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WO2004008137A2 - Methode de diagnostic et de traitement de tumeurs du sein resistant au traitement anti-estrogene - Google Patents

Methode de diagnostic et de traitement de tumeurs du sein resistant au traitement anti-estrogene Download PDF

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Publication number
WO2004008137A2
WO2004008137A2 PCT/EP2003/007449 EP0307449W WO2004008137A2 WO 2004008137 A2 WO2004008137 A2 WO 2004008137A2 EP 0307449 W EP0307449 W EP 0307449W WO 2004008137 A2 WO2004008137 A2 WO 2004008137A2
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WIPO (PCT)
Prior art keywords
locus
acc
protein
swissprot
human
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Application number
PCT/EP2003/007449
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English (en)
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WO2004008137A3 (fr
Inventor
Iduna Fichtner
Michael Becker
Vladimir Besada Perez
Serra Lila Castellanos
Original Assignee
Max-Delbrück-Centrum für Molekulare Medizin
Center For Genetic Engineering And Biotechnology (Cigb)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10310198A external-priority patent/DE10310198A1/de
Application filed by Max-Delbrück-Centrum für Molekulare Medizin, Center For Genetic Engineering And Biotechnology (Cigb) filed Critical Max-Delbrück-Centrum für Molekulare Medizin
Priority to AU2003253050A priority Critical patent/AU2003253050A1/en
Publication of WO2004008137A2 publication Critical patent/WO2004008137A2/fr
Publication of WO2004008137A3 publication Critical patent/WO2004008137A3/fr

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Classifications

    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity

Definitions

  • the invention is about a method to diagnose and therapy of breast tumours resistant to antiestrogen treatment by using specific target proteins and the nucleic acids encoding these proteins.
  • the method is based on the determination of the differential expression of specific target proteins on the level of nucleic acids and proteins in antiestrogen-resistant breast tumour cells. Fields of application exist in medicine and the pharmaceutical industry.
  • breast tumours are the most frequent type of cancer among women in the western industrialized countries.
  • the hormone-dependent growth of mammary tumours is mediated primarily by a nuclear steroid hormone receptor — the estrogen receptor (ER).
  • ER estrogen receptor
  • prognosis and treatment strategies are determined on account of the estrogen receptor status.
  • anti-hormone preparations are applied as an initial medication to these patients after surgical removal of the primary tumour.
  • the anti-hormones are supposed to competitively displace the natural ligands (estrogen) from the receptor and thus inhibit the hormone- mediated growth of the tumours.
  • Tamoxifen a non-steroidal antiestrogen
  • the adjuvant application to prevent the development of metastasis is in the centre of attention (Harris 1992).
  • tamoxifen therapy about one-third of the ER-positive tumours does not respond to tamoxifen therapy and a large number of patients develops resistance to the pharmaceutical drug in the course of treatment.
  • Resistance to tamoxifen comprises a significant clinical problem to this day and its molecular cause is still unknown.
  • the estrogen receptor itself is closely involved in the cellular transcription machinery. In the complex interaction with a large number of co-activator and co-repressor molecules it induces the expression of certain genes which, in turn, may be part of cellular signalling pathways.
  • the objective of the invention consisted in finding new marker proteins which could serve as a therapeutic or diagnostic target when breast tumours show antiestrogen therapy resistance .
  • the problem was solved by comparative investigations on a tamoxifen-sensitive mammary carcinoma xenograft (3366) and a tamoxifen-resistant sub- line (3366/TAM) created by a two-year treatment with tamoxifen (Naundorf et al., 2000). Proteins derived from tissue lysates of both tumour cell lines were examined by means of high-resolution two-dimensional (2D-) polyacrylamide gel-electrophoresis (examples are shown in Fig. 1).
  • Proteins expressed at higher levels in the resistant cell line Proteins expressed at higher levels in the resistant cell line:
  • Proteins expressed at lower levels in the resistant cell line • Glutamine hydrolysing GMP Synthase
  • target proteins With the aid of these proteins (referred to as target proteins in the following) it is possible to assess tumour resistance to antiestrogen therapy.
  • the objective of the invention is to create a method capable of assessing the resistance of breast tumour cells to antiestrogen therapy.
  • the method is characterized by the fact that the concentration of at least one target protein is determined in the tumour tissue and is compared with the standard reference value of the same protein or proteins in breast tumour cells sensitive to antiestrogen treatment, whereat a separate standard reference value is determined once for each protein. If the protein concentration in the sample examined lies above the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a protein which is expressed at higher levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
  • the protein concentration in the sample examined lies below the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a protein which is expressed at lower levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
  • Deteraiination of the protein concentration is performed by applying known immunobiological methods, preferentially the application of antibodies, such as Western blot, immunohistochemistry, ELISA, among others.
  • the invention comprises a test-kit to determine the concentrations of the target proteins in tumour samples.
  • the invention also includes the therapeutic application of target proteins for the treatment of breast tumours that are resistant to antiestrogen treatment.
  • nucleic acid sequences which are either identical or complementary to the cDNA sequences of the target proteins.
  • these nucleic acid sequences can be applied as primers in a method to evaluate the resistance of breast tumour cells to antiestrogen treatment, by determining the concentrations of nucleic acids encoding specific target proteins in the tumour tissue and comparing them with a standard reference value of the same nucleic acids in the breast tumour tissues that are sensitive to antiestrogen treatment, whereat a separate standard reference value is determined once for each nucleic acid fragment.
  • the concentration of the nucleic acid fragment in the sample examined lies above the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a nucleic acid segment which is expressed at a higher level in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment. If the concentration of the nucleic acid segment in the sample examined lies below the standard reference value, resistance of the tumour to antiestrogen treatment will be indicated, provided it is a nucleic acid segment which is expressed at lower levels in breast tumour cells resistant to antiestrogen treatment, as compared to breast tumour cells sensitive to antiestrogen treatment.
  • the invention includes the application of nucleic acid segments which are either identical with or complementary to the cDNA sequences of the target proteins, for example, in the in form of antisense oligonucleotides for the treatment of breast tumours resistant to antiestrogen therapy.
  • the invention includes the blocking of the synthesis of the target proteins on the level of RNA, preferentially by means of antisense oligonucleotides or ribozyme directed against the mRNA encoding these proteins.
  • This blocking is also possible, according to the invention, by means of specific antibodies directed against these proteins.
  • Fig. 1 Examples of comparative 2D gel electrophoresis
  • the images show the differential expression of selected proteins in three samples of tamoxifen-sensitive (above) and tamoxifen-resistant cell lines (below).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biotechnology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Toxicology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Oncology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne une méthode de diagnostic et de traitement de tumeurs du sein résistant à un traitement anti-estrogène, au moyen de protéines cibles spécifiques et des acides nucléiques codant pour ces dernières. Ladite méthode est basée sur la détermination de l'expression différentielle de gènes cibles spécifiques sur les acides nucléiques et du niveau de protéines dans des cellules de tumeurs du sein résistant au traitement anti-estrogène. Ladite méthode trouve des application en médecine et dans l'industrie pharmaceutique. Ladite méthode se caractérise en ce que la concentration d'au moins une protéine cible spécifique est déterminée dans le tissu de la tumeur et est comparée à la valeur de référence standard de la ou des mêmes protéines dans le tissu de tumeur du sein sensible au traitement anti-estrogène. Une concentration de protéine dans l'échantillon examiné supérieure à la valeur de référence standard indique une résistance de la tumeur au traitement anti-estrogène, s'il s'agit d'une protéine exprimée à des niveaux supérieurs dans des cellules de tumeur du sein résistant au traitement anti-estrogène, par rapport aux cellules de tumeur du sein sensibles au traitement anti-estrogène ; ou une concentration de protéine dans l'échantillon examiné inférieure à la valeur de référence standard indique la résistance de la tumeur au traitement anti-estrogène, s'il s'agit d'une protéine exprimée à un niveau inférieur dans les cellules de tumeur du sein résistant au traitement anti-estrogène, par rapport aux cellules de tumeurs du sein sensibles au traitement anti-estrogène.
PCT/EP2003/007449 2002-07-12 2003-07-10 Methode de diagnostic et de traitement de tumeurs du sein resistant au traitement anti-estrogene WO2004008137A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003253050A AU2003253050A1 (en) 2002-07-12 2003-07-10 Diagnosis and therapy of breast tumours resistant to antiestrogen treatment

