US2019120823A1PendingUtilityA1

Methods of treating a neuroendocrine tumor

48
Assignee: SCRIPPS HEALTHPriority: Aug 22, 2017Filed: Nov 16, 2018Published: Apr 25, 2019
Est. expiryAug 22, 2037(~11.1 yrs left)· nominal 20-yr term from priority
Inventors:Darren Sigal
G01N 33/57575G01N 33/5758G01N 33/5753G01N 33/5017C12Q 2600/16C12Q 2600/112C12Q 2600/156G01N 33/5748G01N 33/57446C12Q 1/6886A61K 31/496A61P 35/00
48
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Claims

Abstract

Disclosed herein, are methods of treating a neuroendocrine tumor (NET) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an agent that inhibits a tropomyosin receptor kinase (Trk) protein, wherein the NET is associated with a Trk protein that has undergone a genetic translocation or is an NTRK gene fusion protein. Also disclosed herein are methods of treating a neuroendocrine tumor (NET) in an individual in need thereof, comprising: (a) obtaining a sample of NET genetic material from the individual; (b) determining whether the NET tumor comprises a NTRK translocation or gene fusion; and (c) administering to the individual a therapeutically effective amount of an agent that inhibits a tropomyosin receptor kinase (Trk) protein.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating a neuroendocrine tumor (NET) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an agent that inhibits a tropomyosin receptor kinase (Trk) protein, wherein the NET is associated with a Trk protein that has undergone a genetic translocation or is an NTRK gene fusion protein. 
     
     
         2 . The method of  claim 1 , wherein the NTRK gene fusion protein comprises an NTRK1, NTRK2, or NTRK3 tyrosine kinase signaling domain. 
     
     
         3 . The method of  claim 2 , wherein the NTRK gene fusion protein is constitutively active. 
     
     
         4 . The method of  claim 1 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising a polypeptide sequence other than a TrkA, TrkB, or TrkC polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkA, TrkB, or TrkC polypeptide sequence, wherein the C-terminal polypeptide region has TrkA, TrkB, or TrkC kinase activity.   
     
     
         5 . The method of  claim 1 , wherein the NTRK gene fusion protein comprises a nucleic acid sequence comprising:
 (a) a first region corresponding to a sequence from a MPRIP, CD74, RABGAP1L, TPM3, TPR, TFG, PPL, CHTOP, ARHGEF2, NFASC, BCAN, LMNA, TP53, QKI, NACC2, VCL, AGBL4, TRIM24, PAN3, AFAP1, SQSTM1, ETV6, BTBD1, LYN, RBPMS, RFWD2, IRF2BP2, SSBP2, C18ORF8, RNF213, TBC1, DNER, PLEKHA6, PEAR1, MRPL24, MDM4, GRIPAP1, EPS15, DYNC2H1, CEL, EPHB2, EML4, HOMER2, TEL, or FAT1 gene sequence; and   (b) a second region corresponding to a NTRK1, NTRK2, or NTRK3 gene sequence.   
     
     
         6 . The method of  claim 5 , wherein the NTRK gene fusion protein is an ETV6-NTRK gene fusion protein. 
     
     
         7 . The method of  claim 1 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising the sequence of a MPRIP, CD74, RABGAP1L, TPM3, TPR, TFG, PPL, CHTOP, ARHGEF2, NFASC, BCAN, LMNA, TP53, QKI, NACC2, VCL, AGBL4, TRIM24, PAN3, AFAP1, SQSTM1, ETV6, BTBD1, LYN, RBPMS, RFWD2, IRF2BP2, SSBP2, C18ORF8, RNF213, TBC1, DNER, PLEKHA6, PEAR1, MRPL24, MDM4, GRIPAP1, EPS15, DYNC2H1, CEL, EPHB2, EML4, HOMER2, TEL, or FAT1 polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkA, TrkB, or TrkC polypeptide sequence, wherein the C-terminal polypeptide region has TrkA, TrkB, or TrkC kinase activity.   
     
     
         8 . The method of  claim 7 , wherein the N-terminal polypeptide region comprises an ETV6 polypeptide sequence. 
     
     
         9 . The method of  claim 8 , wherein the C-terminal polypeptide region comprises a TrkC polypeptide sequence. 
     
