Combination Therapy for Treatment of Cancer

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.

1 .- 56 . (canceled) 
     
     
         57 . A combination comprising a therapeutically effective amount of a disintegrin, characterized by having an integrin binding loop stabilized by disulfide bonds, and a microtubule stabilizing agent. 
     
     
         58 .- 59 . (canceled) 
     
     
         60 . The combination of  claim 57  wherein said disintegrin is selected from the group consisting of
 (a) vicrostatin; 
 (b) a contortrostatin monomer; 
 (c) a contortrostatin dimer; and, 
 (d) a contortrostatin precursor or biologically active variant thereof, containing an amino acid sequence selected from the group consisting of:
 (1) amino acid numbers 419 to 483 of SEQ ID NO: 1; 
 (2) amino acid numbers 191 to 410 of SEQ ID NO: 1; 
 (3) amino acid numbers 1 to 190 of SEQ ID NO: 1; 
 (4) SEQ ID NO: 1; 
 (5) an amino acid sequence at least 90% identical to (1), (2) or (4) as determined by FASTA or BLAST using default opening and gap penalties and a default scoring matrix; or, 
 (6) an amino acid sequence at least 95% identical to (3) as determined by FASTA or BLAST using default opening and gap penalties and a default scoring matrix. 
 
 
     
     
         61 . The combination of  claim 57  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 αvβ5 and (ii) induces αvβ3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells. 
     
     
         62 . The combination of  claim 57  wherein said disintegrin is a contortrostatin that comprises a monomer having a molecular mass of about 5 to about 7 kDa. 
     
     
         63 . The combination of  claim 62  wherein said contortrostatin monomer forms a homodimer with another contortrostatin monomer. 
     
     
         64 . The combination of  claim 57  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. 
     
     
         65 . The combination of  claim 57  wherein said disintegrin is vicrostatin. 
     
     
         66 . The combination of  claim 57  wherein said microtubule stabilizing agent is a taxane. 
     
     
         67 . The combination of  claim 66  wherein said taxane is docetaxel. 
     
     
         68 . The combination of  claim 66  wherein said taxane is paclitaxel. 
     
     
         69 . The combination of  claim 57  wherein said taxane has Formula H as follows: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently selected from alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or oxy, each of which may be optionally substituted; 
 R 3  and R 4  are independently selected from alkyl, substituted alkyl, hydroxyl, oxy, C(O)H, or OC(O)R 5 ; and 
 R 5  is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be optionally substituted. 
 
     
     
         70 . The combination of  claim 66  wherein said taxane has Formula III as follows: 
       
         
           
           
               
               
           
         
       
       wherein
 R 10  is selected from alkyl, cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted; and 
 R 11  is selected from hydrogen, alkyl, —C(O)H, —C(O)CH 3 , or —C(O)CH 2 CH 3 . 
 
     
     
         71 . The composition of  claim 70  wherein R 10  is —C(CH 3 ) 3  and R 11  is H. 
     
     
         72 . The combination of  claim 70  wherein R 10  is phenyl and R 11  is acetyl. 
     
     
         73 . The combination of  claim 57  wherein said microtubule stabilizing agent is a non-taxane. 
     
     
         74 . The combination of  claim 73  wherein said non-taxane microtubule stabilizing agent has Formula V as follows: 
       
         
           
           
               
               
           
         
       
       wherein
 Q is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         G is selected from the group consisting of alkyl, substituted alkyl, substituted or unsubstituted aryl, heterocyclo, 
       
       
         
           
           
               
               
           
         
         W is O or NR 45 ; 
         X is O or H, H; 
         Y is selected from the group consisting of O; H, OR 46 ; OR 47 , OR 47 ; NOR 48 ; H, NOR 49 ; H, NR 50 R 51 ; H, H; and CHR 52 ; wherein OR 47  OR 47  can be a cyclic ketal; 
         Z 1  and Z 2  are independently selected from the group consisting of CH 2 , O, NR 53 , S and SO 2 , wherein only one of Z 1  and Z 2  can be a heteroatom; 
         B 1  and B 2  are independently selected from the group consisting of OR 54 , OC(O)R 55 , and OC(O)NR 56 R 57 ; wherein when B 1  is OH and Y is OH, H, B 1  and Y can form a six-membered ring ketal or acetal; 
         D is selected from the group consisting of NR 58 R 59 , NR 60 COR 61  and saturated heterocycle; 
         R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 48 , R 49 , R 50 , R 51 , R 52 , R 56  and R 57  are independently selected from H, alkyl, substituted alkyl, or aryl, wherien when R 31  and R 32  are alkyl, they can be joined to form a cycloalkyl; and when R 33  and R 34  are alkyl, they can be joined to form a cycloalkyl; 
         R 39 , R 40 , R 46  and R 47  are independently selected from H, alkyl, and substituted alkyl; 
         R 38 , R 41 , R 42 , R 58 , R 60 , R 62  and R 63  are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, and heterocyclo; 
         R 13 , R 14  and R 61  are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; 
         R 54  and R 55  are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo; 
         R 45 , R 53  and R 59  are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R 62 C(O), R 63 SO 2 , hydroxy, O-alkyl and O-substituted alkyl. 
       
     
     
         75 . The combination of  claim 73  wherein the non-taxane microtubule stabilizing agent has Formula V as follows: 
       
         
           
           
               
               
           
         
         wherein W is O, NH or NR 64 ; 
         R 35  and R 38  are independently selected from lower alkyl or lower alkenyl; 
         R 64  is selected from H, OH, optionally substituted alkyl, optionally substituted oxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and 
         R h  is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which may be optionally substituted. 
       
     
     
         76 . The combination of  claim 75  wherein W is O or NH; R 35  and R 38  are each CH 3 , and R h  is selected from the group consisting of thiazole, oxazole or pyridine, each of which is optionally substituted. 
     
     
         77 . A pharmaceutical composition comprising the combination of  claim 57  in a pharmaceutically acceptable carrier.