WO2013116742A1 - Prédiction de réponses à une thérapie par privation androgénique et procédés pour traiter le cancer de la prostate - Google Patents

Prédiction de réponses à une thérapie par privation androgénique et procédés pour traiter le cancer de la prostate Download PDF

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WO2013116742A1
WO2013116742A1 PCT/US2013/024465 US2013024465W WO2013116742A1 WO 2013116742 A1 WO2013116742 A1 WO 2013116742A1 US 2013024465 W US2013024465 W US 2013024465W WO 2013116742 A1 WO2013116742 A1 WO 2013116742A1
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polypeptide
elevated level
level
prostate cancer
androgen deprivation
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PCT/US2013/024465
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English (en)
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Manish Kohli
Ann L. Oberg
Douglas W. Mahoney
Roman M. ZENKA
Yuji ZHANG
Sheng Zhang
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Mayo Foundation For Medical Education And Research
Cornell University
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/743—Steroid hormones
    • 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

  • This document relates to methods and materials involved in predicting whether a prostate cancer patient is likely to respond to an androgen deprivation therapy for a prolonged time period. For example, this document provides methods and materials for predicting whether or not a prostate cancer patient is likely to respond to an androgen deprivation therapy for a prolonged time period (e.g., greater than three years) based at least in part on the presence of an elevated level of 17-P-estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, a reduced level of a zinc alpha-2 macroglobulin polypeptide, or a combination thereof.
  • Prostate cancer occurs when a malignant tumor forms in the tissue of the prostate.
  • the prostate is a gland in the male reproductive system located below the bladder and in front of the rectum.
  • the main function of the prostate gland which is about the size of a walnut, is to make fluid for semen.
  • This type of cancer is known as adenocarcinoma.
  • Prostate cancer is the second leading cause of cancer-related death in American men. Most of the time, prostate cancer grows slowly. Autopsy studies show that many older men who died of other diseases also had prostate cancer that neither they nor their doctor were aware of. Sometimes, however, prostate cancer can grow and spread quickly.
  • PSA serum prostate specific antigen
  • ADT continuous androgen deprivation therapy
  • LHRH luteinizing hormone-releasing hormone
  • This document provides methods and materials for predicting whether a prostate cancer patient is likely to respond to an androgen deprivation therapy for a prolonged period of time. For example, this document provides methods and materials for predicting whether or not a prostate cancer patient is likely to respond to an androgen deprivation therapy for a prolonged period of time based at least in part on the presence of an elevated level of 17-P-estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, a reduced level of a zinc alpha-2 macroglobulin polypeptide, or a combination thereof.
  • the presence of an elevated level of 17- ⁇ - estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, or a reduced level of a zinc alpha-2 macroglobulin polypeptide within a serum sample obtained after androgen deprivation therapy can indicate that the cancer patient is likely to respond to the androgen deprivation therapy for a prolonged period of time (e.g., greater than about 15 months).
  • Having the ability to identify prostate cancer patients that are likely to respond to an androgen deprivation therapy can allow doctors and patients to proceed with appropriate treatment options. For example, a patient identified as having an elevated level of 17-P-estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, a reduced level of a zinc alpha-2 macroglobulin polypeptide, or a combination thereof within a serum or blood sample obtained after androgen deprivation therapy can be instructed to rely on the androgen deprivation therapy.
  • a patient identified as not having an elevated level of 17-P-estradiol, as not having an elevated level of estrone, as not having an elevated level of a neuropilin-2 polypeptide, and as not having a reduced level of a zinc alpha-2 macroglobulin polypeptide within a serum sample obtained after androgen deprivation therapy can be instructed to consider additional therapies other than androgen deprivation alone such as therapies such as chemotherapy, abiraterone acetate, and TAK-700 (Orteronel).
  • one aspect of this document features a method for identifying a prostate cancer patient likely to respond to androgen deprivation therapy.
  • the method comprises (a) detecting, in a sample obtained from the patient after receiving the androgen deprivation therapy, the presence of an elevated level of 17-P-estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, a reduced level of a zinc alpha-2 macroglobulin polypeptide, or a combination thereof, and (b) classifying the patient as being likely to respond to the androgen deprivation therapy without failure for a time greater than about 20 months based at least in part on the presence.
  • the prostate cancer patient can be a human.
  • the method can comprise detecting the presence of an elevated level of 17-P-estradiol.
