Modulation of androgen receptor expression

Abstract

Certain embodiments are directed to compounds and compositions targeted to human androgen receptor (AR) for inhibiting androgen receptor levels in a cell, which can be useful for methods of treating cancer and inhibiting cancer cell growth or proliferation.

What is claimed: 
     
       1. A single-stranded modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising an at least 12 11 contiguous nucleobase portion of SEQ ID NO: 12 or 175, wherein the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1 and comprises:
 a gap segment consisting of linked deoxynucleosides; 
 a 5′ wing segment consisting of linked nucleosides; 
 a 3′ wing segment consisting of linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
 
     
     
       2. The single-stranded modified oligonucleotide of  claim 1 , wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
       3. The single-stranded modified oligonucleotide of  claim 1 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar. 
     
     
       4. The single-stranded modified oligonucleotide of  claim 1 , wherein the modified sugar comprises a bicyclic sugar. 
     
     
       5. The single-stranded modified oligonucleotide of  claim 4 , wherein the bicyclic sugar comprises a group selected from: 4′-CH(CH3)-O-2′ 4′-CH(CH 3 )—O-2′, 4′-CH2-O-2′ 4′-CH 2 —O-2′, and 4′-(CH2)2-O-2′ 4′-(CH 2 ) 2 —O-2′. 
     
     
       6. The single-stranded modified oligonucleotide of  claim 1 , wherein each cytosine is a 5-methylcytosine. 
     
     
       7. The single-stranded modified oligonucleotide of  claim 1 , wherein the modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 
     
     
       8. The single-stranded modified oligonucleotide of  claim 1 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides; 
 a 5′ wing segment consisting of linked nucleosides; 
 a 3′ wing segment consisting of linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, each nucleoside of each wing segment comprises a modified sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine. 
 
     
     
       9. The single-stranded modified oligonucleotide of  claim 8 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar. 
     
     
       10. The single-stranded modified oligonucleotide of  claim 8 , wherein the modified sugar comprises a bicyclic sugar. 
     
     
       11. The single-stranded modified oligonucleotide of  claim 10 , wherein the bicyclic sugar comprises a group selected from: 4′-CH(CH3)-O-2′ 4′-CH(CH 3 )—O-2′, 4′-CH2-O-2′ 4′-CH 2 —O-2′, and 4′-(CH2)2-O-2′ 4′-(CH 2 ) 2 —O-2′. 
     
     
       12. A single-stranded modified oligonucleotide consisting of 16 to 30 linked nucleosides having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 12, 13, 35, 39, 43, 124, 150, 155, 169, or 175, wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides; 
 a 5′ wing segment consisting of linked nucleosides; 
 a 3′ wing segment consisting of linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
 
     
     
       13. The single-stranded modified oligonucleotide of  claim 12 , wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
       14. The single-stranded modified oligonucleotide of  claim 12 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar. 
     
     
       15. The single-stranded modified oligonucleotide of  claim 12 , wherein the modified sugar comprises a bicyclic sugar. 
     
     
       16. The single-stranded modified oligonucleotide of  claim 15 , wherein the bicyclic sugar comprises a group selected from: 4′-CH(CH3)-O-2′ 4′-CH(CH 3 )—O-2′, 4′-CH2-O-2′ 4′-CH 2 —O-2′, and 4′-(CH2)2-O-2′ 4′-(CH 2 ) 2 —O-2′. 
     
     
       17. The single-stranded modified oligonucleotide of  claim 12 , wherein each cytosine is a 5-methylcytosine. 
     
     
       18. The single-stranded modified oligonucleotide of  claim 12 , wherein the modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 
     
     
       19. The single-stranded modified oligonucleotide of  claim 12 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides; 
 a 5′ wing segment consisting of linked nucleosides; 
 a 3′ wing segment consisting of linked nucleosides; 
 wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, each nucleoside of each wing segment comprises a modified sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine. 
 
     
     
       20. The single-stranded modified oligonucleotide of  claim 12 , wherein the modified oligonucleotide consists of 16 linked nucleosides having a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 12, 13, 35, 39, 43, 124, 150, 155, 169, or 175. 
     
     
       21. The single-stranded modified oligonucleotide of  claim 20 , wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
       22. The single-stranded modified oligonucleotide of  claim 20 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar. 
     
     
       23. The single-stranded modified oligonucleotide of  claim 20 , wherein the modified sugar comprises a bicyclic sugar. 
     
     
       24. The single-stranded modified oligonucleotide of  claim 23 , wherein the bicyclic sugar comprises a group selected from: 4′-CH(CH3)-O-2′ 4′-CH(CH 3 )—O-2′, 4′-CH2-O-2′ 4′-CH 2 —O-2′, and 4′-(CH2)2-O-2′ 4′-(CH 2 ) 2 —O-2′. 
     
