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WO2017153869A1 - Procédé pour le diagnostic in vitro du cancer de la prostate à l'aide de biomarqueurs urinaires - Google Patents

Procédé pour le diagnostic in vitro du cancer de la prostate à l'aide de biomarqueurs urinaires Download PDF

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Publication number
WO2017153869A1
WO2017153869A1 PCT/IB2017/051177 IB2017051177W WO2017153869A1 WO 2017153869 A1 WO2017153869 A1 WO 2017153869A1 IB 2017051177 W IB2017051177 W IB 2017051177W WO 2017153869 A1 WO2017153869 A1 WO 2017153869A1
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Prior art keywords
seq
polypeptide
prostate cancer
urine sample
individual
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Ceased
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PCT/IB2017/051177
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English (en)
Inventor
Mirella GIOVARELLI
Sergio OCCHIPINTI
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Universita degli Studi di Torino
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Universita degli Studi di Torino
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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
    • G01N33/57434—Specifically defined cancers of prostate
    • 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
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • 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
    • G01N2333/475—Assays involving growth factors
    • G01N2333/49—Platelet-derived growth factor [PDGF]
    • 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
    • G01N2333/475—Assays involving growth factors
    • G01N2333/495—Transforming growth factor [TGF]
    • 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
    • G01N2333/475—Assays involving growth factors
    • G01N2333/51—Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • 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
    • G01N2333/52—Assays involving cytokines
    • G01N2333/521—Chemokines
    • 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
    • G01N2333/52—Assays involving cytokines
    • G01N2333/53—Colony-stimulating factor [CSF]
    • G01N2333/535—Granulocyte CSF; Granulocyte-macrophage CSF
    • 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
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • 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
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5412—IL-6
    • 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
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5421—IL-8