  • the method can comprise detecting the presence of an elevated level of estrone.
  • the method can comprise detecting the presence of an elevated level of a neuropilin-2 polypeptide.
  • the method can comprise detecting the presence of a reduced level of a zinc alpha-2 macroglobulin polypeptide.
  • this document features a method for identifying a prostate cancer patient unlikely to respond to androgen deprivation therapy.
  • the method comprises (a) detecting, in a sample obtained from the patient after receiving the androgen deprivation therapy, the absence of an elevated level of 17-P-estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, and a reduced level of a zinc alpha-2 macroglobulin polypeptide, and (b) classifying the patient as being unlikely to respond to the androgen deprivation therapy without failure for a time greater than about 20 months based at least in part on the absence.
  • the prostate cancer patient can be a human.
  • this document features a method for treating a prostate cancer patient.
  • the method comprises, or consists essentially of, (a) detecting, in a sample obtained from the patient after receiving an androgen deprivation therapy, the absence of (i) an elevated level of 17-P-estradiol, (ii) an elevated level of estrone, (iii) an elevated level of a neuropilin-2 polypeptide, (iv) a reduced level of a zinc alpha-2 macroglobulin polypeptide, or (v) a combination thereof, and (b) administering abiraterone acetate, enzalutamide, or orteronel to the patient, thereby treating prostate cancer.
  • the prostate cancer patient can be a human.
  • the method can comprise detecting the absence of an elevated level of 17-P-estradiol.
  • the method can comprise detecting the absence of an elevated level of estrone.
  • the method can comprise detecting the absence of an elevated level of a neuropilin-2 polypeptide.
  • the method can comprise detecting the absence of a reduced level of a zinc alpha-2 macroglobulin polypeptide.
  • the method can comprise detecting the absence of (i) an elevated level of 17-P-estradiol, (ii) an elevated level of estrone, (iii) an elevated level of a neuropilin-2 polypeptide, and (iv) a reduced level of a zinc alpha-2 macroglobulin polypeptide.
  • the method can comprise administering abiraterone acetate to the patient.
  • the method can comprise administering enzalutamide to the patient.
  • the method can comprise administering orteronel to the patient.
  • Figure 1 is a diagram of the overall workflow for Example 1.
  • Figure 2 is a table of the cohort demographics.
  • Figure 3 is a Venn diagram of the differentially expressed polypeptides.
  • Figure 4 is a graph plotting the follow-up time (years) vs. the change in neuropilin-2 polypeptide expression for patients with or without recurrence.
  • Figure 5 is a graph plotting the follow-up time (years) vs. the change in zinc alpha-2 macroglobulin polypeptide expression for patients with or without recurrence.
  • Figure 6 is a graph plotting the change in PSA levels vs. the change in neuropilin- 2 polypeptide expression for patients with or without recurrence.
  • ⁇ post-AA vs. pre- AA levels.
  • the median ⁇ change is represented by dashed vertical line.
  • Figure 7 is a graph plotting the change in PSA levels vs. the change in zinc alpha- 2 macroglobulin polypeptide expression for patients with or without recurrence.
  • ⁇ post-AA vs. pre-AA levels.
  • the median ⁇ change is represented by dashed vertical line.
  • Figure 8 includes scatter plot graphs.
  • Figure 9 is a Venn diagram showing the number of polypeptides significant with FDR (False Discover Rate) ⁇ 0.2 and the number in common between each of the three comparisons performed.
  • Figure 10 is a plot of pathway enrichment network results of 47 polypeptides after comparing Post-ADT proteome with failure proteome (from the Venn diagram (areas G + C of Figure 9) showing beta estradiol (toward the left of center) as a gene implicated in the pathway network analysis (P value less than 10E-30 considered significant).
  • the single starred items signify a decrease in polypeptide expression in the comparison, and the double starred items signify an increase in polypeptide expression.
  • This document provides methods and materials for predicting whether or not a prostate cancer patient is likely to respond to an androgen deprivation therapy based at least in part on the presence of an elevated level of 17-P-estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, a reduced level of a zinc alpha-2 macroglobulin polypeptide, or a combination thereof.
  • a mammal e.g., a human that has an elevated serum level of 17-P-estradiol, an elevated serum level of estrone, an elevated serum level of a neuropilin-2 polypeptide, a reduced serum level of a zinc alpha-2 macroglobulin polypeptide, or a combination thereof following androgen deprivation therapy can be classified as being likely to respond to the androgen deprivation therapy for a prolonged period of time.
