IP Library › Granted Patent US 12,522,873
Granted Patent B2
US 12,522,873 · App. 17/377,231 · Granted Jan 13, 2026

ALK and NTRK1 fusion molecules and uses thereof

Inventors: Maureen T. Cronin (Boston, MA); Doron Lipson (Chestnut Hill, MA); Roman Yelensky (Newton, MA)
Assignee: Foundation Medicine, Inc.
C12Q1/6886A61K31/4545C07K14/4738C07K14/4748C07K16/40C12N9/12C12N9/1205C12Q1/6804G01N33/5011G01N33/57496A61K38/00C12Y207/10001
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Quick Facts
Patent No.
US 12,522,873
App. No.
17/377,231
Granted
Jan 13, 2026
Kind
B2
Abstract

Novel ALK and NTRK1 fusion molecules and uses are disclosed.

Claims (52)

1 . A method of determining the presence of an LMNA-NTRK1 fusion, comprising:

directly acquiring knowledge that an LMNA-NTRK1 fusion polypeptide, or a nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide, is present in a sample from a subject, wherein:

(i) the LMNA-NTRK1 fusion polypeptide comprises at least encoded exon 2 of LMNA of SEQ ID NO: 10 directly fused to at least encoded exon 11 of NTRK1 of SEQ ID NO: 10;

(ii) the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises an in-frame fusion of at least the nucleotide sequence of exon 2 of LMNA of SEQ ID NO: 9, and at least the nucleotide sequence of exon 11 of NTRK1 of SEQ ID NO: 9; or

(iii) the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises a breakpoint comprising the nucleotide sequence of SEQ ID NO: 8,

wherein the subject has melanoma or a Spitz tumor.

2 . A method of evaluating a subject, comprising:

identifying, selecting, or obtaining information or knowledge that the subject has participated in a clinical trial or has been treated for cancer;

acquiring genotype information that identifies an LMNA-NTRK1 fusion polypeptide or a nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide, as being in the subject,

wherein the presence of the LMNA-NTRK1 fusion polypeptide or the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide identifies the subject as having an increased risk for, or having, melanoma or a Spitz tumor; and treating the subject with a kinase inhibitor,

wherein:

(i) the LMNA-NTRK1 fusion polypeptide comprises at least encoded exon 2 of LMNA of SEQ ID NO: 10 directly fused to at least encoded exon 11 of NTRK1 of SEQ ID NO: 10;

(ii) the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises an in-frame fusion of at least the nucleotide sequence of exon 2 of LMNA of SEQ ID NO: 9, and at least the nucleotide sequence of exon 11 of NTRK1 of SEQ ID NO: 9; or

iii) the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises a breakpoint comprising the nucleotide sequence of SEQ ID NO: 8.

3 . The method of claim 2 , further comprising providing a report to another party.

4 . The method of claim 3 , wherein the party is the subject, a caregiver, a physician, an oncologist, a hospital, a clinic, a third-party payor, an insurance company, or a government office.

5 . The method of claim 3 , wherein the report identifies the presence of the LMNA-NTRK1 fusion polypeptide or the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide, and optionally includes an identifier for the subject from which the genotype information was obtained.

6 . The method of claim 5 , wherein the report comprises;

information on the role of the fusion, or wildtype sequence, in disease;

information on prognosis, resistance, or potential or suggested therapeutic options;

information on the likely effectiveness of a therapeutic option, the acceptability of a therapeutic option, or the advisability of applying the therapeutic option to a subject; or

information, or a recommendation on, the administration of a drug.

7 . A method for generating a personalized cancer treatment report, comprising:

obtaining a sample from a subject having a melanoma or a Spitz tumor,

detecting an LMNA-NTRK1 fusion polypeptide or a nucleic acid molecule encoding an LMNA-NTRK1 fusion polypeptide in the sample according to the method of claim 1 ,

selecting a treatment based on the detection of the LMNA-NTRK1 fusion polypeptide or the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide.

8 . The method of claim 2 , wherein

the LMNA-NTRK1 fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 10 or a fragment thereof, or an amino acid sequence at least 85% identical thereto.

9 . The method of claim 2 , wherein

the LMNA-NTRK1 fusion polypeptide comprises amino acids 168-175 or 289-560 of the amino acid sequence of SEQ ID NO: 10.

10 . The method of claim 2 , wherein

the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises an in-frame fusion of the nucleotide sequence of one or more of exons 1-2 of LMNA of SEQ ID NO: 9 or a fragment thereof, or a nucleotide sequence at least 85% identical thereto, and the nucleotide sequence of one or more of exons 11-19 of NTRK1 of SEQ ID NO: 9 or a fragment thereof, or a nucleotide sequence at least 85% identical thereto.

11 . The method of claim 2 , wherein the kinase inhibitor is administered responsive to the identification of the LMNA-NTRK1 fusion polypeptide or the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide, in a tumor sample from the subject.

