Methods and Compositions for Identifying, Diagnosing, and Treating Neuroblastoma

Abstract

Methods and compositions for identifying, diagnosing, and treating neuroblastoma are disclosed.

1 . A method of identifying an increased risk for neuroblastoma in a subject, said method comprising
 a) obtaining a biological sample from said subject; and   b) determining whether the anaplastic lymphoma kinase (ALK) gene or protein is altered in said biological sample,   wherein the presence of said alteration of said ALK gene is indicative of neuroblastoma in said subject.   
     
     
         2 . The method of  claim 1  further comprising providing a prognosis for said subject, wherein the presence of said alteration of said ALK gene is indicative of an increased risk of metastasis and death. 
     
     
         3 . The method of  claim 1 , wherein said alteration is selected from the group consisting of an amplification the ALK copy number, presence of at least one mutation which increases ALK activity, and increased levels of ALK phosphorylation. 
     
     
         4 . The method of  claim 3 , wherein said mutations which increase ALK activity are in the tyrosine kinase domain. 
     
     
         5 . The method of  claim 3 , wherein at least one of the amino acids of the group consisting of P36, P157, V198, G640, L684, G718, G718, D993, L1204, I1170, A1200, L1204, F1245, G1128, R1192, R1275, D1091, M1166, I1171, F1174, F1245, and I1250 is mutated. 
     
     
         6 . The method of  claim 5 , wherein at least one mutation is selected from the group consisting of P36S, P157S, V198M, G640R, L684M, G718F, G718S, D993G, L1204F, I1170S, A1200V, L1204F, F1245I, G1128A, R1192P, R1275Q, D1091N, M1166R, I1171N, F1174I, F1174L, F1245C, F1245V, and I1250T. 
     
     
         7 . The method of  claim 3 , wherein at least one of amino acids G1128, R1192, R1275, D1091, M1166, I1171, F1174, F1174, F1245, and I1250 is mutated. 
     
     
         8 . The method of  claim 7 , wherein at least one mutation is selected from the group consisting of: G1128A, R1192P, R1275Q, D1091N, M1166R, I1171N, F1174I, F1174L, F1245C, F1245V, and I1250T. 
     
     
         9 . The method of  claim 7 , wherein at least one amino acid R1275 and F1174 is mutated. 
     
     
         10 . The method of  claim 9 , wherein at least one mutation is selected from the group consisting of R1275Q, F1174I, and F1174L. 
     
     
         11 . The method of  claim 1 , wherein said biological sample is blood. 
     
     
         12 . The method of  claim 1 , wherein said biological sample is tumor tissue. 
     
     
         13 . A method for treating neuroblastoma in a patient comprising the administration of at least one composition comprising at least one ALK inhibitor. 
     
     
         14 . The method of  claim 13 , further comprising at least one chemotherapeutic agent. 
     
     
         15 . The method of  claim 13 , further comprising the administration of at least one ALK antibody. 
     
     
         16 . The method of  claim 13 , wherein said patient is screened to determine which ALK inhibitor is most effective against the neuroblastoma of said patient prior to administration of said composition. 
     
     
         17 . A method of determining whether a compound is effective for treating a neuroblastoma comprising
 a) contacting cells comprising mutations in ALK or an amplification of ALK encoding nucleic acid molecules, with at least one compound; and   b) determining the ALK activity or cell viability or proliferation,   wherein a reduction in ALK activity or cell viability or proliferation indicates the compound is therapeutic for treating a neuroblastoma which comprises the mutation or amplification recited in step a).   
     
     
         18 . A microarray comprising oligonucleotide probes which specifically hybridize with at least one ALK mutant. 
     
     
         19 . The microarray of  claim 16 , wherein said ALK mutant comprises a mutation in an amino acid selected from the group consisting of P36, P157, V198, G640, L684, G718, G718, D993, L1204, I1170, A1200, L1204, F1245, G1128, R1192, R1275, D1091, M1166, I1171, F1174, F1245, and I1250.