  • the prolonged period of time can be greater than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 months.
  • the prolonged period of time can be between about 20 and 30 months.
  • a human prostate cancer patient having an elevated serum level of 17-P-estradiol, an elevated serum level of estrone, an elevated serum level of a neuropilin-2 polypeptide, a reduced serum level of a zinc alpha-2 macroglobulin polypeptide, or a combination thereof at least about three months after having received an androgen deprivation therapy can be classified as being likely to respond to the androgen deprivation therapy for a prolonged period of time.
  • a human prostate cancer patient lacking (a) an elevated serum level of 17- ⁇ - estradiol, (b) an elevated serum level of estrone, (c) an elevated serum level of a neuropilin-2 polypeptide, and (d) a reduced serum level of a zinc alpha-2 macroglobulin polypeptide at least about three months after having received an androgen deprivation therapy can be classified as being unlikely to respond to the androgen deprivation therapy for a prolonged period of time.
  • Examples of androgen deprivation therapy include, without limitation, chemical castrations (e.g., treatments with LHRH-analogues or gonadotrophin-releasing hormone (GnRH) antagonists) and physical castrations.
  • chemical castrations e.g., treatments with LHRH-analogues or gonadotrophin-releasing hormone (GnRH) antagonists
  • physical castrations e.g., physical castrations.
  • a neuropilin-2 polypeptide can be a human neuropilin-2 polypeptide and can have the amino acid sequence set forth in GenBank ® accession number NP 957718.1 (GenBank ® GI number 41872562).
  • a zinc alpha-2 macroglobulin polypeptide can be a human zinc alpha-2 macroglobulin polypeptide and can have the amino acid sequence set forth in GenBank ® accession number NP 001176.1 (GenBank ® GI number 4502337).
  • any appropriate method can be used to detect the level of 17-P-estradiol, estrone, a neuropilin-2 polypeptide, or a zinc alpha-2 macroglobulin polypeptide within a serum or blood sample.
  • gas chromatography or ELISA techniques can be used to determine the level of 17-P-estradiol or estrone within a sample (e.g., a serum or blood sample).
  • ELISAs immunocytochemistry, flow cytometry, Western blotting, proteomic, and mass spectrometry techniques can be used to assess polypeptide levels (e.g., neuropilin-2 polypeptide or zinc alpha-2 macroglobulin polypeptide levels) within a sample (e.g., a serum or blood sample).
  • polypeptide levels e.g., neuropilin-2 polypeptide or zinc alpha-2 macroglobulin polypeptide levels
  • a sample e.g., a serum or blood sample.
  • elevated level as used herein with respect to the level of 17- ⁇ - estradiol, estrone, or a neuropilin-2 polypeptide present in a sample obtained from a mammal (e.g., a human prostate cancer patient) after androgen deprivation therapy can be any level that is greater than the level for that molecule that is present in a comparable sample obtained from the same mammal prior to androgen deprivation therapy.
  • the term "elevated level" as used herein with respect to the level of 17-P-estradiol, estrone, or a neuropilin-2 polypeptide present in a sample obtained from a mammal (e.g., a human prostate cancer patient) after androgen deprivation therapy can be any level that is greater than a reference level for that molecule.
  • the reference level can be the median level determined from a random sampling of 5, 10, 15, 20, 30, 40, 50, 100, 500, or more comparable samples obtained from comparable mammals either who do not have prostate cancer or who have prostate cancer but have not received androgen deprivation therapy.
  • reduced level as used herein with respect to the level of a zinc alpha-2 macroglobulin polypeptide present in a sample obtained from a mammal (e.g., a human prostate cancer patient) after androgen deprivation therapy can be any level that is less than the level of a zinc alpha-2 macroglobulin polypeptide that is present in a comparable sample obtained from the same mammal prior to androgen deprivation therapy.
  • the term "reduced level" as used herein with respect to the level of a zinc alpha-2 macroglobulin polypeptide present in a sample obtained from a mammal (e.g., a human prostate cancer patient) after androgen deprivation therapy can be any level that is less than a reference level for a zinc alpha-2 macroglobulin polypeptide.
