Novel ntrk1 fusion molecules and uses thereof

Abstract

Novel NTRK1 fusion molecules, detection reagents, and uses and kits for evaluating, identifying, assessing and/or treating a subject having a cancer are disclosed.

1 .- 51 . (canceled) 
     
     
         52 . A method of treating a subject having a lung cancer, comprising:
 administering to the subject an effective amount of an NTRK1-kinase specific inhibitor,   thereby treating the lung cancer in the subject.   
     
     
         53 . The method of  claim 52 , wherein the NTRK1-kinase specific inhibitor is chosen from danusertib (PHA-739358), lestaurtinib (CEP-701), AZ-23, or ARRY-470. 
     
     
         54 . The method of either of  claim 52 , wherein the NTRK1 kinase inhibitor is administered responsive to a determination of the presence of, or requiring knowledge or information of the presence of, an MPRIP-NTRK1 fusion in a tumor sample from said subject. 
     
     
         55 .- 58 . (canceled) 
     
     
         59 . The method of  claim 52 , further comprising determining the presence of an MPRIP-NTRK1 fusion by sequencing. 
     
     
         60 . The method of  claim 52 , wherein said lung cancer is chosen from: small cell lung cancer (SCLC), adenocarcinoma of the lung, bronchogenic carcinoma, or a combination thereof. 
     
     
         61 . The method of  claim 52 , wherein the lung cancer is non-small cell lung cancer (NSCLC) or squamous cell carcinoma (SCC). 
     
     
         62 . The method of  claim 52 , wherein the lung cancer is an adenocarcinoma of the lung. 
     
     
         63 . The method of  claim 52 , wherein the lung cancer has no detectable altered level or activity in one or more of EGFR, KRAS, ALK, ROS1 or RET. 
     
     
         64 . (canceled) 
     
     
         65 . The method of  claim 52 , wherein the NTRK-1 kinase inhibitor is selected from antisense molecules, ribozymes, RNAi, triple helix molecules that hybridize to a nucleic acid encoding the fusion, or a transcription regulatory region that blocks or reduces mRNA expression of the MPRIP-NTRK1 fusion. 
     
     
         66 . The method of  claim 52 , wherein the NTRK-1 kinase inhibitor is administered in combination with a second therapeutic agent or a different therapeutic modality. 
     
     
         67 . The method of  claim 66 , wherein the second therapeutic agent is an HSP90 inhibitor. 
     
     
         68 . The method of  claim 67 , wherein the HSP90 inhibitor is a benzoquinone or hygroquinone ansamycin HSP90 inhibitor. 
     
     
         69 . The method of  claim 67 , wherein the HSP90 inhibitor is chosen from one or more of 17-AAG, 17-DMAG, BIIB-021, BIIB-028, AUY-922, SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, CNF-1010, Macbecin I, Macbecin II, CCT-018159, CCT-129397, PU-H71, or PF-04928473. 
     
     
         70 .- 113 . (canceled) 
     
     
         114 . A method of treating a subject having a lung cancer, comprising:
 administering to the subject an effective amount of an NTRK1-kinase specific inhibitor chosen from danusertib, lestaurtinib, AZ-23, or ARRY-470, thereby treating the lung cancer in the subject.   
     
     
         115 . A method of treating a subject having a lung cancer, comprising:
 acquiring knowledge of the presence of an NTRK1 fusion in said subject; and   administering to the subject an effective amount of a kinase inhibitor, thereby treating the lung cancer in the subject.   
     
     
         116 . The method of  claim 115 , comprising determining the presence of the NTRK1 fusion by sequencing. 
     
     
         117 . The method of  claim 115 , wherein said lung cancer is chosen from small cell lung cancer (SCLC), adenocarcinoma of the lung, bronchogenic carcinoma, or a combination thereof. 
     
     
         118 . The method of  claim 115 , wherein the lung cancer is non-small cell lung cancer (NSCLC) or squamous cell carcinoma (SCC). 
     
     
         119 . The method of  claim 115 , wherein the lung cancer is an adenocarcinoma of the lung. 
     