12 . The method of claim 2 , wherein acquiring the genotype information comprises determining the presence of the nucleic acid molecule encoding an LMNA-NTRK1 fusion polypeptide by sequencing.

13 . The method of claim 2 , wherein the cancer is selected from the group consisting of: a Spitz tumor, a melanoma, a colorectal cancer, a lung cancer, a pancreatic cancer, an esophageal-gastric cancer, a thyroid cancer, an adenocarcinoma, a breast cancer, a histiocytic cancer, and an inflammatory myofibroblastic tumor.

14 . The method of claim 13 , wherein the cancer is selected from the group consisting of: a small cell lung cancer (SCLC), a non-small cell lung cancer (NSCLC), an adenocarcinoma of the lung, a bronchogenic carcinoma, a squamous cell carcinoma, (SCC), or a combination thereof.

15 . The method of claim 2 ,

wherein the kinase inhibitor is selected from the group consisting of: lestaurtinib (CEP-701), axitinib (AG013736), bosutinib (SKI-606), cediranib (AZD2171), dasatinib (BMS-354825), erlotinib, gefitinib, imatinib (CGP57148B or STI-571), lapatinib, neratinib (HKI-272), nilotinib, semaxanib (semaxinib or SU5416), sunitinib (SUI 1248), toceranib, vandetanib, vatalanib (PTK787 or PTK/ZK), sorafenib, ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258 or CHIR-258), BIBW 2992, SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120, AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, XL228, an ALK-specific inhibitor, TAE-684, PF02341066 (crizotinib), AF-802, LDK-378, ASP-3026, CEP-37440, CEP-28122, CEP-108050, and AP26113; or

wherein the kinase inhibitor is selected from the group consisting of an antisense molecule, a ribozyme, an RNAi molecule, and a triple helix molecule; wherein the kinase inhibitor hybridizes to the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide, or to a transcription regulatory region that blocks or reduces mRNA expression of the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide.

16 . The method of claim 2 , wherein the subject has participated in a clinical trial for evaluating a kinase inhibitor.

17 . The method of claim 7 , wherein

the LMNA-NTRK1 fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 10 or a fragment thereof, or an amino acid sequence at least 85% identical thereto.

18 . The method of claim 7 , wherein

the LMNA-NTRK1 fusion polypeptide comprises amino acids 168-175 or 289-560 of the amino acid sequence of SEQ ID NO: 10.

19 . The method of claim 7 , wherein

the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises an in-frame fusion of the nucleotide sequence of one or more of exons 1-2 of LMNA of SEQ ID NO: 9 or a fragment thereof, or a nucleotide sequence at least 85% identical thereto, and the nucleotide sequence of one or more of exons 11-19 of NTRK1 of SEQ ID NO: 9 or a fragment thereof, or a nucleotide sequence at least 85% identical thereto.

20 . The method of claim 7 , wherein the sample is a tumor sample.

21 . The method of claim 7 , wherein detecting the LMNA-NTRK1 fusion polypeptide or the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide in the sample comprises acquiring a sequence for a position in a nucleic acid molecule by sequencing at least one nucleotide of the nucleic acid molecule, thereby determining that the fusion is present in the nucleic acid molecule.

22 . The method of claim 7 ,

wherein the kinase inhibitor is selected from the group consisting of: lestaurtinib (CEP-701), axitinib (AG013736), bosutinib (SKI-606), cediranib (AZD2171), dasatinib (BMS-354825), erlotinib, gefitinib, imatinib (CGP57148B or STI-571), lapatinib, neratinib (HKI-272), nilotinib, semaxanib (semaxinib or SU5416), sunitinib ( SUI 1248), toceranib, vandetanib, vatalanib (PTK787 or PTK/ZK), sorafenib, ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258 or CHIR-258), BIBW 2992, SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120, AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, XL228, an ALK-specific inhibitor, TAE-684, PF02341066 (crizotinib), AF-802, LDK-378, ASP-3026, CEP-37440, CEP-28122, CEP-108050, and AP26113; or

wherein the kinase inhibitor is selected from the group consisting of an antisense molecule, a ribozyme, an RNAi molecule, and a triple helix molecule, wherein the kinase inhibitor hybridizes to the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide, or to a transcription regulatory region that blocks or reduces mRNA expression of the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide.

23 . The method of claim 7 , further comprising providing a personalized cancer treatment report that annotates the selected treatment or lists two or more treatment options based on the fusion polypeptide or the nucleic acid molecule encoding the polypeptide identified.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 30, 2021
From: CRONIN, MAUREEN T.; LIPSON, DORON; YELENSKY, ROMAN
To: FOUNDATION MEDICINE, INC.
Reel/Frame 057036/0916 →
Continuity (5)
Division 15978701 · May 14, 2018
Division 14257607 · Apr 21, 2014
Continuation PCTUS2012061211 · Oct 19, 2012
Provisional Application 61550327 · Oct 21, 2011
Related Publication 20220002818A1 · Jan 6, 2022
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