WO2015049985A1 - Composition médicinale pour tumeur à gène fgf4 amplifié - Google Patents

Composition médicinale pour tumeur à gène fgf4 amplifié Download PDF

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WO2015049985A1
WO2015049985A1 PCT/JP2014/074530 JP2014074530W WO2015049985A1 WO 2015049985 A1 WO2015049985 A1 WO 2015049985A1 JP 2014074530 W JP2014074530 W JP 2014074530W WO 2015049985 A1 WO2015049985 A1 WO 2015049985A1
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fgf4
gene
pharmaceutical composition
tumor
amplified
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Japanese (ja)
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西尾和人
荒尾徳三
松本和子
福島雅夫
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住友ベークライト株式会社
学校法人近畿大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present disclosure relates to a pharmaceutical composition of an FGF4 gene-amplified tumor, a method for predicting the effect of the pharmaceutical composition, a kit used therefor, the use of the pharmaceutical composition, and a method for improving, suppressing progression and / or treating an FGF4 gene-amplified tumor. .
  • Patent Document 1 predicts whether therapeutic administration of an epidermal growth factor receptor (EGFR) inhibitor is effective or ineffective is an increase in EGFR gene copy number, tyrosine kinase receptor type receptor (HER2) copy. Disclose what is possible by detecting an increase in number.
  • EGFR epidermal growth factor receptor
  • HER2 tyrosine kinase receptor type receptor
  • Patent Document 2 discloses that it is possible to predict the therapeutic effect of sorafenib, which is a multi-target kinase inhibitor and a cancer molecular target therapeutic agent, by detecting an increase in the copy number of the FGF3 gene.
  • Patent Document 3 discloses that an increase in the copy number of the ⁇ -actinin-4 gene may indicate the presence of cancer.
  • JP 2013-5800 A JP 2012-249633 A Japanese Patent Application Laid-Open No. 2009-10073
  • the present disclosure provides a pharmaceutical composition of an FGF4 gene amplified tumor. Moreover, this indication provides the effect prediction method of this pharmaceutical composition in one or some embodiment.
  • the present disclosure is a pharmaceutical composition for improving, suppressing progression, and / or treating an FGF4 gene-amplified tumor, comprising an anti-FGF4 antibody, an FGF receptor inhibitor, an FGF4 siRNA, And a pharmaceutical composition containing as an active ingredient at least one selected from the group consisting of FGF4 shRNA.
  • the present disclosure detects the gene amplification level of the FGF4 gene in the target tumor tissue sample or tumor cell sample, and the target FGF4 gene is amplified. If the effectiveness of therapeutic administration of the pharmaceutical composition according to the present invention is predicted, the subject is classified, or the therapeutic administration of the pharmaceutical composition according to the present disclosure is effective when the subject FGF4 gene is not amplified. It relates to a method comprising classifying said object if gender is not predicted.
  • the present disclosure detects the gene amplification level of the FGF4 gene in the tumor tissue sample or tumor cell sample of the subject, and the FGF4 protein when the subject FGF4 gene is amplified.
  • the present invention relates to a method for improving, suppressing the progression of and / or treating FGF4 gene-amplified tumor, comprising administering to the subject a pharmaceutical composition comprising a substance that suppresses the expression of or inhibits the function thereof as an active ingredient.
  • FIG. 1 is a graph showing an example of the results of measuring the FGF4 gene copy number of 194 esophageal cancer specimens.
  • the horizontal axis is the sample sample and is arranged in order of copy number.
  • the vertical axis represents the measured copy number.
  • FIG. 2 shows an example of the results of measuring the tumor size of a cell line (WiDr / FGF4) over time when FGF4 gene is introduced into colon cancer cell line WiDr and FGF4 protein is overexpressed. It is a graph.
  • an EGFP gene was introduced (WiDr / EGFP).
  • FIG. 3 is a graph showing an example of the results of measuring the tumor size of a cell line (A549 / FGF4) over time when the FGF4 gene was introduced into the lung cancer cell line A549 and the FGF4 protein was overexpressed. It is.
  • an EGFP gene was introduced (A549 / EGFP).
  • FIG. 4 shows the results of measuring the tumor size of the cell line (KYSE-270 / FGF4) over time when the FGF4 gene was introduced into the esophageal cancer cell line KYSE-270 and the FGF4 protein was overexpressed. It is a graph which shows an example.
  • an EGFP gene was introduced (KYSE-270 / EGFP).
  • FIG. 5 is a graph showing an example of the results of confirming the effect of anti-FGF4 antibody on FGF4 overexpressing esophageal cancer cell line KYSE-270 / FGF4 transplanted into mice.
