         8 . The antisense compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified nucleobase.  
     
     
         9 . The antisense compound of  claim 8  wherein the modified nucleobase is a 5-methyl cytosine.  
     
     
         10 . The antisense compound of  claim 2  wherein the antisense oligonucleotide is a chimeric oligonucleotide.  
     
     
         11 . A pharmaceutical composition comprising the antisense compound of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         12 . The pharmaceutical composition of  claim 11  further comprising a colloidal dispersion system.  
     
     
         13 . The pharmaceutical composition of  claim 11  wherein the antisense compound is an antisense oligonucleotide.  
     
     
         14 . The pharmaceutical composition of  claim 11  further comprising a chemotherapeutic agent.  
     
     
         15 . The pharmaceutical composition of  claim 14  wherein the chemotherapeutic agent is 5-fluorouracil.  
     
     
         16 . A method of inhibiting the growth of a tumor in an animal comprising administering to said animal an effective amount of the pharmaceutical composition of  claim 14 .  
     
     
         17 . A method of inhibiting the expression of focal adhesion kinase in cells or tissues comprising contacting said cells or tissue with the antisense compound of  claim 1  so that expression of focal adhesion kinase is inhibited.  
     
     
         18 . An antisense compound up to 30 nucleobases in length targeted to the coding region, or start site of a nucleic acid molecule encoding focal adhesion kinase, wherein said antisense compound inhibits the expression of said focal adhesion kinase and has a sequence comprising at least an 8 nucleobasic portion of SEQ ID NO: 10, 11, 12, 14, 15, 30, 31 or 33.  
     
     
         19 . The antisense compound of  claim 18  which is an antisense oligonucleotide.  
     
     
         20 . The antisense compound of  claim 19  wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.  
     
     
         21 . The antisense compound of  claim 20  wherein the modified internucleoside linkage is a phosphorothioate linkage.  
     
     
         22 . The antisense compound of  claim 19  wherein the antisense oligonucleotide comprises at least one modified sugar moiety.  
     
     
         23 . The antisense compound of  claim 22  wherein the modified sugar moiety is a 2′-O-methoxyethyl moiety.  
     
     
         24 . The antisense compound of  claim 19  wherein the antisense oligonucleotide comprises at least one modified nucleobase.  
     
     
         25 . The antisense compound of  claim 24  wherein the modified nucleobase is a 5-methyl cytosine.  
     
     
         26 . The antisense compound of  claim 19  wherein the antisense oligonucleotide is a chimeric oligonucleotide.  
     
     
         27 . A pharmaceutical composition comprising the antisense compound of  claim 18  and a pharmaceutically acceptable carrier or diluent.  
     
     
         28 . The pharmaceutical composition of  claim 27  further comprising a colloidal dispersion system.  
     
     
         29 . The pharmaceutical composition of  claim 27  wherein the antisense compound is an antisense oligonucleotide.  
     
     
         30 . The pharmaceutical composition of  claim 27  further comprising a chemotherapeutic agent.  
     
     
         31 . The pharmaceutical composition of  claim 30  wherein the chemotherapeutic agent is 5-fluorouracil.  
     
     
         32 . A method of inhibiting the growth of a tumor in an animal comprising administering to said animal an effective amount of the pharmaceutical composition of  claim 30 .  
     
     
         33 . A method of inhibiting the expression of focal adhesion kinase in cells or tissues comprising contacting said cells or tissue with the antisense compound of  claim 18  so that expression of focal adhesion kinase is inhibited.  
     
     
         34 . A method of treating an animal having a disease or condition associated with focal adhesion kinase comprising administering to said animal a therapeutically or prophylactically effective amount of an antisense compound 8 to 30 nucleobases in length targeted to a nucleic acid molecule encoding human focal adhesion kinase wherein said antisense compound inhibits the expression of human focal adhesion kinase.  
     
     
         35 . The method of  claim 34  wherein the disease or condition is cancer.  
     
     
         36 . The method of  claim 35  wherein said cancer is of the breast, colon, mouth or skin.  
     
     
         37 . The method of  claim 34  wherein said disease or condition is an angiogenic disorder.  
     
     
         38 . The method of  claim 37  wherein said angiogenic disorder is retinal neovascularization.  
     
     
         39 . A method of preventing migration of cells associated with expression of focal adhesion kinase comprising administering to said cells a therapeutically or prophylactically effective amount of an antisense compound 8 to 30 nucleobases in length targeted to a nucleic acid molecule encoding human focal adhesion kinase wherein said antisense compound inhibits the expression of human focal adhesion kinase.  
     
     
         40 . A method of preventing neovascularization associated with expression of focal adhesion kinase in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of an antisense compound 8 to 30 nucleobases in length targeted to a nucleic acid molecule encoding human focal adhesion kinase wherein said antisense compound inhibits the expression of human focal adhesion kinase.  
     
     
         41 . A method of treating an animal having a disease or condition associated with focal adhesion kinase comprising administering to said animal a therapeutically or prophylactically effective amount of an antisense compound 8 to 30 nucleobases in length targeted to a nucleic acid molecule encoding human focal adhesion kinase in combination with a therapeutically or prophylactically effective amount of a chemotherapeutic agent.  
     
     
         42 . The method of  claim 41  wherein the chemotherapeutic agent is 5-fluorouracil.  
     
     
         43 . The method of  claim 41  wherein the disease or condition is cancer.  
     
     
         44 . The method of  claim 43  wherein said cancer is melanoma.