[go: up one dir, main page]

WO2002031500A2 - METHODE DE CLASSIFICATION ET DE DIAGNOSTIC DE CARCINOMES FONDEE SUR LA DETECTION DE IGF-IRss ET IRS-1 - Google Patents

METHODE DE CLASSIFICATION ET DE DIAGNOSTIC DE CARCINOMES FONDEE SUR LA DETECTION DE IGF-IRss ET IRS-1 Download PDF

Info

Publication number
WO2002031500A2
WO2002031500A2 PCT/DE2001/003988 DE0103988W WO0231500A2 WO 2002031500 A2 WO2002031500 A2 WO 2002031500A2 DE 0103988 W DE0103988 W DE 0103988W WO 0231500 A2 WO0231500 A2 WO 0231500A2
Authority
WO
WIPO (PCT)
Prior art keywords
igf
irs
irß
expression
level
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/DE2001/003988
Other languages
German (de)
English (en)
Other versions
WO2002031500A3 (fr
Inventor
Bernd Schnarr
Doris Mayer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Deutsches Krebsforschungszentrum DKFZ
Original Assignee
Deutsches Krebsforschungszentrum DKFZ
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
Application filed by Deutsches Krebsforschungszentrum DKFZ filed Critical Deutsches Krebsforschungszentrum DKFZ
Publication of WO2002031500A2 publication Critical patent/WO2002031500A2/fr
Publication of WO2002031500A3 publication Critical patent/WO2002031500A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/62—Insulins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/65—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2