  • goat polyclonal IgG was used instead of anti-FGF4 antibody.
  • the vertical axis represents the tumor size (mm 3 )
  • the horizontal axis represents the culture time (days).
  • the vertical axis represents the mouse body weight (g)
  • the horizontal axis represents the culture time (days).
  • FIG. 6 is a graph showing an example of the results of confirming the effect of an FGFR inhibitor on the FGF4-overexpressing lung cancer cell line A549 / FGF4 transplanted into mice.
  • the control is an example in which no FGFR inhibitor is administered.
  • the vertical axis represents the tumor size (mm 3 ), and the horizontal axis represents the culture time (days).
  • the present disclosure indicates that some tumors and cancers have an amplified copy number of the FGF4 gene, and suppress or inhibit the function of the FGF4 protein in such an FGF4 gene-amplified tumor. Based on the finding that a pharmaceutical composition containing a substance as an active ingredient has an antitumor effect. The present disclosure is also based on the finding that, in one or more embodiments, amplification of the FGF4 gene copy number occurs in about 40% of esophageal cancers.
  • the present disclosure is a pharmaceutical composition for improving, suppressing progression and / or treating FGF4 gene-amplified tumor, and contains a substance that suppresses the expression of FGF4 protein or inhibits its function as an active ingredient.
  • the present invention relates to a pharmaceutical composition.
  • the tumor that is the target of the pharmaceutical composition according to the present disclosure is a tumor in which the copy number of FGF4 (Fibroblast growth factor 4) gene is amplified (hereinafter also referred to as “FGF4 gene amplified tumor”). It is.
  • FGF4 gene amplified tumors can be present in various cancers. For example, about 40% of esophageal cancers are FGF4 gene amplified tumors. In addition, for example, there is a report that FGF4 gene amplification is observed in tumor samples of about 10% of bladder cancer and about 35% of head and neck squamous cell carcinoma.
  • the pharmaceutical composition according to the present disclosure can exert an antitumor effect on an FGF4 gene-amplified tumor.
  • the pharmaceutical composition according to the present disclosure can be used for improvement, suppression of progression, and / or treatment of an individual having an FGF4 gene-amplified tumor.
  • the FGF4 gene amplified tumor is esophageal cancer.
  • the effectiveness of the pharmaceutical composition according to the present disclosure can be determined by examining the presence or absence of amplification of the copy number of the FGF4 gene in the subject tumor. Therefore, in another aspect, the present disclosure detects the gene amplification level of the FGF4 gene in the target tumor tissue sample or tumor cell sample, and the pharmaceutical composition according to the present disclosure when the target FGF4 gene is amplified Classifying the subject as the efficacy of therapeutic administration of the product is predicted, or the efficacy of therapeutic administration of the pharmaceutical composition according to the present disclosure is not expected when the subject's FGF4 gene is not amplified And a method including classifying the object (hereinafter, also referred to as “classification method according to the present disclosure”). Examples of the classification method according to the present disclosure include humans and mammals other than humans in one or a plurality of embodiments.
  • the presence or absence of amplification of the copy number of the FGF4 gene a conventionally performed method or a method developed in the future can be used in one or a plurality of embodiments.
  • the presence or absence of amplification of the copy number of the FGF4 gene can be performed by fluorescent fluorescence in situ hybridization (FISH), a next-generation sequencer, a DNA chip, or real-time quantitative PCR.
  • FISH fluorescent fluorescence in situ hybridization
  • the fact that the copy number of the FGF4 gene is increased means that the copy number of the FGF4 gene of the target tumor is larger than the copy number of the control gene of normal cells.
  • Amplification of gene copy number by fluorescence in situ hybridization can be detected / measured in one or more embodiments as follows.
  • FISH fluorescence in situ hybridization
  • a fragment DNA (probe) of a specific gene is hybridized with a chromosome or nuclear DNA using a fluorescent substance, and the increase / decrease (deletion or amplification) of the gene and the position (mapping) in a staining pair are examined. It is. Therefore, cells can be stained with a probe specific to the sequence of the target gene, and the increase or decrease in copy number can be measured according to the number of signals.
