WO2020179712A1 - Methods for predicting tumor response to eribulin - Google Patents

Methods for predicting tumor response to eribulin Download PDF

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WO2020179712A1
WO2020179712A1 PCT/JP2020/008485 JP2020008485W WO2020179712A1 WO 2020179712 A1 WO2020179712 A1 WO 2020179712A1 JP 2020008485 W JP2020008485 W JP 2020008485W WO 2020179712 A1 WO2020179712 A1 WO 2020179712A1
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Roma KAUL
Susan L. Mooberry
April L. RISINGER
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Eisai R&D Management Co Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
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    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

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Abstract

The invention provides methods, compositions, and kits for determining approaches for treating cancer, as well as methods for treating cancer.

Description

METHODS FOR PREDICTING TUMOR RESPONSE TO ERIBULIN BACKGROUND OF THE INVENTION
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Claims (42)

  1. 　　A method for determining whether eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, may be used to treat a subject having breast cancer, the method comprising determining the level of expression of SMAD4 in a sample derived from said subject, wherein a high level of expression of SMAD4 in the sample, relative to a control, indicates that eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, will be effective in treating said subject.
  2. 　　A method of treating a subject having breast cancer, the method comprising identifying a subject having breast cancer in which SMAD4 has a high level of expression, and administering a therapeutically effective amount of eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, to said subject.
  3. 　　A method of treating a subject having breast cancer, the method comprising assaying a sample derived from said subject to determine the level of expression in said sample of SMAD4, and administering a therapeutically effective amount of eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, to said subject when a high level of expression of SMAD4 is detected in said sample.
  4. 　　A method for determining whether eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, may be effective in treating a subject having breast cancer, the method comprising determining the level of expression of Slug in a sample derived from said subject, wherein a high level of expression of Slug in the sample, relative to a control, indicates that eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, may be less effective in treating said subject; or a low level of expression of Slug in the sample, relative to a control, indicates that eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, may be effective in treating said subject.
  5. 　　A method of treating a subject having breast cancer, the method comprising identifying a subject having breast cancer in which Slug has a low level of expression, and administering a therapeutically effective amount of eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, to said subject.
  6. 　　A method of treating a subject having breast cancer, the method comprising assaying a sample derived from said subject to determine the level of expression in said sample of Slug, and administering a therapeutically effective amount of eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, to said subject when a low level of expression of Slug is detected in said sample.
  7. 　　The method of claim 4, wherein said determining is carried out before treatment with eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, to determine whether to administer eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent.
  8. 　　The method of claim 4, wherein said determining is carried out after treatment with eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, to determine whether to continue to administer eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent.
  9. 　　A method for determining whether eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, may be used to treat a subject having breast cancer, or for treating a subject having breast cancer, the method comprising carrying out a combination of two or more of the methods of two or more of claims 1-8.
  10. 　　The method of any one of claims 1, 3, 4, or 6-9, wherein the sample comprises cells of a breast tumor obtained from a subject.
  11. 　　The method of any one of claims 1-10, wherein the pharmaceutically acceptable salt of eribulin is eribulin mesylate.
  12. 　　The method of any one of claims 1-11, wherein said subject has not been previously treated with eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof.
  13. 　　The method of any one of claims 1-11, wherein said subject has been previously treated with eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof.
  14. 　　The method of any one of claims 1-13, wherein said other microtubule destabilizing agent is selected from the group consisting of vinorelbine, vinblastine, and maytansine.
  15. 　　The method of any one of claims 1-14, wherein said breast cancer is an Estrogen Receptor (ER) negative breast cancer; a Progesterone Receptor (PR) negative breast cancer; a HER-2 negative breast cancer; an Estrogen Receptor (ER) negative and Progesterone Receptor (PR) negative breast cancer; an Estrogen Receptor (ER) negative and HER-2 negative breast cancer; a Progesterone Receptor (PR) negative and HER-2 negative breast cancer; or an Estrogen Receptor (ER) negative, Progesterone Receptor (PR) negative and HER-2 negative breast cancer.
  16. 　　The method of any one of claims 1-15, wherein the level of expression of SMAD4 and/or Slug is determined at the nucleic acid level.
  17. 　　The method of claim 16, the level of expression of SMAD4 and/or Slug is determined by detecting cDNA.