Definitions

  • the present invention relates to a method for diagnosing and / or classifying carcinomas, preferably macarcinomas. This detection is preferably carried out using an anti-IGF-IR ⁇ and / or anti-IRS-1 antibody.
  • a reduced IRS-1 and / or IGF-IRß expression is a diagnostic sign of a low differentiated carcinoma (stage 3), while a high IRS-1 and / or IGF-IRß expression is a diagnostic sign of a good or moderately differentiated carcinoma (stages 1 and 2).
  • the present invention also relates to a kit containing anti-IRS1 and / or anti-IGF-IR ⁇ antibodies for carrying out the method according to the invention.
  • estrogen has been known as a mitogen for epithelial cells of the breast for decades, recent studies have also linked high insulin plasma levels (insulinemia due to obesity or type II diabetes) to "insulin like growth factor-I" (IGF- I) and an increased risk of breast cancer for pre-menopausal women. It has been shown that estrogen and IGF-I synergistically promote the growth of breast cancer cells and there is increasing evidence from in vitro studies for a complex mutual interaction of the systems of the two signal transmission pathways, which are triggered by estradiol and IGF-I.
  • Oestradiol increases by inducing the expression of IGF-I and the IGF-I receptor (IGF-IR) and by stimulating the phosphorylation and activation of IGF-IR and its downstream signal transmission molecules such as, for example, the insulin receptor substrate 1 (IRS -1) IGF-I signal transmission.
  • IGF-IR insulin receptor substrate 1
  • IGF-I signaling leads to phosphorylation and activation of the oes trogen receptor.
  • IGF-IR is a heterodimer consisting of two transmembrane- ⁇ subunits that show tyrosine kinase activity and two extracellular alpha chains that span the ligand binding domain. IGF-IR is activated by both IGF-I and insulin.
  • the insulin receptor is structurally closely related to the IGF-IR and is mainly activated by insulin and - to a lesser extent - by IGF-I.
  • Both the insulin receptor and IGF-I receptor kinases (IRS-1) are known to phosphorylate and activate, which is the key molecule activated by IGF-I and insulin signaling and a central "docking" protein represents that is involved in a large number of other signal transmission paths.
  • the expression of the ⁇ s trogen receptor has mainly been used as a prognostic marker in breast cancer and as a target for therapy, but it has been shown that the diagnostic findings obtained with this marker were often unreliable and also did not allow classification of breast tumors.
  • the present invention is therefore based on the technical problem of providing markers which allow an improved and more specific diagnosis or classification of carcinomas, in particular breast carcinomas, which may be necessary. the selection of the most appropriate therapeutic measures, e.g. surgical measures, facilitated.
  • IRS-1 and IGF-IRß are highly specific markers, especially in tissue sections, and, in addition to the diagnosis, above all allow classification of breast carcinomas.
  • cell proliferation Ki67-positive Nuclei
  • ER estrogen receptor
  • IGF-IRß While IRß-expression was low in all tissues examined, IRS-1 were found and IGF-IRß in control tissues and in well and moderately differentiated carcinomas expressed in high levels, but only in low levels in low-differentiated breast cancers.
  • Statistical analysis suggests that downregulation of IGF-IRß and IRS -1 correlated better with tumor progression than lowering ER expression or increasing cell proliferation, with IGF-IRß being the best correction lation showed followed by IRS-1 and, less significantly, ER or Ki67.
  • the present invention thus relates to a method for diagnosing and / or determining the differentiation stage of a carcinoma, which is characterized in that the IRS-1 and / or IGF-IR ⁇ level or level of the IRS-1 and / or IGF-IRß encoding mRNA is determined, the level of IRS-1 and / or IGF-IRß level or level of IRS-1 and / or IGF-IRß encoding mRNA being correlated with the differentiation stage of the carcinoma.
  • the method according to the invention is suitable in principle for the diagnosis / classification of any type of tumor, preferably of breast, liver and kidney carcinomas.
  • IRS-1 or IGF-IRß can be carried out using conventional methods, starting from the known amino acid equen z of the two proteins or the nucleic acid sequence of the corresponding genes (cf. EMBL databases).
  • the detection can relate to the transcription (detection of the concentration of the mRNA using standard methods, for example Northern blots, PCR, RT-PCR etc.) or the IRS-1 or IGF-IR ⁇ protein itself, the latter preferred is.
  • a lowered IRS-1 and / or IGF-IRß level is a diagnostic sign of a low differentiated carcinoma.
  • the term "reduced IRS-1 and / or IGF-IRß level” preferably refers to the IRS-1 or IGF-IRß level compared to a control sample, which is preferably from the same, but healthy tissue or organ comes.
  • a high IRS-1 and / or IGF-IRß level is a diagnostic sign of a well or moderately differentiated carcinoma.