Definitions

  • the present invention concerns a method for in vitro diagnosis of prostate cancer by means of urinary biomarkers .
  • Prostate cancer represents the most common pathology and the second cause of tumour-related death for men worldwide.
  • diagnosis of prostate cancer is made only after histological evaluation of the tumour on several samples of prostate tissue taken by means of biopsy.
  • a prostate biopsy is advised following evaluation of the levels of the prostate-specific antigen (PSA) in circulation combined with digital rectal examination (DRE) .
  • PSA prostate-specific antigen
  • DRE digital rectal examination
  • PSA and DRE are preliminary examinations performed in order to identify patients who are most likely to have developed a prostate tumour.
  • a prostate biopsy is performed to confirm or disprove the clinical evidence.
  • the limited accuracy of these tests leads to a high number of over-diagnoses and consequently over- treatments.
  • only one individual is affected by prostate cancer after bioptic examination.
  • many of the prostate cancers diagnosed progress very slowly and may never give rise to symptoms during the patient's life.
  • the immune system is able to recognize the presence of prostate cancer and activate an inflammatory response.
  • the immune system cells that react and infiltrate the prostate cancer are very heterogeneous and can be located both inside and around the tumour mass, creating profound interactions that can have a significant effect on the disease.
  • soluble factors produced by the prostate tissue can modify the immune system cells, making them protumoral .
  • the urinary tract is in close contact with the prostate, following prostate massage the factors produced by the immune system cells infiltrating the prostate and by the prostate tissue itself can be released into and therefore detected in the urine, representing biological markers for diagnosis and prognosis of prostate cancer.
  • the biological markers are sought in samples of peripheral blood plasma or serum.
  • this approach is influenced by the fact that different cells in our body can produce the same molecules in pathological and non-pathological conditions.
  • prostate cancer biomarkers that can be detected in the urine instead of in the plasma or serum.
  • WO2011016031 describes the use of interleukin 13 (IL-13) or interleukin 1 beta (IL- ⁇ ) as biomarkers for prostate cancer in the urine.
  • IL-13 interleukin 13
  • IL- ⁇ interleukin 1 beta
  • the object of the present invention is therefore to provide a method for the in vitro diagnosis of prostate cancer in an individual by means of urinary biomarkers, which provide reliable accurate results rapidly and inexpensively.
  • said object is achieved by means of the method according to claim 1.
  • a kit is also provided according to claim 4.
  • FIG. 1 shows the graphs of the absolute values of the biomarkers interleukin 6 (IL-6), osteopontin (OPN) , vascular endothelial growth factor (VEGF) , transforming growth factor beta 1 (TGF- ⁇ ) and interleukin 1 beta (IL- ⁇ ) in individuals affected by prostate cancer and healthy individuals;
  • IL-6 interleukin 6
  • OPN osteopontin
  • VEGF vascular endothelial growth factor
  • TGF- ⁇ transforming growth factor beta 1
  • IL- ⁇ interleukin 1 beta
  • FIG. 2 shows the graphs of the values of the biomarkers IL-6, OPN, VEGF, TGF- ⁇ and IL- ⁇ normalized on the creatinine in individuals affected by prostate cancer and healthy individuals;
  • FIG. 3 shows the ROC (receiver operating characteristic) curve for the PSA (prostate specific antigen) ;
  • FIG. 4 shows the ROC curves for IL-6, OPN, VEGF, TGF- ⁇ and IL- ⁇ ;
  • FIG. 5 shows a multivariate analysis of the values of IL- 6, OPN, VEGF, and of IL-6, VEGF and TGF- ⁇ respectively;
  • FIG. 6 shows the graphs of the values of the biomarkers interleukin 17 (IL-17), granulocytes-monocytes colony simulating factor (GM-CSF) , Interferon gamma-induced protein 10 (IP-10), platelet-derived growth factor (PDGF) , Chemokine (C-C motif) ligand 5 (CCL5) , Eotaxin and interleukin 8 (IL-8) normalized on the creatinine in individuals affected by prostate cancer and healthy individuals;
  • IL-17 interleukin 17
  • GM-CSF granulocytes-monocytes colony simulating factor
  • IP-10 Interferon gamma-induced protein 10
  • PDGF platelet-derived growth factor
  • CCL5 Chemokine (C-C motif) ligand 5
  • Eotaxin and interleukin 8 (IL-8) normalized on the creatinine in individuals affected by prostate cancer and healthy individuals;
  • FIG. 7 shows the ROC curves for IL-17, GM-CSF, IP-10, PDGF, CCL5, Eotaxin and IL-8;
  • FIG. 8 shows the graphs of the values of the biomarkers GM-CSF, IL-6, OPN, PDGF-bb and CCL5 normalized on the creatinine in individuals affected by prostate cancer and healthy individuals;
  • FIG. 9 shows the ROC curves for GM-CSF, IL-6, OPN, PDGF-bb and CCL5;
  • FIG. 10 shows a multivariate analysis of the values of GM- CSF, IL-6, OPN, PDGF-bb and CCL5, and of GM-CSF, IL-6, OPN, and CCL5 respectively;
  • the polypeptide comprising SEQ ID NO: 1 (IL-6), the polypeptide comprising SEQ ID NO: 2 (osteopontin, OPN), the polypeptide comprising SEQ ID NO: 3 (VEGF), the polypeptide comprising SEQ ID NO: 4 (TGF- ⁇ ), the polypeptide comprising SEQ ID NO: 5 (IL-17), the polypeptide comprising SEQ ID NO: 6 (GM-CSF), the polypeptide comprising SEQ ID NO: 7 (IP-10), the polypeptide comprising SEQ ID NO: 8 (PDGF, also called PDGF-bb or PDGF-BB), the polypeptide comprising SEQ ID NO: 9 (CCL5) , the polypeptide comprising SEQ ID NO: 10 (Eotaxin), or the polypeptide comprising SEQ ID NO: 11 (IL-8) can be used as a biomarker for prostate cancer in a urine sample.
  • the method for in vitro diagnosis of prostate cancer in an individual according to the present invention comprises the following steps.
  • a urine sample of the individual is provided.
  • the urine sample is preferably obtained after performing a prostate massage on the patient.
  • a polypeptide comprising SEQ ID NO: 1 a polypeptide comprising SEQ ID NO: 2 and a polypeptide comprising SEQ ID NO: 3, or a polypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO: 2 and a polypeptide comprising SEQ ID NO: 4, or a polypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO: 2, a polypeptide comprising SEQ ID NO: 6 and a polypeptide comprising SEQ ID NO: 9, or a polypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO: 2, a polypeptide comprising SEQ ID NO: 6, a polypeptide comprising SEQ ID NO : 8 and a polypeptide comprising SEQ ID NO: 9.