     
         10 . The method of  claim 1 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising a polypeptide sequence other than a TrkA, TrkB, or TrkC polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkA polypeptide sequence, wherein the C-terminal polypeptide comprises TrkA kinase activity;   wherein the fusion protein is a TP53-TrkA, LMNA-TrkA, CD74-TrkA, TFG-TrkA, TPM3-TrkA, NFASC-TrkA, BCAN-TrkA, MPRIP-TrkA, TPR-TrkA, RFWD2-TrkA, IRF2BP2-TrkA, SQSTM1-TrkA, SSBP2-TrkA, RABGAP1L-TrkA, C18ORF8-TrkA, RNF213-TrkA, TBC1D22A-TrkA, C200RF112-TrkA, DNER-TrkA, ARHGEF2-TrkA, CHTOP-TrkA, PPL-TrkA, PLEKHA6-TrkA, PEAR1-TrkA, MRPL24-TrkA, MDM4-TrkA, LRRC71-TrkA, GRIPAP1-TrkA, EPS15-TrkA, DYNC2H1-TrkA, CEL-TrkA, EPHB2-TrkA, or TGF-TrkA fusion protein.   
     
     
         11 . The method of  claim 1 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising a polypeptide sequence other than a TrkA, TrkB, or TrkC polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkB polypeptide sequence, wherein the C-terminal polypeptide comprises TrkB kinase activity;   wherein the fusion protein is a NACC2-TrkB, QKI-TrkB, AFAP1-TrkB, PAN3-TrkB, SQSTM1-TrkB, TRIM24-TrkB, VCL-TrkB, AGBL4-TrkB, or DAB2IP-TrkB fusion protein.   
     
     
         12 . The method of  claim 1 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising a polypeptide sequence other than a TrkA, TrkB, or TrkC polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkC polypeptide sequence, wherein the C-terminal polypeptide comprises TrkC kinase activity;   wherein the fusion protein is a ETV6-TrkC, BTBD1-TrkC, LYN-TrkC, RBPMS-TrkC, EML4-TrkC, HOMER2-TrkC, TFG-TrkC, FAT1-TrkC, or TEL-TrkC fusion protein.   
     
     
         13 . The method of  claim 1 , wherein the agent that inhibits a Trk protein is a kinase inhibitor. 
     
     
         14 . The method of  claims 1 , wherein the agent that inhibits a Trk protein is entrectinib, RXDX-102, altiratinib, larotrectinib, LOXO-195, sitravatinib, cabozantinib, merestinib, dovitinib, crizotinib, TSR-011, DS-6051, PLX7486, lestaurtinib, danusertib, F17752, AZD6918, AZD7451, or AZ-23, or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 14 , wherein the agent is entrectinib, or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 1 , wherein the NET is a foregut, midgut, or hindgut NET. 
     
     
         17 . The method of  claim 1 , wherein the NET is a gastrointestinal NET. 
     
     
         18 . The method of  claim 1 , wherein the NET is a small intestine NET (SI-NET). 
     
     
         19 . The method of  claim 1 , wherein the NET is a large intestine NET. 
     
     
         20 . The method of  claim 1 , wherein the NET is a rectal intestine NET. 
     
     
         21 . The method of  claim 1 , wherein the NET is a gastric intestine NET. 
     
     
         22 . The method of  claim 1 , wherein the NET is a pancreatic NET (PNET). 
     
     
         23 . The method of  claim 1 , wherein the NET is a bronchial NET. 
     
     
         24 . The method of  claim 1 , wherein the NET is an appendix, ovarian, or thyroid NET. 
     
     
         25 . The method of  claim 1 , wherein the NET is of unknown primary origin. 
     
     
         26 . The method of  claim 1 , wherein the primary NET has metastasized to a secondary tissue. 
     
     
         27 . The method of  claim 26 , wherein the secondary tissue is a lymph node, mesentery, liver, bone, lung, or brain. 
     
     
         28 . The method of  claim 1 , wherein the agent is utilized as a primary or frontline therapy. 
     
     
         29 . The method of  claim 1 , wherein the agent is utilized as a secondary or salvage therapy. 
     
     
         30 . The method of  claim 1 , wherein the individual has stable or progressive disease after a previous chemotherapy treatment regimen. 
     
     
         31 . The method of  claim 30 , wherein the previous chemotherapy treatment regimen comprises treatment with capecitabine, 5-fluorouracil, doxorubicin, etoposide, dacarbazine, streptozocin, temozolomide, cisplatin, cyclophosphamide, thalidomide, or any combination thereof. 
     
     
         32 . The method of  claim 1 , further comprising administering to the individual an additional therapy. 
     
     
         33 . The method of  claim 32 , wherein the additional therapy is a second agent that inhibits a Trk protein. 
     
     
         34 . The method of  claim 32 , wherein the additional therapy comprises a PI3K/Akt/mTOR pathway inhibitor, a TGF-β pathway inhibitors, a cell cycle inhibitor, a somatostatin analogue, an interferon, or an angiogenesis inhibitor. 
     
     
         35 . The method of  claim 34 , wherein the somatostatin analogue is octreotide, octreotate, pasireotide, or lanreotide. 
     
     
         36 . The method of  claim 34 , wherein the somatostatin analogue is radiolabeled. 
     