  18. 　　The method of claim 16, the level of expression of SMAD4 and/or Slug is determined by detecting mRNA.
  19. 　　The method of any one of claims 16-18, wherein the level of expression of SMAD4 and/or Slug is determined by using a technique selected from the group consisting of RNA-seq, polymerase chain reaction (PCR) amplification reaction, reverse-transcriptase PCR analysis, quantitative reverse-transcriptase PCR analysis, Northern blot analysis, RNAase protection assay, digital RNA detection/ quantitation, and combinations or subcombinations thereof.
  20. 　　The method of any one of claims 1-15, wherein the level of expression of SMAD4 and/or Slug is determined at the protein level.
  21. 　　The method of claim 20, wherein the presence of SMAD4 and/or Slug is detected using an antibody or antigen binding fragment thereof, which specifically binds to the protein.
  22. 　　The method of claim 21, wherein the antibody or antigen binding fragment thereof is selected from the group consisting of a murine antibody, a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody, a Fab, Fab', F(ab')2, ScFv, SMIP, affibody, avimer, versabody, nanobody, a domain antibody, and an antigen binding fragment of any of the foregoing.
  23. 　　The method of claim 21 or 22, wherein the antibody or antigen binding fragment thereof is labeled.
  24. 　　The method of claim 23, wherein the antibody or antigen binding fragment thereof is labeled with a label selected from the group consisting of a radio-label, a biotin-label, a chromophore-label, a fluorophore-label, and an enzyme-label.
  25. 　　The method of any one of claims 20-24, wherein the level of expression of SMAD4 and/or Slug is determined by using a technique selected from the group consisting of an immunoassay, a western blot analysis, a radioimmunoassay, immunofluorimetry, immunoprecipitation, equilibrium dialysis, immunodiffusion, electrochemiluminescence immunoassay (ECLIA), ELISA assay, immunopolymerase chain reaction and combinations or sub-combinations thereof.
  26. 　　The method of claim 25, wherein the immunoassay is a solution-based immunoassay selected from the group consisting of electrochemiluminescence, chemiluminescence, fluorogenic chemiluminescence, fluorescence polarization, and time-resolved fluorescence.
  27. 　　The method of claim 25, wherein the immunoassay is a sandwich immunoassay selected from the group consisting of electrochemiluminescence, chemiluminescence, and fluorogenic chemiluminescence.
  28. 　　The method of any one of claims 1, 3, 4, or 6-27, wherein said sample comprises a fluid, or component thereof, obtained from said subject.
  29. 　　The method of claim 28, wherein the fluid is selected from the group consisting of blood, lymph, serum, plasma, cystic fluid, nipple aspirates, urine, sputum, and fluid collected from a biopsy.
  30. 　　The method of any one of claims 1, 3, 4, or 6-27, wherein the sample comprises a tissue, or component thereof, obtained from said subject.
  31. 　　The method of claim 30, wherein said tissue is selected from the group consisting of breast tissue, connective tissue, lymphatic tissue, tissue obtained from a biopsy and tissue obtained from a lump biopsy.
  32. 　　The method of claim 30 or 31, wherein the tissue is breast tissue or a component thereof.
  33. 　　The method of claim 32, wherein said component of said breast tissue comprises breast tissue cells.
  34. 　　The method of claim 33, wherein said breast tissue cells are circulating breast tumor cells.
  35. 　　The method of any one of claims 1-34, wherein said subject is a human subject.
  36. 　　A kit for predicting whether eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, may be used to treat a subject having breast cancer, the kit comprising reagents for determining the level of expression of SMAD4 and/or Slug; and instructions for use of the kit to predict whether eribulin, an analog thereof, or a pharmaceutically acceptable salt thereof, or another microtubule destabilizing agent, may be used to treat a subject having breast cancer.
  37. 　　The kit of claim 36, wherein the pharmaceutically acceptable salt of eribulin is eribulin mesylate.
  38. 　　The kit of claim 36, wherein the other microtubule destabilizing agent is selected from the group consisting of vinorelbine, vinblastine, and maytansine.
  39. 　　The kit of any one of claims 36-38, wherein the reagent for determining the level of expression of SMAD4 and/or Slug is a probe for amplifying and/or detecting SMAD4 and/or Slug.
  40. 　　The kit of any one of claims 36-38, wherein the reagent for determining the level of expression of SMAD4 and/or Slug is an antibody.
  41. 　　The kit of any one of claims 36-40, further comprising reagents for obtaining a biological sample from a subject.
  42. 　　The kit of any one of claims 36-41, further comprising a control sample.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113512733A (en) * 2021-05-13 2021-10-19 浙江工业大学 Method for synthesizing eribulin intermediate through electrochemical NHK reaction

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COOMBES R C; ARMSTRONG A; AHMED S; PAGE K; HASTINGS R K; SALARI R; SETHI H; BOYDELL A R; SHCHEGROVA S V; FERNANDEZ-GARCIA D; GLEAS: "Abstract P4-01-02: Early detection of residual breast cancer through a robust, scalable and personalized analysis of circulating tumour DNA (ctDNA) antedates overt metastatic recurrence", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 79, no. 4, Supplement 1, Abstract P4-01-02, 1 February 2019 (2019-02-01), US, XP009514404, ISSN: 1538-7445, Retrieved from the Internet <URL:http://cancerres.aacrjournals.org/content/79/4_Supplement/P4-01-02> DOI: 10.1158/1538-7445.SABCS18-P4-01-02 *
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113512733A (en) * 2021-05-13 2021-10-19 浙江工业大学 Method for synthesizing eribulin intermediate through electrochemical NHK reaction

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