  • the reference level can be the median level determined from a random sampling of 5, 10, 15, 20, 30, 40, 50, 100, 500, or more comparable samples obtained from comparable mammals either who do not have prostate cancer or who have prostate cancer but have not received androgen deprivation therapy.
  • This document also provides methods and materials to assist medical or research professionals in determining whether or not a prostate cancer patient is likely to respond to an androgen deprivation therapy.
  • Medical professionals can be, for example, doctors, nurses, medical laboratory technologists, and pharmacists.
  • Research professionals can be, for example, principle investigators, research technicians, postdoctoral trainees, and graduate students.
  • a professional can be assisted by (1) determining the presence of one or more of the elevated or reduced levels described herein, and (2) communicating information about those one or more levels to that professional.
  • Any method can be used to communicate information to another person (e.g., a professional).
  • information can be given directly or indirectly to a professional.
  • any type of communication can be used to communicate the information.
  • mail, e-mail, telephone, and face-to-face interactions can be used.
  • the information also can be communicated to a professional by making that information electronically available to the professional.
  • the information can be communicated to a professional by placing the information on a computer database such that the professional can access the information.
  • the information can be communicated to a hospital, clinic, or research facility serving as an agent for the professional.
  • a patient identified as being unlikely to respond to an androgen deprivation therapy based at least in part on the absence of an elevated level of 17- ⁇ - estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, and/or a reduced level of a zinc alpha-2 macroglobulin polypeptide can be administered or instructed to receive an alternative or adjunct therapy to ADT.
  • a patient lacking an elevated level of 17-P-estradiol, an elevated level of estrone, an elevated level of a neuropilin-2 polypeptide, and a reduced level of a zinc alpha-2 macroglobulin polypeptide can be instructed to proceed with an abiraterone acetate, MDV3100
  • Example 1 Serum proteomics guided discovery of predictive biomarkers of response to androgen ablation (AA) in prostate cancer
  • Serum from three non-localized prostate cancer cohorts was analyzed ( Figures 1 and 2).
  • the first cohort included 15 paired untreated hormone-sensitive "pre-AA” and 3- month “post-AA” specimens.
  • Six additional patients on AA were added to cohorts 1 and 2 for patient analyses to verify proteomic results using ELISAs.
  • BD SSTTM 6.0 mL vacutainers For serum processing, blood was collected in BD SSTTM 6.0 mL vacutainers and processed within 30-45 minutes. Processing included an initial centrifugation at 3,000 rpm for 10 minutes to generate a serum preparation that was fractioned into multiple aliquots that were labeled with coded identifiers and stored at -80°C. After the initial centrifugation, a protease inhibitor cocktail was added; the ingredients of which included 10 mL PBS (Invitrogen No. 14190300), one tablet complete of mini, EDTA-free protease inhibitor (Roche No. 11 836 170 001), sodium vanadate Na 3 V0 4 , and PMSF (Sigma No. P7626-5G).
  • protease inhibitor was completely dissolved in 10 mL PBS and 5 ⁇ /mL Na 3 V0 4 with 10 ⁇ /mL PMSF added for stock solution preparation (with 100 mM of PMSF). 50 of the stock solution was added to each serum specimen. No serum specimen retrieved for research underwent any freeze-thaw cycles prior to performing affinity depletion and preparation for iTRAQ labeling.
  • HPLC buffers were obtained from the column manufacturer, and the separation followed the manufacturer's recommended protocol with UV monitoring at 280 nm.
  • Protein concentrations obtained after depletion for each of the samples was determined by Bradford assay using BSA as the calibrant and further quantified by running SDS-mini gel followed by ImageQuant Software (GE Healthcare).
  • Protein samples were digested with trypsin, and the tryptic peptides from four different samples were each labeled with iTRAQ reagents 114, 115, 116, and 117, respectively, according to the manufacturer's protocols in a randomized setting.
  • a total of 13 sets of iTRAQ 4-plex tagged samples was prepared and designed to cover all individually depleted samples with two samples in duplicates. After labeling, the four samples were pooled in each of the 13 sets and subjected to cation exchange chromatography using an Applied Biosystems cation-exchange cartridge system. This was followed by performing high pH reverse phase fractionation, which was completed using a Dionex UltiMate3000 HPLC system with built-in micro fraction collection option in its autosampler and UV detection (Sunnyvale, CA).