  • polypeptides have SEQ ID NO:l, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO : 8 and SEQ ID NO : 9.
  • the quantification is performed by means of immunoassay, more preferably by means of ELISA (enzyme-linked immunosorbent assay), Luminex technology or biosensor.
  • immunoassay more preferably by means of ELISA (enzyme-linked immunosorbent assay), Luminex technology or biosensor.
  • the absolute value quantified is compared with a reference value.
  • the reference value corresponds to a typical value of an individual not affected by prostate cancer .
  • the method according to the present invention comprises the following steps.
  • a urine sample of the individual is provided.
  • the urine sample is preferably obtained after performing a prostate massage on the patient.
  • a polypeptide comprising SEQ ID NO: 1 a polypeptide comprising SEQ ID NO: 2 and a polypeptide comprising SEQ ID NO: 3, or a polypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO: 2 and a polypeptide comprising SEQ ID NO: 4, or a polypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO: 2, a polypeptide comprising SEQ ID NO: 6 and a polypeptide comprising SEQ ID NO: 9, or a polypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO: 2, a polypeptide comprising SEQ ID NO: 6, a polypeptide comprising SEQ ID NO : 8 and a polypeptide comprising SEQ ID NO: 9.
  • polypeptides have SEQ ID NO:l, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO : 8 and SEQ ID NO : 9.
  • the quantification is performed by means of immunoassay, more preferably by means of ELISA (enzyme-linked immunosorbent assay), Luminex technology or biosensor.
  • a molecule with molecular formula C 4 H 7 N 3 O is quantified in the urine sample.
  • the quantification is performed by means of immunoassay, enzymatic method or Jaffe method.
  • the quantified value of polypeptide comprising SEQ ID NO: 1, polypeptide comprising SEQ ID NO: 2 and polypeptide comprising SEQ ID NO: 3, or of polypeptide comprising SEQ ID NO: 1, polypeptide comprising SEQ ID NO: 2 and polypeptide comprising SEQ ID NO: 4, or a polypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO: 2, a polypeptide comprising SEQ ID NO: 6 and a polypeptide comprising SEQ ID NO: 9, or a polypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO: 2, a polypeptide comprising SEQ ID NO: 6, a polypeptide comprising SEQ ID NO: 8 and a polypeptide comprising SEQ ID NO: 9 is normalized with the quantified value of a molecule having molecular formula C 4 H 7 N 3 O (creatinine) .
  • the normalized value is compared with a reference value.
  • the reference value corresponds to a value typical of an individual not affected by prostate cancer.
  • the kit according to the present invention comprises:
  • the kit according to the present invention comprises :
  • the means for quantifying the polypeptides are preferably monoclonal antibodies.
  • Urine samples were collected from 39 patients aged between 52 and 80 who had been prescribed a prostate biopsy or re-biopsy.
  • PSA > 3 ng/ml and age ⁇ 65; PSA velocity > 07 ng/ml/year and age ⁇ 65; DRE suspect at any age; ultrasound or magnetic resonance examination suspect at any age; previous histological examination showing High Grade Prostate Intraepithelial Neoplasia (HGPIN) multifocal and/or Atypical Small Acinar Proliferation (ASAP) .
  • HGPIN High Grade Prostate Intraepithelial Neoplasia
  • ASAP Atypical Small Acinar Proliferation
  • the urine samples were collected after digital rectal examination and prostate massage consisting of 3 digital compressions in each lobe, starting from the base, towards the median part and the apex for 180 seconds. The sample was stirred and frozen in Falcon tubes at -80°C within 30 minutes from collection.
  • Creatinine is a substance produced by the body and excreted via the urine and its level is an indicator of the urine concentration. The higher the creatinine value, the greater the urine concentration. The lower the creatinine value, the greater the dilution of the urine .
  • kits were used for the simultaneous evaluation of 27 analytes: FGF basic, Eotaxin, G-CSF, GM-CSF, IFN- ⁇ , IL- ⁇ , IL-lra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, IP-10, MCP-1 (MCAF) , ⁇ - ⁇ , MIP- 1 ⁇ , PDGF-BB, CCL5, TNF- , VEGF (Bio-Rad Laboratories) .
  • Protease Inhibitors DDP-IV Inhibitor and Aprotinin, Sigma Aldrich were added to the urine samples and they were analysed pure and diluted 1:2 in PBS to evaluate the presence of inhibitor effects due to salts or urea.
  • the samples were read at two sensitivity levels. To do this, in addition to using the standard calibration curve indicated in the user' s manual, a high sensitivity calibration curve was also prepared (suitable for low concentrations) .
  • the high sensitivity reading is performed with a photomultiplier: the samples are first read with the photomultiplier and analysed with the high sensitivity curve and subsequently re-read using the instrument without photomultiplier and analysed with the low sensitivity curve.
  • the urine of 61 healthy individuals and 65 individuals with prostate tumour was analysed by means of Luminex technology for the presence of GM-CSF, IL-6, PDGF-BB, CCL5 (Bio-Rad Laboratories) and by means of ELISA for the presence of OPN.
  • the method according to the present invention represents a rapid and inexpensive way of obtaining a reliable diagnosis, avoiding invasive procedures.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
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  • Hospice & Palliative Care (AREA)
  • Food Science & Technology (AREA)
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  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un procédé pour le diagnostic in vitro du cancer de la prostate chez un individu, qui comprend les étapes consistant à : fournir un échantillon d'urine de l'individu ; quantifier dans l'échantillon d'urine des combinaisons spécifiques de polypeptides ; quantifier éventuellement dans l'échantillon d'urine une molécule ayant la formule moléculaire C4H7N3O (créatinine) et normaliser la valeur quantifiée des combinaisons de polypeptides ; comparer les valeurs absolues quantifiées des polypeptides ou les valeurs normalisées à des valeurs de référence correspondantes.
PCT/IB2017/051177 2016-03-07 2017-02-28 Procédé pour le diagnostic in vitro du cancer de la prostate à l'aide de biomarqueurs urinaires Ceased WO2017153869A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITUA2016A001418A ITUA20161418A1 (it) 2016-03-07 2016-03-07 Biomarcatori urinari per la diagnosi del carcinoma della prostata
IT102016000023626 2016-03-07