     
         37 . The method of  claim 37 , wherein the radiolabeled somatostatin analogue is [DOTA 0 ,Tyr 3 ]octreotate (Lutathera). 
     
     
         38 . The method of  claim 34 , wherein the interferon is a type I interferon. 
     
     
         39 . The method of  claim 38 , wherein the type I interferon is IFN-α. 
     
     
         40 . The method of  claim 34 , wherein the additional therapy is everolimus, temsirolimus, bevacizumab, sunitinib, or sorafenib. 
     
     
         41 . The method of  claim 32 , wherein the additional therapy comprises surgery, chemotherapy, or radiation therapy. 
     
     
         42 . The method of  claim 1 , wherein the individual has a carcinoid syndrome. 
     
     
         43 . The method of  claim 42 , further comprising administering to the individual a treatment for the carcinoid syndrome. 
     
     
         44 . The method of  claim 43 , wherein the treatment for the carcinoid syndrome is an anti-serotonin agent. 
     
     
         45 . The method of  claim 44 , wherein the anti-serotonin agent is a somatostatin analogue. 
     
     
         46 . The method of  claim 45 , wherein the somatostatin analogue is octreotide, octreotate, pasireotide, or lanreotide. 
     
     
         47 . A method of treating a neuroendocrine tumor (NET) in an individual in need thereof comprising: (a) obtaining a sample of NET genetic material from the individual; (b) determining whether the NET tumor comprises a NTRK translocation or gene fusion; and (c) administering to the individual an agent that inhibits a tropomyosin receptor kinase (Trk) protein. 
     
     
         48 . The method of  claim 47 , wherein the sample of NET genetic material is total nucleic acid obtained from formalin-fixed paraffin-embedded (FFPE) tumor biopsy sample. 
     
     
         49 . The method of  claim 47 , further comprising sequencing the NET genetic material to determine whether the tumor sample comprises a NTRK translocation or gene fusion. 
     
     
         50 . The method of  claim 49 , wherein the NET genetic material is sequenced by whole genome DNA sequencing, whole exome sequencing, targeted DNA sequencing, targeted RNA sequencing, or whole transcriptome RNA sequencing. 
     
     
         51 . The method of  claim 47 , further comprising amplifying the NET genetic material using NTRK1, NTRK2, or NTRK3-specific primers prior to determining whether the NET tumor comprises a NTRK translocation or gene fusion. 
     
     
         52 . The method of  claim 48 , further comprising detecting the amount of NTRK expression or Trk protein levels in a NET tumor sample, wherein elevated levels of NTRK expression or Trk protein levels is indicative of a NTRK translocation or gene fusion. 
     
     
         53 . A method of treating a gastrointestinal neuroendocrine tumor (NET) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an agent that inhibits a tropomyosin receptor kinase (Trk) protein, wherein the NET is associated with a Trk protein that has undergone a genetic translocation or is an NTRK gene fusion protein. 
     
     
         54 . The method of  claim 53 , wherein the NTRK gene fusion protein comprises an NTRK1, NTRK2, or NTRK3 tyrosine kinase signaling domain. 
     
     
         55 . The method of  claim 54 , wherein the NTRK gene fusion protein is constitutively active. 
     
     
         56 . The method of  claim 53 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising a polypeptide sequence other than a TrkA, TrkB, or TrkC polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkA, TrkB, or TrkC polypeptide sequence, wherein the C-terminal polypeptide region has TrkA, TrkB, or TrkC kinase activity.   
     
     
         57 . The method of  claim 53 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising the sequence of a MPRIP, CD74, RABGAP1L, TPM3, TPR, TFG, PPL, CHTOP, ARHGEF2, NFASC, BCAN, LMNA, TP53, QKI, NACC2, VCL, AGBL4, TRIM24, PAN3, AFAP1, SQSTM1, ETV6, BTBD1, LYN, RBPMS, RFWD2, IRF2BP2, SSBP2, C18ORF8, RNF213, TBC1, DNER, PLEKHA6, PEAR1, MRPL24, MDM4, GRIPAP1, EPS15, DYNC2H1, CEL, EPHB2, EML4, HOMER2, TEL, or FAT1 polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkA, TrkB, or TrkC polypeptide sequence, wherein the C-terminal polypeptide region has TrkA, TrkB, or TrkC kinase activity.   
     
     
         58 . The method of  claim 57 , wherein the N-terminal polypeptide region comprises an ETV6 polypeptide sequence. 
     
     
         59 . The method of  claim 58 , wherein the C-terminal polypeptide region comprises a TrkC polypeptide sequence. 
     