  • Nano-scale reverse phase chromatography and tandem mass spectrometry was then carried out using a LTQ-Orbitrap Velos (Thermo-Fisher Scientific, San Jose, CA) mass spectrometer equipped with a "Plug and Play” nano ion source (CorSolutions, LLC, Ithaca, NY).
  • Differentially expressed candidate polypeptides were identified by comparisons of (i) paired pre/post- AA proteomes and (ii) post-AA proteome with the combined AA failure cohorts at a false discovery rate of 0.2.
  • ELISA assays (NRP2 ELISA assays, LifeSciences Inc. UK; and ZAG ELISA assays, Bio Vendor Research and Diagnostics, USA) were used to verify candidate markers in a second stored aliquot of first cohort specimens. This cohort was followed for AA failure. Association of post-AA ELISA levels of candidate markers with time to AA failure was performed using Cox
  • Median PSA values in pre/post- AA first cohort were 3.15 ng/mL and 0.29 ng/mL.
  • Median PSA values in the second and third cohorts were 27.3 and 4.3 ng/mL.
  • 149 polypeptides were differentially expressed.
  • ELISA assays verified expression levels of 2/47 polypeptides in the first cohort, zinc alpha-2 macroglobulin (ZAG) and Neuropilin-2 (NPL2). Median change in ZAG decreased by 2073.5 ng/mL (post versus pre-AA), while median change in NPL2 levels increased by 2.9 ng/mL. After a median follow-up of 43 months from the post-AA time- point, 4/15 first cohort subjects had failed AA. The recovery rate of AA failure for ZAG levels below the median change was 3.8 (95% CI: 0.4-37), and 3.0 (95% CI: 0.3-29) for NPL2. See, Figures 4-7. 6/20 patients failed AA during median follow up of 43 months.
  • Example 2 - 17-P-estradiol and estrone levels can predict response to androgen ablation in prostate cancer
  • the derivatized analytes were separated by gas chromatography using a XTI-5MS GC column and detected by tandem mass spectrometry using negative ion chemical ionization. Calibration curves were obtained by performing a linear regression (weighted 1/x 2 ) on the calibration standards. Concentration results were determined for testosterone, estradiol, and estrone.
  • a proteomic guided analytic approach was used to identify serum candidate polypeptides that predict response to ADT in hormone-sensitive, non-localized stage prostate cancer patients.
  • the approach was performed using isobaric mass tags for relative and absolute quanititation (iTRAQ) analyzed by reverse-phase liquid
  • the serum proteome of three non-localized prostate cancer cohorts was analyzed.
  • the first cohort included fifteen untreated hormone-sensitive patients with paired "pre- ADT" serum specimen and a 4-month "post-ADT" serum specimen.
  • the second included a cohort of ten patients failing ADT in a short period of time ("early ADT failure"), and the third included a separate cohort of ten patients failing ADT after a long response duration ("late ADT failure").
  • Differentially expressed polypeptides were identified at a False Discovery Rate of 0.2 by comparing proteomes of (i) the paired pre- versus post-ADT hormone sensitive patients; (ii) post-ADT hormone sensitive proteome with the combined ADT failure cohorts.
  • IP A Ingenuity Pathway Analysis
  • Median PSAs of the pre/post- ADT first cohort were 3.15 ng/mL and 0.29 ng/mL.
  • Median PSA values for the second and third cohorts were 27.3 and 4.3 ng/mL.
  • 149 serum polypeptides were differentially expressed.
  • 98 serum polypeptides were differentially expressed.

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Abstract

La présente invention concerne des procédés et des substances pour prédire si un patient atteint d'un cancer de la prostate est susceptible de répondre à une thérapie par privation androgénique pendant une durée prolongée. Par exemple, la présente invention concerne des procédés et des substances pour prédire si un patient atteint du cancer de la prostate est susceptible de répondre à une thérapie par privation androgénique pendant une période prolongée sur la base au moins en partie de la présence d'un taux élevé de 17β-estradiol, d'un taux élevé d'estrone, d'un taux élevé d'un polypeptide neuropiline-2, d'un taux réduit d'un polypeptide alpha-2 macroglobuline de zinc, ou d'une combinaison de ces éléments. La présente invention concerne également des procédés et substances pour traiter des patients atteints du cancer de la prostate.
PCT/US2013/024465 2012-02-01 2013-02-01 Prédiction de réponses à une thérapie par privation androgénique et procédés pour traiter le cancer de la prostate WO2013116742A1 (fr)

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