COMBINATION THERAPY FOR TREATMENT OF CANCER

• US 20080064634A1
• Filed: 04/30/2007
• Published: 03/13/2008
• Est. Priority Date: 05/01/2006
• Status: Active Grant

• Current Assignee: University of Southern California
• Original Assignee: University of Southern California
• Inventors: Markland, Francis, Swenson, Steven, Pinski, Jacek
• Granted Patent: US 8,008,256 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 38/1703 from vertebrates
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention relates to compositions and methods for treating diseases. In particular aspects, the invention relates to administering a combination of a disintegrin with a microtubule stabilizing agent useful for treatment of cancer.

Claims

1. A method of treating an individual suffering from cancer, said method comprising administering to said individual an effective amount of a disintegrin and at least one microtubule stabilizing agent.

2. The method of claim 1 wherein said cancer is an integrin expressing cancer.

3. The method of claim 2 wherein said integrin is α

vβ

5.

4. The method of claim 1 wherein said cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, renal cancer, central nervous system (CNS) cancer, and leukemia.

5. The method of claim 1 wherein said disintegrin is contortrostatin.

6. The method of claim 1 wherein said disintegrin is a contortrostatin monomer.

7. The method of claim 1 wherein said disintegrin is a contortrostatin dimer, a contortrostatin precursor or biologically active variant thereof, containing an amino acid sequence selected from the group consisting of:

(a) amino acid numbers 419 to 483 of SEQ ID NO;

1;

(b) amino acid numbers 191 to 410 of SEQ ID NO;

1;

(c) amino acid numbers 1 to 190 of SEQ ID NO;

1;

(d) SEQ ID NO;

1;

(e) an amino acid sequence at least 90% identical to (a), (b) or (d) as determined by FASTA or BLAST using default opening and gap penalties and a default scoring matrix; and

(f) an amino acid sequence at least 95% identical to (c) as determined by FASTA or BLAST using default opening and gap penalties and a default scoring matrix.

8. The method of claim 7 wherein said biologically active variant contains an amino acid sequence that is at least 95% identical to:

(a) amino acid numbers 419 to 483 of SEQ ID NO;

1;

(b) amino acid numbers 191 to 410 of SEQ ID NO;

1;

(c) amino acid numbers 1 to 190 of SEQ ID NO;

1;

or

(d) SEQ ID NO;

1.

9. The method of claim 1 wherein said disintegrin comprises a contortrostatin which has an amino acid sequence which is at least 90% percent identical to amino acid numbers 419 to 483 of SEQ ID NO:

1, wherein said disintegrin (i) binds to integrin α

vβ

5 and (ii) induces α

vβ

3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells.

10. The method of claim 1 wherein said disintegrin is a contortrostatin that comprises a monomer having a molecular mass of about 5 to about 7 kDa.

11. The method of claim 10 wherein said contortrostatin monomer forms a homodimer with another contortrostatin monomer.

12. The method of claim 1 wherein said disintegrin comprises a constrained Arg-Gly-Asp (RGD) sequence of a peptide loop of about 13 amino acid residues flanked by two Cys residues, wherein the peptide loop is an integrin antagonist which has an amino acid sequence comprising amino acid numbers 457 to 469 of SEQ ID NO:

1.

13. The method of claim 1 wherein said disintegrin is vicrostatin.

14. The method of claim 1 wherein said microtubule stabilizing agent is a taxane.

15. The method of claim 14 wherein said taxane is docetaxel.

16. The method of claim 14 wherein said taxane is paclitaxel.

17. The method of claim 14 wherein said taxane has Formula II as follows:

18. The method of claim 14 wherein said taxane has Formula III as follows:

19. The method of claim 18 wherein R¹⁰ is —

C(CH₃)₃ and R¹¹ is H.

20. The method of claim 18 wherein R¹⁰ is phenyl and R¹¹ is acetyl.

21. The method of claim 1 wherein said microtubule stabilizing agent is a non-taxane.

22. The method of claim 21 wherein said non-taxane microtubule stabilizing agent has Formula V as follows:

23. The method of claim 21 wherein the non-taxane microtubule stabilizing agent has Formula V as follows:

24. The method of claim 23 wherein W is O or NH;

R³⁵ and R³⁸ are each CH₃, and R^h is selected from the group consisting of thiazole, oxazole or pyridine, each of which is optionally substituted.