     
         120 . The method of  claim 115 , wherein the lung cancer has no detectable altered level or activity in one or more of EGFR, KRAS, ALK, ROS1 or RET. 
     
     
         121 . The method of  claim 115 , wherein the kinase inhibitor is chosen from one or more of: lestaurtinib; AZ-23; indenopyrrolocarboazole 12a; GW 441756; oxindole 3; isothiazole 5n; thiazole 20h; pyridocarbazole; GNF 5837; AG 879; Ro 08-2750; AZ623; AR523; a Pyrazolo[1;5a]pyrimidine; a pyrrolidinyl urea; a pyrrolidinyl thiourea; a pyrazole derivatives; a macrocyclic compound; a substituted pyrazolo[1;5a]pyrimidine; a pyridotriazole; a benzotriazole; a quinazolinyl; a pyridoquinazolinyl; a pyrrolo[2;3-d]pyrimidine; danusertib; PHA-848125; CEP-2563; an anti-Trk1 antibody; or ARRY-470. 
     
     
         122 . The method of  claim 115 , wherein the kinase inhibitor is danusertib, lestaurtinib, AZ-23, or ARRY-470. 
     
     
         123 . The method of  claim 115 , wherein the kinase inhibitor is administered in combination with a second therapeutic agent or a different therapeutic modality. 
     
     
         124 . The method of  claim 123 , wherein the second therapeutic agent is an HSP90 inhibitor. 
     
     
         125 . The method of  claim 124 , wherein the HSP90 inhibitor is a benzoquinone or hygroquinone ansamycin HSP90 inhibitor. 
     
     
         126 . The method of  claim 124 , wherein the HSP90 inhibitor is chosen from one or more of 17-AAG, 17-DMAG, BIIB-021, BIIB-028, AUY-922, SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, CNF-1010, Macbecin I, Macbecin II, CCT-018159, CCT-129397, PU-H71, or PF-04928473. 
     
     
         127 . The method of  claim 115 , wherein the NTRK1 fusion is an MPRIP-NTRK1 nucleic acid molecule, comprising a nucleotide sequence selected from the group consisting of:
 (i) a nucleotide sequence comprising one or more, or all, exons 1-21 of SEQ ID NO:1 (MPRIP) and one or more, or all, exons 12-17 of SEQ ID NO:3 (NTRK1), or a nucleotide sequence at least 85% identical thereto;   (ii) a nucleotide sequence comprising the open reading frame of SEQ ID NO:5, or a nucleotide sequence at least 85% identical thereto;   (iii) a nucleotide sequence of SEQ ID NO:6, or a nucleotide sequence at least 85% identical thereto;   (iv) a nucleotide sequence encoding the amino acid sequence of SEQ ID NO:7, or a nucleotide sequence at least 85% identical thereto;   (v) a nucleotide sequence comprising all or a portion of the Breakpoint 1 and/or Breakpoint 2 depicted in  FIG. 1A ; and   (vi) a fragment of any of (i)-(v) comprising a nucleotide sequence from MPRIP and NTRK1.   
     
     
         128 . The method of  claim 115 , wherein the NTRK1 fusion is an MPRIP-NTRK1 polypeptide, comprising an amino acid sequence selected from the group consisting of:
 (i) the amino acid sequence encoded by one or more, or all, exons 1-21 of SEQ ID NO:1 (MPRIP) and one or more, or all, exons 12-17 of SEQ ID NO:3 (NTRK1), or an amino acid sequence at least 85% identical thereto;   (ii) the amino acid sequence encoded by the open reading frame of SEQ ID NO:5, or an amino acid sequence at least 85% identical thereto;   (iii) the amino acid sequence of SEQ ID NO:7, or an amino acid sequence at least 85% identical thereto;   (iv) the amino acid sequence encoded by a nucleotide sequence comprising all or a portion of the Breakpoint 1 and/or Breakpoint 2 depicted in  FIG. 1C ; and   (v) a fragment of any of (i)-(iii) comprising a amino acid sequence from MPRIP and NTRK1.