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10231873 2002-07-12
DE10231873.5 2002-07-12
DE10310198A DE10310198A1 (de) 2002-07-12 2003-03-06 Verfahren zur Diagnose und Therapie von antiöstrogentherapieresistenten Brusttumoren
DE10310198.5 2003-03-06

Publications (2)

Publication Number Publication Date
WO2004008137A2 true WO2004008137A2 (fr) 2004-01-22
WO2004008137A3 WO2004008137A3 (fr) 2004-09-02

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PCT/EP2003/007449 WO2004008137A2 (fr) 2002-07-12 2003-07-10 Methode de diagnostic et de traitement de tumeurs du sein resistant au traitement anti-estrogene

Country Status (2)

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AU (1) AU2003253050A1 (fr)
WO (1) WO2004008137A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005123944A1 (fr) * 2004-06-18 2005-12-29 Roche Diagnostics Gmbh Utilisation de la proteine pdx1 comme marqueur pour le cancer du sein
WO2012100600A1 (fr) * 2011-01-24 2012-08-02 中国人民解放军第三军医大学 Utilisation d'anticorps spécifiques anti-peroxyrédoxine iv dans la préparation de réactifs diagnostiques in vitro pour la polyarthrite rhumatoïde de stade précoce

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001238700A1 (en) * 2000-02-22 2001-09-03 Board Of Regents, The University Of Texas System Compositions and methods of use of het, a novel modulator of estrogen action

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005123944A1 (fr) * 2004-06-18 2005-12-29 Roche Diagnostics Gmbh Utilisation de la proteine pdx1 comme marqueur pour le cancer du sein
WO2012100600A1 (fr) * 2011-01-24 2012-08-02 中国人民解放军第三军医大学 Utilisation d'anticorps spécifiques anti-peroxyrédoxine iv dans la préparation de réactifs diagnostiques in vitro pour la polyarthrite rhumatoïde de stade précoce

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Publication number Publication date
AU2003253050A1 (en) 2004-02-02
AU2003253050A8 (en) 2004-02-02
WO2004008137A3 (fr) 2004-09-02

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