  • the expression "high IRS-1 and / or IGF-IRß level” preferably refers to the IRS-1 or IGF-IRß level compared to a control sample, which is preferably from the same, but healthy tissue or organ comes. The level is just as high or higher compared to the control sample.
  • the patient sample is a tissue section which can be produced by generally customary methods, e.g. as indicated in Example 1 below.
  • the IRS-1 and / or IGF-IRß level is determined by bringing the patient sample into contact with an anti-IRSl and / or anti-IGF-IRß antibody and then determined to what extent the anti-IRSl and / or anti-IGF-IR ⁇ antibodies bound to the patient sample.
  • the suitable antibodies can be monoclonal, polyclonal or synthetic antibodies or fragments thereof.
  • fragment means all parts of the antibody (e.g. Fab, Fv or "single chain Fv” fragments) which have the same epitope specificity as the complete antibody. The production of such fragments is known to the person skilled in the art.
  • the antibodies according to the invention are preferably polyclonal or monoclonal antibodies.
  • the antibodies according to the invention can be produced according to standard methods, preferably using IRS-1 or IGF-IR ⁇ or synthetic fragments thereof as an immunogen. These polypeptides or peptides or the fragments thereof can e.g. by generating the appropriate gene, cloning and recombinant expression. Methods for obtaining polyclonal or monoclonal antibodies are known to the person skilled in the art.
  • Antibodies suitable for the diagnostic expiration according to the invention are also commercially available; see the information in Example 1 below.
  • the IRS-1 and / or IGF-IRß level is controlled via a primary polyclonal or monoclonal anti-IRS-1 antibody and / or anti-IGF-IRß antibody and a secondary antibody and alkaline-phosphatase-anti-alkaline-phosphatase complex (APAAP). Detection systems with peroxidase or fluorescent dye labels are also to be mentioned.
  • APAAP alkaline-phosphatase-anti-alkaline-phosphatase complex
  • the detection of the binding of the antibody (s) can be carried out using conventional methods, e.g. immunohistochemical methods, Western blot, ELISA, radioimmunoassay (RIA) etc., with immunohistochemical methods being preferred.
  • kits suitable for the Diagnostic or classification methods according to the invention are useful and preferably contain an anti-IRSl and / or anti-IGF-IR ⁇ antibody and optionally also IRS-1 or IGF-IR ⁇ or a binding-active part thereof for control purposes.
  • binding-active part denotes a fragment that reacts with the antibody, with which the whole molecule also reacts.
  • the antibody can be conjugated to a further unit, for example a label and / or it can be immobilized on a solid support (substrate).
  • the kit can also contain a second antibody for the detection of anti-IRS-1 or anti-IR ⁇ -antibody complexes.
  • the antibody or fragment thereof can be free or immobilized on a solid support, for example a plastic dish, a test tube, a microtiter plate, a test stick etc.
  • the kit can also contain instructions on how to use the antibodies in the tumor classification assay describe.
  • the kit can also contain suitable reagents for the detection of labels or for labeling positive and negative controls, washing solutions, dilution buffers etc.
  • FIG. 1 Expression of the insulin receptor substrate 1 (IRS-1) and the “insulin-like growth factor-1 receptor-ß (IGF-IRß) in normal breast tissue and in breast cancer
  • AC Lobulus from normal breast tissue.
  • DF Part of a well-differentiated ductal carcinoma (arrows) surrounded by connective tissue.
  • GI low differentiated ductal carcinoma.
  • A, D, G cuts stained with hematoxilin & eosin (H&E).
  • AC Lobulus, the strong expression of IRS-1 (B) and a shows somewhat less stressed expression of IGF-IRß (c) in all epithelial cells.
  • DF stage 1 carcinoma (arrows) with strong expression of IRS-1 (E) and moderate to strong Expression of IGF-IRß (F).
  • GI stage 3 carcinoma with poor expression of IRS-1 (H) and IGF-IRß (I).
  • K In some tumors, IRS-1 showed a noticeable perinuclear accumulation (arrows).
  • the specificity of the immunohistochemical assay was demonstrated by replacing the antibody against rabbit IgG () and pre-incubating the antibody against IRS-1 with the immunizing peptide (M, adsorption control).
  • the cuts used in L and M are serial cuts to K.
  • the data points are randomly scattered to make the individual results more visible.
  • Tumor stages are characterized as stage 3 tumors (closed circles) and stage 1 or stage 2 tumors (open circles).
  • Estrogen receptor (ER) dotted line.
  • FIG. 3 Expression of IRS-1 and IGF-IRß in Lvsaten of human breast cancer tissue detected by Western blots lanes 1-4: stage 2 carcinomas; Lanes 5-8: stage 3 carcinomas (20 ⁇ g protein per lane). Note the high variation in protein expression among tumors of the same stage.
  • Figure 4 Pattern of tyrosine phosphorylation in four different stage 3 breast cancer samples
  • the samples correspond to the samples shown in FIG. 3.
  • 20 ⁇ g protein were separated electrophoretically, blotted and incubated with antibodies specific for phosphotyrosine. Note the high variation in the Tyrosine phosphorylation.