     
       25. The single-stranded modified oligonucleotide of  claim 20 , wherein each cytosine is a 5-methylcytosine. 
     
     
       26. The single-stranded modified oligonucleotide of  claim 20 , wherein the modified oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of any one of SEQ ID NOs: 43, 124, 150, 155, 169, or 175, and wherein the modified oligonucleotide comprises:
 a gap segment consisting of ten linked deoxynucleosides; 
 a 5′ wing segment consisting of 3 linked nucleosides; and 
 a 3′ wing segment consisting of 3 linked nucleosides; 
 
       wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of each wing segment comprises a constrained ethyl nucleoside; wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage; and wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine. 
     
     
       27. A method of treating cancer in a subject comprising administering to the subject the compound of  claim 26 , thereby treating cancer in the subject. 
     
     
       28. The method of  claim 27 , wherein the cancer is prostate cancer, breast cancer, ovarian cancer, gastric cancer, or bladder cancer. 
     
     
       29. The method of  claim 27 , wherein the cancer is castrate-resistant prostate cancer. 
     
     
       30. The method of  claim 29 , wherein the castrate-resistant prostate cancer is resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700, and VT464. 
     
     
       31. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence consisting of the sequence of SEQ ID NO: 35, and is a pharmaceutically acceptable salt selected from the group consisting of sodium and potassium salts, wherein the modified oligonucleotide comprises:
 a gap segment consisting of 9 linked deoxynucleosides;   a 5′ wing segment consisting of three linked nucleosides; and   a 3′ wing segment consisting of four linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein the sugars of the three linked nucleosides of the 5′ wing segment are each a constrained ethyl (cEt) sugar; wherein the sugars of the four linked nucleosides of the 3′ wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a 2′-O-methoxyethyl sugar in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.   
     
     
       32. A compound comprising a single-stranded modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence consisting of the sequence of SEQ ID NO: 39 and is a pharmaceutically acceptable salt selected from the group consisting of sodium and potassium salts, wherein the modified oligonucleotide comprises:
 a gap segment consisting of 7 linked deoxynucleosides;   a 5′ wing segment consisting of four linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein the sugars of the four linked nucleosides of the 5′ wing segment are a 2′-O-methoxyethyl sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, and a constrained ethyl (cEt) sugar in the 5′ to 3′ direction; wherein the sugars of the five linked nucleosides of the 3′ wing segment are a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a constrained ethyl (cEt) sugar, a 2′-O-methoxyethyl sugar, and a 2′-O-methoxyethyl sugar in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.   
     
     
       33. A composition comprising the compound of claim 31 or claim 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 
     
     
       34. A combination comprising the compound of claim 31 or claim 32, or a pharmaceutically acceptable salt thereof, and an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. 
     
     
       35. The combination of claim 34, wherein the anti-androgenic agent is MDV3100. 
     
     
       36. A method of treating cancer comprising administering to a subject having cancer a compound or salt of claim 31 or claim 32, thereby treating cancer in the subject. 
     
     
       37. The method of claim 36, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, gastric cancer or bladder cancer. 
     
     
       38. The method of claim 36, wherein the cancer is castrate-resistant prostate cancer. 
     
     
       39. The method of claim 38, wherein the castrate-resistant prostate cancer is resistant to an anti-androgenic agent selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. 
     
     
       40. A method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a compound or salt of claim 31 or claim 32 and an anti-androgenic agent. 
     
     
       41. The method of claim 40, wherein the anti-androgenic agent is selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. 
     
     
       42. The method of claim 40, wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell. 
     
     
       43. The method of claim 40, wherein the patient is administered an amount of the compound and an amount of anti-androgenic agent that are each or both less in combination than the amount of either the compound or anti-androgenic agent alone effective in inhibiting the growth or proliferation of said prostate cancer cell. 
     
     
       44. A method of inhibiting growth or proliferation of an androgen receptor (AR)-positive breast cancer cell comprising contacting the breast cancer cell with a compound or salt of claim 31 or claim 32 wherein the growth or proliferation of the breast cancer cell is inhibited. 
     
     
       45. A method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a composition of claim 33 and an anti-androgenic agent. 
     
     
       46. The method of claim 45, wherein the anti-androgenic agent is selected from: MDV3100, ARN-059, ODM-201, abiraterone, TOK001, TAK700 and VT464. 
     
     
       47. The method of claim 41, wherein the anti-androgenic agent is MDV3100. 
     
     
       48. The method of claim 47, wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell. 
     
     
       49. The method of claim 46, wherein the anti-androgenic agent is MDV3100. 
     
     
       50. The method of claim 49, wherein the compound and the anti-androgenic agent synergize in combination to inhibit the growth or proliferation of the prostate cancer cell.