Raf1 fusions

Abstract

The invention provides to RAF1 gene fusions, RAF1 fusion proteins, and fragments of those genes and polypeptides. The invention further provides methods of diagnosing and treating diseases or disorders associated with RAF1 fusions, such as conditions mediated by aberrant RAF1 expression or activity, or overexpression of RAF1.

1 - 76 . (canceled) 
     
     
         77 . A method for detecting in a patient a RAF1 fusion protein or a RAF1 gene fusion that results in aberrant activity or expression of RAF1 or overexpression of RAF1, wherein the RAF1 fusion protein is an AGGF1:RAF1, LMNA:RAF1, MPRIP:RAF1, PAPD7:RAF1, CLCN6:RAF1, or a TRAK1:RAF1 fusion protein, and the RAF1 gene fusion is an LMNA:RAF1, MPRIP:RAF1, PAPD7:RAF1, CLCN6:RAF1, or a TRAK1:RAF1 gene fusion, said method comprising:
 a) contacting a biological sample from the patient with a reagent selected from
 i) an antibody that specifically binds to the RAF1 fusion protein, but does not specifically bind to wild-type RAF1, AGGF1, LMNA, MPRIP, PAPD7, CLCN6, or TRAK1; or 
 ii) an oligonucleotide that hybridizes to the fusion junction of the RAF1 gene fusion; and 
   b) detecting binding between the RAF1 fusion protein or the RAF1 gene fusion and the reagent.   
     
     
         78 . The method of  claim 77 , wherein:
 a) the RAF1 gene fusion comprises:
 i) SEQ ID NO:3, 5, 7, 9, or 11, or 
 ii) a portion of SEQ ID NO:3, 5, 7, 9, or 11, wherein the portion comprises a fusion junction between RAF1 and its fusion partner and the gene fusion encodes a polypeptide having RAF1 kinase activity, or 
   b) the RAF1 fusion protein comprises:
 i) SEQ ID NO:2, 4, 6, 8, 10, or 12, or 
 ii) a portion of SEQ ID NO:2, 4, 6, 8, 10, or 12, wherein the portion comprises a fusion junction between RAF1 and its fusion partner and the fusion protein has RAF1 kinase activity. 
   
     
     
         79 . The method of  claim 77 , wherein the reagent is an oligonucleotide that hybridizes under stringent conditions to:
 a) a fragment of SEQ ID NO:3 comprising nucleotides 1693-1702 of SEQ ID NO:3;   b) a fragment of SEQ ID NO:5 comprising nucleotides 3041-3050 of SEQ ID NO:5;   c) a fragment of SEQ ID NO:7 comprising nucleotides 1265-1274 of SEQ ID NO:7;   d) a fragment of SEQ ID NO:9 comprising nucleotides 143-152 of SEQ ID NO:9;   e) a fragment of SEQ ID NO:11 comprising nucleotides 971-980 of SEQ ID NO:11; or   f) a complementary oligonucleotide of any one of a)-e).   
     
     
         80 . The method of  claim 77 , wherein the reagent is an antibody that specifically binds to:
 a) a fragment of SEQ ID NO:2 comprising amino acids 286-295 of SEQ ID NO:2;   b) a fragment of SEQ ID NO:4 comprising amino acids 562-572 of SEQ ID NO:4;   c) a fragment of SEQ ID NO:6 comprising amino acids 1011-1020 of SEQ ID NO:6; or   d) a fragment of SEQ ID NO:8 comprising amino acids 419-428 of SEQ ID NO:8;   e) a fragment of SEQ ID NO:10 comprising amino acids 45-54 of SEQ ID NO:10; or   f) a fragment of SEQ ID NO:12 comprising amino acids 321-330 of SEQ ID NO:12.   
     
     
         81 . The method of  claim 77 , wherein the patient is suffering from or susceptible to a cancer. 
     
     
         82 . The method of  claim 81 , wherein the cancer is prostate adenocarcinoma or melanoma. 
     
     
         83 . A method of treating a patient in which a RAF1 fusion protein selected from AGGF1:RAF1, LMNA:RAF1, MPRIP:RAF1, PAPD7:RAF1, CLCN6:RAF1, and TRAK1:RAF1 or a RAF1 gene fusion selected from LMNA:RAF1, MPRIP:RAF1, PAPD7:RAF1, CLCN6:RAF1, and TRAK1:RAF1 has been detected, said method comprising administering to the patient a therapeutically effective amount of a compound that inhibits RAF1 activity or the activity or expression of the RAF1 fusion protein or RAF1 gene fusion, wherein the RAF1 fusion protein or RAF1 gene fusion has been detected in the patient by a method comprising:
 a) contacting a biological sample from the patient with a reagent selected from:
 i) an antibody that specifically binds to a RAF1 fusion protein, but does not specifically bind to wild-type RAF1, AGGF1, LMNA, MPRIP, PAPD7, CLCN6, or TRAK1; or 
 ii) an oligonucleotide that hybridizes to the fusion junction of a RAF1 gene fusion; and 
   b) detecting binding between the RAF1 fusion protein or the RAF1 gene fusion and the reagent.   
     