25. The method of claim 1 wherein said disintegrin is administered before said microtubule stabilizing agent.

26. The method of claim 1 wherein said disintegrin is administered after said microtubule stabilizing agent.

27. The method of claim 1 wherein said disintegrin and microtubule stabilizing agent are co-administered.

28. The method of claim 1 wherein said treatment is repeated.

29. A method of preventing or inhibiting the growth of metastases in an individual suffering from an integrin expressing cancer, said method comprising administering to said individual an effective amount of a disintegrin and at least one microtubule stabilizing agent.

30. The method of claim 29 wherein said cancer is an integrin expressing cancer.

31. The method of claim 30 wherein said integrin is α

vβ

5.

32. The method of claim 29 wherein said cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, renal cancer, central nervous system (CNS) cancer, and leukemia.

33. The method of claim 29 wherein said disintegrin is contortrostatin.

34. The method of claim 29 wherein said disintegrin is a contortrostatin monomer.

35. The method of claim 29 wherein said disintegrin is a contortrostatin dimer, a contortrostatin precursor or biologically active variant thereof containing an amino acid sequence selected from the group consisting of:

(a) amino acid numbers 419 to 483 of SEQ ID NO;

1;

(b) amino acid numbers 191 to 410 of SEQ ID NO;

1;

(c) amino acid numbers 1 to 190 of SEQ ID NO;

1;

(d) SEQ ID NO;

1;

(e) an amino acid sequence at least 90% identical to (a), (b) or (d) as determined by FASTA or BLAST using default opening and gap penalties and a default scoring matrix; and

(f) an amino acid sequence at least 95% identical to (c) as determined by FASTA or BLAST using default opening and gap penalties and a default scoring matrix.

36. The method of claim 35 wherein said biologically active variant contains an amino acid sequence that is at least 95% identical to:

(a) amino acid numbers 419 to 483 of SEQ ID NO;

1;

(b) amino acid numbers 191 to 410 of SEQ ID NO;

1;

(c) amino acid numbers 1 to 190 of SEQ ID NO;

1;

or

(d) SEQ ID NO;

1.

37. The method of claim 29 wherein said disintegrin comprises a contortrostatin which has an amino acid sequence which is at least 90% percent identical to amino acid numbers 419 to 483 of SEQ ID NO:

1, wherein said disintegrin (i) binds to integrin α

vβ

5 and (ii) induces α

vβ

3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells.

38. The method of claim 29 wherein said disintegrin is a contortrostatin that comprises a monomer having a molecular mass of about 5 to about 7 kDa.

39. The method of claim 38 wherein said contortrostatin monomer forms a homodimer with another contortrostatin monomer.

40. The method of claim 29 wherein said disintegrin comprises a constrained Arg-Gly-Asp (RGD) sequence of a peptide loop of about 13 amino acid residues flanked by two Cys residues, wherein the peptide loop is an integrin antagonist which has an amino acid sequence comprising amino acid numbers 457 to 469 of SEQ ID NO:

1.

41. The method of claim 29 wherein said disintegrin is vicrostatin.

42. The method of claim 29 wherein said microtubule stabilizing agent is a taxane.

43. The method of claim 42 wherein said taxane is docetaxel.

44. The method of claim 42 wherein said taxane is paclitaxel.

45. The method of claim 42 wherein said taxane has Formula II as follows:

46. The method of claim 42 wherein said taxane has Formula III as follows:

47. The method of claim 46 wherein R¹⁰ is —

C(CH₃)₃ and R¹¹ is H.

48. The method of claim 46 wherein R¹⁰ is phenyl and R¹¹ is acetyl.

49. The method of claim 29 wherein said microtubule stabilizing agent is a non-taxane.

50. The method of claim 49 wherein said non-taxane microtubule stabilizing agent has Formula V as follows:

51. The method of claim 49 wherein the non-taxane microtubule stabilizing agent has Formula VI as follows:

52. The method of claim 51 wherein W is O or NH;

R³⁵ and R³⁸ are each CH₃, and R^h is selected from the group consisting of thiazole, oxazole or pyridine, each of which is optionally substituted.

53. The method of claim 29 wherein said disintegrin is administered before said microtubule stabilizing agent.

54. The method of claim 29 wherein said disintegrin is administered after said microtubule stabilizing agent.

55. The method of claim 29 wherein said disintegrin and microtubule stabilizing agent are co-administered.

56. The method of claim 29 wherein said treatment is repeated.

57. A combination comprising a therapeutically effective amount of a disintegrin and a microtubule stabilizing agent.

58. A combination comprising a therapeutically effective amount of a disintegrin and a taxane.

59. The combination of claim 58, further comprising a non-taxane microtubule stabilizing agent.