  • FGF3 / FGF4 amplification and multiple lung metastasesin responders to sorafenib in hepatocellular carcinoma. ”
  • amplification of gene copy number by a next-generation sequencer can be detected / measured as follows. Unlike conventional Sanger methods, next-generation sequencers can process tens of millions to hundreds of millions of DNA fragments in parallel. Therefore, by increasing and decreasing the copy number of the target gene by sequencing the DNA from the tumor sample and the control sample and comparing the coverage of the target gene. Also, “PLoS One. 2013; 8 (5): e64271. Targeted Sequencing of Cancer-Related Genes in Colorectal Cancer Using Next-Generation Sequencing” and “Clin Cancer Res. 2013 May 15; 19 (10): 2668-76. Relapsed classic E-cadherin (CDH1) -mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations. ”
  • amplification of gene copy number by a DNA chip can be detected / measured as follows. That is, CGH (comparative genomic hybridization) analysis is performed using a slide glass (DNA chip) in which a large number of DNA fragments are arrayed. Tumor samples and control samples labeled with different fluorescent dyes are hybridized with DNA fragments on the DNA chip. Based on the intensity ratio of fluorescent signals derived from each sample, the copy number of tumor DNA in the region corresponding to the arrayed DNA fragments is quantified. Also, “http://www.cghtmd.jp/CGHDatabase/about/about#high.jsp” and “Hepatology. 2013 Apr; 57 (4): 1407-15. FGF3 / FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. ”
  • Amplification of gene copy number by real-time quantitative PCR can be detected / measured as follows. That is, using a sample DNA as a template, a target gene site is amplified by a PCR reaction using primers specific to the target gene. The amplification reaction is detected in real time, the number of PCR cycles for amplification up to a certain amount is compared between the control sample and the tumor sample, and the copy number is calculated according to the difference. Also, “http://tools.invitrogen.com/content/sfs/manuals/cms#062368.pdf” and “Hepatology. 2013 Apr; 57 (4): 1407-15. FGF3 / FGF4 amplification and multiple lung metastases in Refer to "responders to sorafenib in hepatocellular carcinoma.”
  • the active ingredient of the pharmaceutical composition according to the present disclosure is a substance that suppresses the expression of FGF4 protein or a substance that inhibits the function.
  • the active ingredient of the pharmaceutical composition according to the present disclosure includes at least one selected from the group consisting of an anti-FGF4 antibody, an FGF receptor inhibitor, FGF4 siRNA, and FGF4 shRNA.
  • the anti-FGF4 antibody has neutralizing activity or high neutralizing activity in one or a plurality of embodiments.
  • the anti-FGF4 antibody is a monoclonal antibody in one or more embodiments. Further, in one or a plurality of embodiments, the anti-FGF4 antibody may be in the form of an antibody fragment or may be modified with a sugar chain.
  • FGF receptor is a receptor for FGF4 protein. Therefore, the FGF receptor inhibitor can be used as an active ingredient of the pharmaceutical composition according to the present disclosure.
  • the FGF receptor inhibitor conventionally known and future developed ones can be used.
  • FGF4 gene siRNA small interfering RNA
  • shRNA small hairpin
  • a person skilled in the art can design and manufacture appropriate FGF4 gene siRNA and shRNA according to standard methods.
  • the “pharmaceutical composition” may be a dosage form suitable for an administration form by applying a well-known formulation technique in one or a plurality of embodiments.
  • the dosage form include, but are not limited to, oral administration in a dosage form such as a tablet, capsule, granule, powder, pill, troche, syrup, and liquid.
  • parenteral administration in dosage forms such as injections, liquids, aerosols, suppositories, patches, lotions, liniments, ointments, eye drops and the like can be mentioned.
  • These preparations can be produced by known methods using additives such as, but not limited to, excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.
  • the pharmaceutical composition according to the present disclosure does not contain other active ingredients having a therapeutic effect, or further contains one or a plurality of active ingredients.
  • excipient examples include, but are not limited to, starch such as starch, potato starch, and corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, and the like.
  • coating agent examples include, but are not limited to, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin, and the like.
  • binder include, but are not limited to, polyvinyl pyrrolidone, macrogol and the same compound as the excipient.
  • disintegrant examples include, but are not limited to, compounds similar to the excipients and chemically modified starch and celluloses such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
  • stabilizer examples include, but are not limited to, paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenol, cresol Mention may be made of such phenols; thimerosal; dehydroacetic acid; and sorbic acid.
  • flavoring agent examples include, but are not limited to, sweeteners, acidulants, and fragrances that are commonly used.
  • the solvent is not limited to these, but ethanol, phenol, chlorocresol, purified water, distilled water and the like can be used, and a surfactant or an emulsifier can also be used as necessary.
  • a surfactant or an emulsifier include, but are not limited to, polysorbate 80, polyoxyl 40 stearate, lauromacrogol, and the like.
  • the method of using the pharmaceutical composition according to the present disclosure may vary depending on symptoms, age, administration method, and the like.