     
         84 . The method of  claim 83 , wherein:
 a) the RAF1 gene fusion comprises:
 i) SEQ ID NO:3, 5, 7, 9, or 11, or 
 ii) a portion of SEQ ID NO:3, 5, 7, 9, or 11, wherein the portion comprises a fusion junction between RAF1 and its fusion partner and the gene fusion encodes a polypeptide having RAF1 kinase activity, or b) the RAF1 fusion protein comprises: 
 i) SEQ ID NO:2, 4, 6, 8, 10, or 12, or 
 ii) a portion of SEQ ID NO:2, 4, 6, 8, 10, or 12, wherein the portion comprises a fusion junction between RAF1 and its fusion partner and the fusion protein has RAF1 kinase activity. 
   
     
     
         85 . The method of  claim 83 , wherein the reagent is an oligonucleotide that hybridizes under stringent conditions to:
 a) a fragment of SEQ ID NO:3 comprising nucleotides 1693-1702 of SEQ ID NO:3;   b) a fragment of SEQ ID NO:5 comprising nucleotides 3041-3050 of SEQ ID NO:5;   c) a fragment of SEQ ID NO:7 comprising nucleotides 1265-1274 of SEQ ID NO:7;   d) a fragment of SEQ ID NO:9 comprising nucleotides 143-152 of SEQ ID NO:9;   e) a fragment of SEQ ID NO:11 comprising nucleotides 971-980 of SEQ ID NO:11; or   f) a complementary oligonucleotide of any one of a)-e).   
     
     
         86 . The method of  claim 83 , wherein the reagent is an antibody that specifically binds to:
 a) a fragment of SEQ ID NO:2 comprising amino acids 286-295 of SEQ ID NO:2;   b) a fragment of SEQ ID NO:4 comprising amino acids 562-572 of SEQ ID NO:4;   c) a fragment of SEQ ID NO:6 comprising amino acids 1011-1020 of SEQ ID NO:6; or   d) a fragment of SEQ ID NO:8 comprising amino acids 419-428 of SEQ ID NO:8;   e) a fragment of SEQ ID NO:10 comprising amino acids 45-54 of SEQ ID NO:10; or   f) a fragment of SEQ ID NO:12 comprising amino acids 321-330 of SEQ ID NO:12.   
     
     
         87 . The method of  claim 83 , wherein the patient is suffering from or susceptible to a cancer. 
     
     
         88 . The method of  claim 87 , wherein the cancer is prostate adenocarcinoma or melanoma. 
     
     
         89 . A molecule capable of specifically binding to a RAF1 fusion protein or a RAF1 gene fusion that results in aberrant activity or expression of RAF1 or overexpression RAF1, wherein the molecule is selected from:
 a) an antibody that specifically binds to the RAF1 fusion protein selected from AGGF1:RAF1, LMNA: RAF1, MPRIP:RAF1, PAPD7:RAF1, CLCN6:RAF1, and TRAK1:RAF1, but does not specifically bind to wild-type RAF1, AGGF1, LMNA, MPRIP, PAPD7, CLCN6, or TRAK1; or   b) an oligonucleotide that hybridizes to the fusion junction of the RAF1 gene fusion selected from AGGF1:RAF1, LMNA:RAF1, MPRIP:RAF1, PAPD7:RAF1, CLCN6:RAF1, and TRAK1:RAF1.   
     
     
         90 . The molecule of  claim 89 , wherein:
 a) the RAF1 gene fusion that the molecule specifically binds to comprises:
 i) SEQ ID NO:1, 3, 5, 7, 9, or 11, or 
 ii) a portion of SEQ ID NO:1, 3, 5, 7, 9, or 11, wherein the portion comprises a fusion junction between RAF1 and its fusion partner and the gene fusion encodes a polypeptide having RAF1 kinase activity, or 
   b) the RAF1 fusion protein that the molecule specifically binds to comprises:
 i) SEQ ID NO:2, 4, 6, 8, 10, or 12, or 
 ii) a portion of SEQ ID NO:2, 4, 6, 8, 10, or 12, wherein the portion comprises a fusion junction between RAF1 and its fusion partner and the fusion protein has RAF1 kinase activity. 
   
     
     
         91 . The molecule of  claim 89 , wherein the molecule is an oligonucleotide that hybridizes under stringent conditions to:
 a) a fragment of SEQ ID NO:1 comprising nucleotides 866-875 of SEQ ID NO:1;   b) a fragment of SEQ ID NO:3 comprising nucleotides 1693-1702 of SEQ ID NO:3;   c) a fragment of SEQ ID NO:5 comprising nucleotides 3041-3050 of SEQ ID NO:5;   d) a fragment of SEQ ID NO:7 comprising nucleotides 1265-1274 of SEQ ID NO:7;   e) a fragment of SEQ ID NO:9 comprising nucleotides 143-152 of SEQ ID NO:9;   f) a fragment of SEQ ID NO:11 comprising nucleotides 971-980 of SEQ ID NO:11; or   g) a complementary oligonucleotide of any one of a)-f).   
     
     
         92 . The molecule of  claim 89 , wherein the molecule is an antibody that specifically binds to:
 a) a fragment of SEQ ID NO:2 comprising amino acids 286-295 of SEQ ID NO:2;   b) a fragment of SEQ ID NO:4 comprising amino acids 562-572 of SEQ ID NO:4;   c) a fragment of SEQ ID NO:6 comprising amino acids 1011-1020 of SEQ ID NO:6; or   d) a fragment of SEQ ID NO:8 comprising amino acids 419-428 of SEQ ID NO:8;   e) a fragment of SEQ ID NO:10 comprising amino acids 45-54 of SEQ ID NO:10; or   f) a fragment of SEQ ID NO:12 comprising amino acids 321-330 of SEQ ID NO:12.