Cancer treatment
In certain embodiments, methods, compounds, and compositions for treating B-cell lymphoma or hepatocellular carcinoma by inhibiting expression of ST AT3 mRNA or protein in an animal are provided herein. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate B-cell lymphoma or hepatocellular carcinoma. The STAT (signal transducers and activators of transcription) family of proteins are DNA-binding proteins that play a dual role in signal transduction and activation of transcription.
1. A method of treating cancer comprising administering to a subject having cancer a pharmaceutical composition comprising an antisense compound complementary to a nucleic acid encoding human STATS, wherein administering the antisense compound comprises:
a loading phase comprising a total weekly dose in the range of about 100-750 mg for the first 1-10 weeks, and
a maintenance phase comprising a total weekly dose in the range of 100-250 mg for at least 1 week after the loading phase;
wherein the antisense compound comprises a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of nucleobases 3016 to 3031 of SEQ ID NO: 1, wherein the nucleobase sequence is complementary to SEQ ID NO: 1.
2. The method of claim 1 , wherein the dose is 3.0 milligrams of the antisense compound per kilogram of the subject's body weight per week (3.0 mg/kg/wk).
3. The method of claim 1 wherein the dose is administered for at least 1-52 weeks.
4. The method of claim 1 , wherein the dose is administered to the subject 1-6 times per week.
5. The method of claim 1 , wherein the dose is administered 1-6 times during the first week and 1 time each subsequent week.
6. The method of claim 1 , wherein the loading phase is 1 week.
7. The method of claim 1 , wherein the total weekly dose of the antisense compound in the loading phase is an amount of any of about 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750 mg.
8. The method of claim 1 , wherein the total weekly dose of the antisense compound in the maintenance phase is an amount of any of about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg.
9. The method of claim 1 , wherein the cancer is B-cell lymphoma or hepatocellular carcinoma (HCC).
10. The method of claim 9 , wherein the B-cell lymphoma is a non-Hodgkin's B-cell lymphoma.
11. The method of claim 10 , wherein the non-Hodgkin's B-cell lymphoma is selected from the group consisting of: diffuse large B cell lymphoma (DLBCL), follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, Waldenström macroglobulinemia, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis.
12. The method of claim 10 , wherein the non-Hodgkin's B-cell lymphoma is diffuse large B cell lymphoma (DLBCL).
13. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide comprises the sequence of SEQ ID NO: 12.
14. The method of claim 1 , wherein the modified oligonucleotide is a single-stranded modified oligonucleotide.
15. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.
16. The method of claim 15 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
17. The method of claim 1 , wherein at least one nucleoside comprises a modified sugar.
18. The method of claim 17 , wherein at least one modified sugar is a bicyclic sugar.
19. The method of claim 18 , wherein the bicyclic sugar comprises a 4′-CH 2 -O-2′ bridge, a 4′-CH(CH 3 )—O-2′ bridge or a 2′-O(CH 2 ) 2 -OCH 3 group.
20. The method of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.
21. The method of claim 20 , wherein the modified nucleobase is a 5-methylcytosine.
22. The method of claim 1 , wherein the modified oligonucleotide is single-stranded consisting of 16 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 12, comprising:
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.
23. The method of claim 2 , wherein the subject's body weight is calculated as ideal body weight using the Devine formula.
24. The method of claim 2 , wherein the subject's body weight is calculated as an average adult body weight of 70 kilograms.
25. The method of claim 22 , wherein the total weekly dose of the antisense compound in the loading phase is an amount of any of about 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750 mg.
26. The method of claim 22 , wherein the total weekly dose of the antisense compound in the maintenance phase is an amount of any of about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg.
27. The method of claim 22 , wherein the cancer is B-cell lymphoma or hepatocellular carcinoma (HCC).
28. The method of claim 27 , wherein the B-cell lymphoma is a non-Hodgkin's B-cell lymphoma.
29. The method of claim 28 , wherein the non-Hodgkin's B-cell lymphoma is selected from the group consisting of: diffuse large B cell lymphoma (DLBCL), follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, Waldenström macroglobulinemia, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis.
30. The method of claim 28 , wherein the non-Hodgkin's B-cell lymphoma is diffuse large B cell lymphoma (DLBCL).
31. A method of treating cancer in a subject comprising administering to the subject a weekly dose of an antisense compound complementary to a nucleic acid encoding human STAT3, wherein the antisense compound comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 12, comprising:
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; and
wherein the dose is about 3.0 milligrams of the antisense compound per kilogram of the subject's body weight per week (3.0 mg/kg/wk).
32. The method of claim 31 , wherein the dose is administered to the subject for at least 1 to 52 weeks.
33. The method of claim 31 , wherein the dose is administered to the subject 1 to 6 times per week.
34. The method of claim 31 , wherein the cancer is B-cell lymphoma or hepatocellular carcinoma (HCC).
35. The method of claim 34 , wherein the B-cell lymphoma is a non-Hodgkin's B-cell lymphoma.
36. The method of claim 35 , wherein the non-Hodgkin's B-cell lymphoma is diffuse large B cell lymphoma (DLBCL).
37. A method of treating cancer comprising administering to a subject having cancer a pharmaceutical composition comprising an antisense compound complementary to a nucleic acid encoding human STAT3, wherein administering the antisense compound comprises administering to the subject a total weekly dose in the range of 100-750 mg for at least 1 week;
wherein the antisense compound comprises a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of nucleobases 3016 to 3031 of SEQ ID NO: 1, wherein the nucleobase sequence is complementary to SEQ ID NO: 1.
38. The method of claim 37 , wherein the antisense compound comprises a single-stranded modified oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 12, comprising:
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.