  • the band migrating at approximately 170 kDa was identified as IRS-1.
  • Table 1 Patient characteristics and clinical parameters of examined breast tissue and breast cancer
  • a This group included tubular cancer, mixed ductal-tubular cancer and 4 mixed lobular-ductal cancers.
  • Sections of frozen samples were stained with 0.1% toluidine blue and examined for the presence of tumor tissue.
  • Serial sections were freeze-dried and lysed in a buffer containing 50 mM Hepes (pH 7.1), 150 mM NaCl, 1.5 mM MgCl 2 , 1% Nonidet P-40, 10% Glycerin, 10 M Na 4 P 2 0 7 , 5 mM EDTA, 1 M phenylmethylsulfonyl fluoride, 1 ⁇ g / ml aprotinin, 1 ⁇ g / ml antipain, 1 ⁇ g / ml leupeptin, 1 ⁇ g / ml Pepstatin, 1 mM Na 3 V0 4 and 1 mM NaF contained.
  • the membranes were then treated with 3% BSA in TBST (10 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.1% Tween-20) for 1 hour, with 1 ⁇ g / ml primary polyclonal rabbit anti - IRS-1, -anti-IGF-IRß, -anti-IRß (Santa Cruz, Heidelberg, Germany) and -anti-Phosphotyrosin (Zy ed Laboratories, San Francisco, CA, USA) 30 min. At room temperature and at 4 ° C incubated overnight.
  • TBST 10 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.1% Tween-20
  • the secondary antibody was horseradish peroxidase (POD) labeled goat anti-rabbit IgG (Dianova, Hamburg, Germany) and immunoreactive bands were detected using the "ECLplus” system from Amersham Pharmacia Biotech (Freiburg, Germany). Protein loading was checked by staining the membrane with Ponceau.
  • POD horseradish peroxidase
  • Paraffin sections (3 ⁇ g thick) were dewaxed with xylene and transferred to an aqueous medium using a graduated series of ethanol incubations. The slides were immersed in boiling 0.01 M citrate buffer (pH 6.0) for 10-15 minutes to expose the antigen.
  • the slides were coated with 5 ⁇ g / ml anti-IRS-1, 10 ⁇ g / ml anti-IRß, 10 ⁇ g / ml anti IGF-IR ⁇ or 7.5 ⁇ g / ml anti-estrogen receptor (ER; Santa Cruz, Heidelberg, Germany) antibodies were incubated for 30 minutes at room temperature, followed by a further incubation (24 hours, 4 ° C.).
  • DAKO Diagnostika GmbH, Hamburg, Germany
  • the specificity of the immune response was verified by replacing the primary antibody with 5 ⁇ g / ml affinity-purified rabbit IgG (Dianova, Hamburg, Germany).
  • a liquid adsorption control was carried out by pre-incubating the ant i - IRS - 1 antibody with the corresponding peptide used for immunization (Santa Cruz, Heidelberg, Germany) at a ratio of 1:20 mg / mg (3 hours, room temperature ) carried out.
  • the solid phase adsorption control was carried out by binding the immunizing peptide to nitrocellulose powder and incubating the antibody with the bound peptide. After centrifugation, the supernatant was used for immunohistochmia.
  • the proliferation of the tissue was checked by immunohistochemical detection of Ki67 expression, the antibody used was MIB-1 (Dianova, Hamburg, Germany). To determine the percentage of Ki67-positive cells, at least 1000 cell nuclei per section were subjected to an evaluation.
  • insulin receptor substrate insulin receptor substrate
  • IRß insulin-ß-receptor
  • IGF-IR-ß insulin-like growth factor-I receptor-ß
  • ER estrogen receptor
  • the rating is the sum of the intensity of ER expression and the percentage of labeled cells. E ER not determined in 9 controls.
  • ROC Receiveiver Operating Characteristic
  • the age was recorded as a covariable together with the IRS-1, IGF-IRß and IRß expression (O rd i na lmesss tb), ER expression (dichotomized) and log10-transformed values of Percentage of Ki67 positive nuclei included as possible diagnostic factors.
  • a backward selection method was used to find relevant combinations of factors (Harreil, Predicting outcomes, applied survival analysis and logistic regression. University of Virginia, 1998, 1-610).
  • the model was validated using "bootstrap resampling" (Harreil, see above).
  • Classification and regression trees (CART; Breiman et al., Classification and Regression Trees. Belmont, CA.
  • Wadsworth, Inc., 1984, 1-358 have also been used to find combinations of diagnostic markers for distinguishing between poorly differentiated and high or moderate differentiated tumors used.
  • CART allows the interaction effects between the markers to be analyzed.
  • the trees are grown using recursive partitioning. At each level that corresponds to a maximum selected test statistic that is related to the splits based on each marker, an intersection is selected for splitting a group into two sub-groups.
  • the P-value was adjusted according to Lausen et al. (Classification and regression trees (CART) for the exploration of prognostic factors measured on different scales. In: Computational Statistics. Edited by Dirschedl, Ostermann, Heidelberg: Physica Verlag 1994, 4834-496).
  • Example 2 Determination of IGF-IR ⁇ , IRS-1 and IRß expression and the rate of proliferation in normal tissue