  • the method of use is not limited to these, but intermittently or continuously, orally, transdermally, submucosally, subcutaneously, intramuscularly, vascularly, so that the concentration of the active ingredient in the body is between 100 nM and 1 mM. It can be administered internally, intracerebrally, or intraperitoneally.
  • the lower limit is 0.01 mg (preferably 0.1 mg) and the upper limit is 2000 mg as converted into the active ingredient per day for a subject (adult if human). (Preferably 500 mg, more preferably 100 mg) may be divided into 1 or several times and administered according to symptoms.
  • the lower limit is 0.001 mg (preferably 0.01 mg) and the upper limit is 500 mg (preferably 50 mg) per day for a subject (adult if human). Is divided into one or several times and administered according to symptoms.
  • the present disclosure relates to at least one use selected from the group consisting of an anti-FGF4 antibody, an FGF receptor inhibitor, FGF4 siRNA, and FGF4 shRNA for producing a pharmaceutical composition according to the present disclosure.
  • the present disclosure relates to a method for improving, suppressing progression, and / or treating an FGF4 gene-amplified tumor, comprising administering a pharmaceutical composition according to the present disclosure to a subject in need.
  • the present disclosure detects the gene amplification level of the FGF4 gene in the target tumor tissue sample or tumor cell sample, and suppresses the expression of the FGF4 protein when the target FGF4 gene is amplified.
  • the present invention relates to a method for improving, suppressing progression and / or treating an FGF4 gene-amplified tumor, comprising administering to the subject a pharmaceutical composition containing a substance that inhibits function as an active ingredient.
  • the present disclosure provides at least one selected from the group consisting of an anti-FGF4 antibody, an FGF receptor inhibitor, FGF4 siRNA, and FGF4 shRNA in the above-described improvement, suppression of progression, and / or treatment of an FGF4 gene-amplified tumor.
  • Use, or use of a pharmaceutical composition according to the present disclosure are examples of a pharmaceutical composition according to the present disclosure.
  • the present disclosure provides a reagent for detecting the FGF4 gene amplification level by a method selected from the group consisting of fluorescence in situ hybridization (FISH), next-generation sequencer, DNA chip, and real-time quantitative PCR, And a reagent for detecting the FGF4 gene amplification level and a nucleotide that hybridizes to the FGF4 gene by a method selected from the group consisting of fluorescence in situ hybridization (FISH), next-generation sequencer, DNA chip, and real-time quantitative PCR Relates to a kit comprising:
  • a pharmaceutical composition for improvement, suppression of progression and / or treatment of FGF4 gene-amplified tumor which is selected from the group consisting of anti-FGF4 antibody, FGF receptor inhibitor, FGF4 siRNA, and FGF4 shRNA.
  • a pharmaceutical composition containing at least one of these as an active ingredient [2] The pharmaceutical composition according to [1], wherein the FGF4 gene-amplified tumor is esophageal cancer. [3] The pharmaceutical composition according to [1] or [2], wherein the anti-FGF4 antibody is a neutralizing antibody having specificity for FGF4.
  • [4] detecting the gene amplification level of the FGF4 gene in the tumor tissue sample or tumor cell sample of the subject; and Classifying the subject when the efficacy of therapeutic administration of the pharmaceutical composition according to any one of [1] to [3] is predicted when the subject's FGF4 gene is amplified, or Categorizing the subject as not predicting the effectiveness of therapeutic administration of the pharmaceutical composition of any of [1] to [3] when the FGF4 gene is not amplified.
  • [5] The method according to [4], wherein the FGF4 gene amplification level is detected by a method selected from the group consisting of fluorescence in situ hybridization (FISH), next-generation sequencer, DNA chip, and real-time quantitative PCR.
  • FISH fluorescence in situ hybridization
  • [6] The method according to [4] or [5], wherein the tumor tissue or tumor cell is collected from the subject's esophagus.
  • a reagent for detecting the FGF4 gene amplification level and the FGF4 gene are hybridized by a method selected from the group consisting of fluorescence in situ hybridization (FISH), next-generation sequencer, DNA chip, and real-time quantitative PCR.
  • FISH fluorescence in situ hybridization
  • a method for improving, suppressing progression and / or treating an FGF4 gene-amplified tumor comprising administering the pharmaceutical composition according to any one of [1] to [3] to a subject in need.
  • [11] Detecting the gene amplification level of the FGF4 gene in the target tumor tissue sample or tumor cell sample, and effectively inhibiting the function or inhibiting the function of the FGF4 protein when the target FGF4 gene is amplified
  • a method for improving, suppressing progression and / or treating FGF4 gene-amplified tumor comprising administering a pharmaceutical composition as a component to the subject.