     
         60 . The method of  claim 53 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising a polypeptide sequence other than a TrkA, TrkB, or TrkC polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkA polypeptide sequence, wherein the C-terminal polypeptide comprises TrkA kinase activity;   wherein the fusion protein is a TP53-TrkA, LMNA-TrkA, CD74-TrkA, TFG-TrkA, TPM3-TrkA, NFASC-TrkA, BCAN-TrkA, MPRIP-TrkA, TPR-TrkA, RFWD2-TrkA, IRF2BP2-TrkA, SQSTM1-TrkA, SSBP2-TrkA, RABGAP1L-TrkA, C18ORF8-TrkA, RNF213-TrkA, TBC1D22A-TrkA, C200RF112-TrkA, DNER-TrkA, ARHGEF2-TrkA, CHTOP-TrkA, PPL-TrkA, PLEKHA6-TrkA, PEAR1-TrkA, MRPL24-TrkA, MDM4-TrkA, LRRC71-TrkA, GRIPAP1-TrkA, EPS15-TrkA, DYNC2H1-TrkA, CEL-TrkA, EPHB2-TrkA, or TGF-TrkA fusion protein.   
     
     
         61 . The method of  claim 53 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising a polypeptide sequence other than a TrkA, TrkB, or TrkC polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkB polypeptide sequence, wherein the C-terminal polypeptide comprises TrkB kinase activity;   wherein the fusion protein is a NACC2-TrkB, QKI-TrkB, AFAP1-TrkB, PAN3-TrkB, SQSTM1-TrkB, TRIM24-TrkB, VCL-TrkB, AGBL4-TrkB, or DAB2IP-TrkB fusion protein.   
     
     
         62 . The method of  claim 53 , wherein the NTRK gene fusion protein comprises:
 (a) an N-terminal polypeptide region comprising a polypeptide sequence other than a TrkA, TrkB, or TrkC polypeptide sequence; and   (b) a C-terminal polypeptide region comprising a TrkC polypeptide sequence, wherein the C-terminal polypeptide comprises TrkC kinase activity;   wherein the fusion protein is a ETV6-TrkC, BTBD1-TrkC, LYN-TrkC, RBPMS-TrkC, EML4-TrkC, HOMER2-TrkC, TFG-TrkC, FAT1-TrkC, or TEL-TrkC fusion protein.   
     
     
         63 . The method of  claim 53 , wherein the agent that inhibits a Trk protein is a kinase inhibitor. 
     
     
         64 . The method of  claim 53 , wherein the agent that inhibits a Trk protein is entrectinib, RXDX-102, altiratinib, larotrectinib, LOXO-195, sitravatinib, cabozantinib, merestinib, dovitinib, crizotinib, TSR-011, DS-6051, PLX7486, lestaurtinib, danusertib, F17752, AZD6918, AZD7451, or AZ-23, or a pharmaceutically acceptable salt thereof. 
     
     
         65 . The method of  claim 64 , wherein the agent is entrectinib, or a pharmaceutically acceptable salt thereof. 
     
     
         66 . The method of  claim 53 , wherein the gastrointestinal NET is a small intestine, large intestine, pancreatic, appendix, gastric, rectal, or unknown primary origin NET. 
     
     
         67 . The method of  claim 53 , wherein the primary NET has metastasized to a secondary tissue. 
     
     
         68 . The method of  claim 67 , wherein the secondary tissue is a lymph node, mesentery, liver, bone, lung, or brain. 
     
     
         69 . A method of treating a gastrointestinal neuroendocrine tumor (NET) in an individual in need thereof comprising: (a) obtaining a sample of NET genetic material from the individual; (b) determining whether the NET tumor comprises a NTRK translocation or gene fusion; and (c) administering to the individual a therapeutically effective amount of an agent that inhibits a tropomyosin receptor kinase (Trk) protein. 
     
     
         70 . The method of  claim 69 , wherein the sample of NET genetic material is total nucleic acid obtained from formalin-fixed paraffin-embedded (FFPE) tumor biopsy sample. 
     
     
         71 . The method of  claim 69 , further comprising sequencing the NET genetic material to determine whether the tumor sample comprises a NTRK translocation or gene fusion. 
     
     
         72 . The method of  claim 71 , wherein the NET genetic material is sequenced by whole genome DNA sequencing, whole exome sequencing, targeted DNA sequencing, targeted RNA sequencing, or whole transcriptome RNA sequencing. 
     
     
         73 . The method of  claim 69 , further comprising amplifying the NET genetic material using NTRK1, NTRK2, or NTRK3-specific primers prior to determining whether the NET tumor comprises a NTRK translocation or gene fusion. 
     
     
         74 . The method of  claim 69 , further comprising detecting the amount of NTRK expression or Trk protein levels in a NET tumor sample, wherein elevated levels of NTRK expression or Trk protein levels is indicative of a NTRK translocation or gene fusion.

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