  • IGF-IRß was expressed in luminal and myoepithelial cells of the glandular lobes and milk ducts, the cells showed a moderate to strong staining of the membrane and usually also of the cytoplasm. In some cases the nuclei of the glandular epithelial cells were positive. Here, all cells of a single duct or groups of duct showed a signal in the nucleus, while other ducts were negative with regard to the nuclear staining, which excludes fixation or staining artifacts. IRS-1 was strongly to moderately expressed in the cytoplasm of cells of the glandular epithelium and myoepithelium of the ducts as well as of Acinus cells, positive nuclei were sometimes observed.
  • IRS-1 and IGF-IRß were also expressed in single stroma cells and in blood vessels. Typical expression patterns of IRS-1 and IGF-IR ⁇ in a lobule are shown in Figures 1B and C. IRß was poorly expressed in the duct and lobule of normal tissues. Expression patterns in samples from benign breast disease were no different from those in normal breast. The intensity assessment data is shown in Table 2. The mean age of the controls with surgical breast reduction was 28 years (range: 16-60 years), that of the controls with benign breast disease 41 (range: 22-53 years). There was no significant difference in the intensity of IRS-1 and IGF-IRß expression in the two groups and no age-related changes. The wide range observed with IRS-1 and IGF-IRß expression in control tissue was in each case due to one case.
  • IGF-IRß and IRS-1 were significantly down-regulated in weakly differentiated carcinomas (stage 3) of both ductal ( Figures 1H and I) and lobular origin. Some of the poorly differentiated tumors were even negative for both IGF-IRß (3/29) and IRS-1 (3/29). Other tumors showed a clear micro-heterogeneity of IRS-1 expression, with some areas being positive and others being negative. These were classified according to the most predominant pattern or intermediate ratings were assigned if coherent tumor masses with different intensities of expression were observed. The expression of IRß was weak in all tumors examined and did not change significantly as the disease progressed. Some carcinomas (6/69) were completely negative. The data are summarized in Table 2.
  • FIG. 2A shows a scatter diagram of IRS-1, IGF-IR ⁇ and the classification of all examined tumors.
  • the CART model allowed a "first level cut-off" of 1.00 (p cor ⁇ 0.001) for IGF-IRß and 1.25 (p cor ⁇ 0.008) for IRS-1 for stage 1 / stage 2 or Stage 3 tumors.
  • stage 1 and stage 2 tumors can be assigned to one group, while stage 3 tumors form another group.
  • the significance of the correlation of the IRS-1 / IGF-IRß expression and classification is not further improved by the addition of the data regarding ER expression, proliferation rate or age.
  • FIG. 2B shows a graphic estimate of the sensitivity and specificity of IGF-IR ⁇ , IRS-1 and ER as markers for the classification (ROC analysis). It is evident that IGF-IR ⁇ expression is the best marker for tumor classification, followed by IRS-1. ER expression is less significant. The contribution of Ki67 was comparable to that of ER.
  • the area under the ROC curve (AUC) describes the ability of the different markers to differentiate between highly or moderately differentiated tumors and weakly differentiated tumors. The best result was obtained for IGF-IRß, which is also statistically significantly different from the areas estimated for IRß and ER expression.
  • FIG. 3 shows expression of IRS-1 and IGF-IR ⁇ in four stage 2 carcinomas and 4 stage 3 tumors using the same antibody as used for immunohistochemistry.
  • the intensity of the bands showed a marked variation and sometimes did not match the intensity of the protein expression observed via immunohistochemistry, which was mainly due to different amounts of stromal tissue and fat in the samples. Different patterns of protein phosphorylation were detected by anti-phosphotyrosine immunoblot analysis.
  • FIG. 4 shows the phosphotyrosine pattern of four different stage 3 tumors.
  • the band migrating at approximately 170 kDa corresponds to IRS-1 (demonstrated by renewed incubation of the membrane with the corresponding antibody).
  • the intensity of the protein bands did not correlate with the intensity of the tyrosine phosphorylation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • Biotechnology (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne une méthode de diagnostic et/ou de classification de carcinomes, de préférence de carcinomes mammaires. Cette détection s'effectue de préférence par l'intermédiaire d'un anticorps anti-IGF-IRß et/ou anti-IRS-1. Une expression faible de IRS-1 et/ou de IGF-IRß constitue un signe diagnostique d'un carcinome peu différencié (stade 3), tandis qu'une expression élevée de IRS-1 et/ou de IGF-IRß constitue un signe diagnostique d'un carcinome bien ou modérément différencié (stades 1 et 2).
PCT/DE2001/003988 2000-10-11 2001-10-10 METHODE DE CLASSIFICATION ET DE DIAGNOSTIC DE CARCINOMES FONDEE SUR LA DETECTION DE IGF-IRss ET IRS-1 Ceased WO2002031500A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2000150338 DE10050338A1 (de) 2000-10-11 2000-10-11 Auf dem Nachweis von IGF-IRbeta und IRS-1 beruhendes Diagnose- bzw. Klassifizierungsverfahren für Carcinome
DE10050338.1 2000-10-11