  • the ID of the primer used was HS01235235 # cn (Forward: 5'-GAG CAG CAA GGG CAA GCT CTA-3 ': SEQ ID No.1, Reverse: 5'-ACC TTC ATG GTG GGC GAC A-3': SEQ ID No.2).
  • TERT locus was used as an internal control (Forward: 5′-GCA CCG TCA AGGCTG AGA AC-3 ′: SEQ ID No. 3, Reverse: 5′-ATG GTG GTG AAG ACG CCA GT-3 ′: SEQ ID No .Four).
  • Human Genomic DNA (Clontech) was used as a normal control. The result is shown in FIG.
  • FIG. 1 is a graph showing an example of the results of measuring the FGF4 gene copy number of 194 esophageal cancer specimens.
  • the horizontal axis is the sample sample and is arranged in order of copy number.
  • the vertical axis represents the measured copy number.
  • the copy number of the FGF4 gene was 5 or more in about 40% of the esophageal cancer specimens.
  • the CGH method was performed using the trade name: Oncoscan, and FISH used a probe obtained from a human genomic clone library (GSP Laboratory, Kawasaki, Japan).
  • the FGF4 gene was introduced into the colon cancer cell line WiDr, the lung cancer cell line A549, and the esophageal cancer cell line KYSE-270 to prepare cell lines that overexpress the FGF4 protein.
  • the prepared FGF4 overexpressing strains are referred to as WiDr / FGF4, A549 / FGF4, and KYSE-270 / FGF4, respectively.
  • cell lines WiDr / EGFP, A549 / EGFP, and KYSE-270 / EGFP in which the EGFP gene was introduced and the EGFP protein was overexpressed were prepared as these controls. (Evaluation of tumorigenicity)
  • the prepared FGF4 overexpression strain was examined for tumorigenicity.
  • FIG. 2 is a graph showing an example of the results of measuring the tumor size of a cell line (WiDr / FGF4) over time when FGF4 gene is introduced into a colon cancer cell line WiDr and overexpressed in culture.
  • FIG. 3 is a graph showing an example of the results of measuring the tumor size of the cell line (A549 / FGF4) over time when the FGF4 gene was introduced into the lung cancer cell line A549 and overexpressed.
  • FIG. 4 shows an example of the results of measuring the tumor size of a cell line (KYSE-270 / FGF4) over time when the FGF4 gene was introduced into the cell line KYSE-270 of esophageal cancer and overexpressed. It is a graph to show. In any case, significant enhancement of tumor-forming ability was observed with respect to the control into which the EGFP gene was introduced. Moreover, these results show that the FGF4 gene can exert a function (oncogenic activity) as an oncogene.
  • a tumor-bearing mouse model in which the FGF4-overexpressing esophageal cancer cell line KYSE-270 / FGF4 was transplanted was prepared. Specifically, a mouse model was prepared by transplanting KYSE-270 / FGF4 cells subcutaneously into nude mice.
  • mice were divided into 2 groups of 4 mice, goat polyclonal IgG was administered to the control group, and anti-FGF4 antibody was administered intraperitoneally to the other group (5 mg / kg, 2 times / week, 2 weeks). . Tumor diameter and body weight were measured every few days.
  • FIG. 5 is a graph showing an example of the result of confirming the effect of the anti-FGF4 antibody on the tumor of KYSE-270 / FGF4 transplanted into a mouse.
  • the vertical axis represents the tumor size (mm 3 ), and the horizontal axis represents the culture time (days).
  • the vertical axis represents the mouse body weight (g), and the horizontal axis represents the culture time (days).
  • T / C 0.7
  • FIG. 6 is a graph showing an example of the results of confirming the effect of an FGFR inhibitor on the FGF4-overexpressing lung cancer cell line A549 / FGF4 transplanted into mice.
  • the vertical axis represents the tumor size (mm 3 ), and the horizontal axis represents the culture time (days).
  • the FGFR inhibitor showed significant antitumor activity.

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  • Endocrinology (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne, dans un ou plusieurs modes de réalisation, une composition médicinale pour une tumeur à gène FGF4 (facteur de croissance fibroblastique 4) amplifié. Dans un mode de réalisation, la présente invention concerne une composition médicinale pour améliorer une tumeur à gène FGF4 amplifié, inhiber sa progression et/ou la traiter, ladite composition médicinale comprenant comme principe actif au moins un élément choisi dans le groupe consistant en anticorps anti-FGF4, d'inhibiteur de récepteur de FGF, d'ARNsi FGF4 et d'ARNsh FGF4.
PCT/JP2014/074530 2013-10-03 2014-09-17 Composition médicinale pour tumeur à gène fgf4 amplifié WO2015049985A1 (fr)

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