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WO2017153869A1 true WO2017153869A1 (fr) 2017-09-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113439212A (zh) * 2018-10-05 2021-09-24 美侬米克国际有限公司 用于确定侵袭性前列腺癌的生物标志物组合
IT202000029948A1 (it) * 2020-12-04 2022-06-04 Nib Biotec S R L Metodo per la diagnosi di tumore alla prostata in pazienti in differente fascia di età
US20220291221A1 (en) * 2019-05-02 2022-09-15 Belgian Volition Sprl Method for the detection of prostate cancer

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WO2008067065A2 (fr) * 2006-10-19 2008-06-05 Shiv Srivastava Procédés, kits et systèmes pour diagnostiquer et pronostiquer le cancer de la prostate en utilisant des biomarqueurs sécrétés
WO2011016031A2 (fr) * 2009-08-03 2011-02-10 Yeda Research And Development Co. Ltd. Biomarqueurs urinaires pour diagnostic du cancer

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113439212A (zh) * 2018-10-05 2021-09-24 美侬米克国际有限公司 用于确定侵袭性前列腺癌的生物标志物组合
EP3861348A4 (fr) * 2018-10-05 2022-07-20 Minomic International Ltd. Combinaisons de biomarqueurs pour déterminer le cancer agressif de la prostate
US20220291221A1 (en) * 2019-05-02 2022-09-15 Belgian Volition Sprl Method for the detection of prostate cancer
IT202000029948A1 (it) * 2020-12-04 2022-06-04 Nib Biotec S R L Metodo per la diagnosi di tumore alla prostata in pazienti in differente fascia di età

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