Publications (2)

Publication Number Publication Date
WO2002031500A2 true WO2002031500A2 (fr) 2002-04-18
WO2002031500A3 WO2002031500A3 (fr) 2002-08-08

Family

ID=7659405

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2001/003988 Ceased WO2002031500A2 (fr) 2000-10-11 2001-10-10 METHODE DE CLASSIFICATION ET DE DIAGNOSTIC DE CARCINOMES FONDEE SUR LA DETECTION DE IGF-IRss ET IRS-1

Country Status (2)

Country Link
DE (1) DE10050338A1 (fr)
WO (1) WO2002031500A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7217796B2 (en) 2002-05-24 2007-05-15 Schering Corporation Neutralizing human anti-IGFR antibody
US7326567B2 (en) 2003-11-12 2008-02-05 Schering Corporation Plasmid system for multigene expression
US7811562B2 (en) 2004-12-03 2010-10-12 Schering Corporation Biomarkers for pre-selection of patients for anti-IGF1R therapy
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5798266A (en) * 1996-08-27 1998-08-25 K-Quay Enterprises, Llc Methods and kits for obtaining and assaying mammary fluid samples for breast diseases, including cancer
DE19739360C2 (de) * 1997-09-09 1999-12-09 Deutsches Krebsforsch Verfahren zur Diagnose von frühen Krebsvorstufen der Leber und Niere

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7217796B2 (en) 2002-05-24 2007-05-15 Schering Corporation Neutralizing human anti-IGFR antibody
US7326567B2 (en) 2003-11-12 2008-02-05 Schering Corporation Plasmid system for multigene expression
US8062886B2 (en) 2003-11-12 2011-11-22 Schering Corporation Plasmid system for multigene expression
US7811562B2 (en) 2004-12-03 2010-10-12 Schering Corporation Biomarkers for pre-selection of patients for anti-IGF1R therapy
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r

Also Published As

Publication number Publication date
DE10050338A1 (de) 2002-04-25
WO2002031500A3 (fr) 2002-08-08

Similar Documents

Publication Publication Date Title
EP2097754B2 (fr) Her3 activé servant de marqueur pour prédire l'efficacité thérapeutique
Schlegel et al. Immunoperoxidase localization of keratin in human neoplasms: a preliminary survey
KR101976219B1 (ko) 유방암의 바이오마커
DE19829473A1 (de) Verfahren zur frühen Diagnose von Carcinomen
WO2011039289A1 (fr) Séquences de marqueurs pour affections cancéreuses du pancréas, carcinome pancréatique et leur utilisation
Fox et al. Oestrogen receptor and epidermal growth factor receptor expression in male breast carcinoma
EP1493034B1 (fr) Methode pour diagnostiquer des maladies inflammatoires et des infections par determination de lasp-1-immunoreactivite
WO2002031500A2 (fr) METHODE DE CLASSIFICATION ET DE DIAGNOSTIC DE CARCINOMES FONDEE SUR LA DETECTION DE IGF-IRss ET IRS-1
WO2010000874A2 (fr) Séquences de marqueurs pour maladies inflammatoires de la prostate, le cancer de la prostate, et leurs utilisations
DE102007034993A1 (de) Lösliches Cadherin 17 für die Diagnose und Risikostratifizierung von Darmtumor oder Darmkrebs
EP1906999A1 (fr) Frizzled 9 en tant que marqueur tumoral
WO2003048776A1 (fr) Procede de diagnostic de la septicemie par determination de la quantite de ca 125
DE602004005859T2 (de) Verwendung des proteins crabp ii (cellular retinoic acid-binding protein ii) als marker für brustkrebs
WO2012041494A1 (fr) Diagnostic différentiel d'adénomes du pancréas
Detta et al. Rapid estimation of the proliferating index of brain tumours
DE3879684T2 (de) Von protein ps2 abgeleitete peptide.
WO2003056341A2 (fr) Methode de diagnostic de cancers du sein, peptides associes et leurs utilisations
DE19739360C2 (de) Verfahren zur Diagnose von frühen Krebsvorstufen der Leber und Niere
DE60221151T2 (de) Verfahren zur bestimmung der prognose von krebspatienten mittels tucan
JPWO2018101328A1 (ja) 診療補助情報の取得方法
DE102010018736A1 (de) Thyroidhormonrezeptorexpression zur Diagnose und Prognose von Brustkrebs und Eierstockkrebs
AT505003B1 (de) Antikörper verwendbar für die therapie und diagnose von krebs
DE10300861A1 (de) Verwendung von an FABP4 bindenden Substanzen zur Diagnose und Behandlung des Harnblasenkarzinoms
DE3940209A1 (de) Verfahren zum nachweis eines kleinzelligen bronchial-karzinoms
AT505028B1 (de) Neuer antikörper gegen ein retrovirales epitop

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP