Targeting parp1 for treatment of tsc and cancers

Abstract

The present invention relates to methods of treating a condition associated with mTORC1 hyperactivation or TSC2-deficient cancer, the method comprising administering to a subject having the cancer a pharmaceutically-effective amount of a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor. In some embodiments, the condition associated with mTORC1 hyperactivation is tuberous sclerosis complex (TSC). In some embodiments, the condition associated with mTORC1 hyperactivation is lymphangioleiomyomatosis (LAM). In some embodiments, the condition associated with mTORC1 hyperactivation is TSC2-deficient cancer.

What is claimed: 
     
         1 . A method of treating a subject for a condition associated with mTORC1 hyperactivation, wherein the condition comprises the growth of a tumor, the method comprising:
 receiving results of an assay on a sample from the subject's tumor showing that the tumor is TSC2 deficient; and   administering to the subject having the condition a pharmaceutically-effective amount of a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor.   
     
     
         2 . The method of  claim 1 , wherein the condition associated with mTORC1 hyperactivation is selected from the group consisting of tuberous sclerosis complex (TSC), lymphangioleiomyomatosis (LAM), and TSC2-deficient cancer. 
     
     
         3 . The method of  claim 1 , wherein the condition associated with mTORC1 hyperactivation is tuberous sclerosis complex (TSC). 
     
     
         4 . The method of  claim 1 , wherein the condition associated with mTORC1 hyperactivation is lymphangioleiomyomatosis (LAM). 
     
     
         5 . The method of  claim 1 , wherein the PARP1 inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a nucleic acid analog or derivative, a peptide, a peptidomimetic, a protein, an antibody or an antigen-binding fragment thereof, a monosaccharide, a disaccharide, a trisaccharide, an oligosaccharide, a polysaccharide, a lipid, a glycosaminoglycan, an extract made from a biological material, and combinations thereof. 
     
     
         6 . The method of  claim 1 , wherein the PARP1 inhibitor is selected from the group consisting of 8-hydroxy-2-methylquinazoline-4-one, 3,4-dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline, 3-aminobenzamide, olaparib, iniparib, rucaparib, veliparib, talazoparib, niraparib, CEP-9722, BGB-290, AG-14361, A-966492 and BMN673. 
     
     
         7 . The method of  claim 5 , wherein the PARP1 inhibitor is a small interfering RNA (siRNA). 
     
     
         8 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         9 . The method of  claim 8 , wherein the subject is a human. 
     
     
         10 . The method of  claim 1 , wherein the administering is systemic. 
     
     
         11 . The method of  claim 1 , wherein the administering is local. 
     
     
         12 - 18 . (canceled) 
     
     
         19 . A method of treating TSC2-deficient cancer in a subject, the method comprising:
 receiving results of an assay on a sample from the subject's cancer showing that the cancer is TSC2 deficient; and   administering to the subject a pharmaceutically-effective amount of a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor.   
     
     
         20 . The method of  claim 19 , wherein the PARP1 inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a nucleic acid analog or derivative, a peptide, a peptidomimetic, a protein, an antibody or an antigen-binding fragment thereof, a monosaccharide, a disaccharide, a trisaccharide, an oligosaccharide, a polysaccharide, a lipid, a glycosaminoglycan, an extract made from a biological material, and combinations thereof. 
     
     
         21 . The method of  claim 19 , wherein the PARP1 inhibitor is selected from the group consisting of 8-hydroxy-2-methylquinazoline-4-one, 3,4-dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline, 3-aminobenzamide, olaparib, iniparib, rucaparib, veliparib, talazoparib, niraparib, CEP-9722, BGB-290, AG-14361, A-966492, and BMN673. 
     
     
         22 . The method of  claim 20 , wherein the PARP1 inhibitor is a small interfering RNA (siRNA). 
     
     
         23 . The method of  claim 19 , wherein the subject is a mammal. 
     
     
         24 . The method of  claim 23 , wherein the subject is a human. 
     
     
         25 . The method of  claim 19 , wherein the administering is systemic. 
     
     
         26 . The method of  claim 19 , wherein the administering is local.