NOVEL NTRK1 FUSION MOLECULES AND USES THEREOF
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.