WO2014162008A2 - Nouvelle signature de biomarqueur et ses utilisations - Google Patents

Nouvelle signature de biomarqueur et ses utilisations Download PDF

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Publication number
WO2014162008A2
WO2014162008A2 PCT/EP2014/056879 EP2014056879W WO2014162008A2 WO 2014162008 A2 WO2014162008 A2 WO 2014162008A2 EP 2014056879 W EP2014056879 W EP 2014056879W WO 2014162008 A2 WO2014162008 A2 WO 2014162008A2
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Prior art keywords
proteins
mrna encoding
same
computer
lymphoma
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PCT/EP2014/056879
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WO2014162008A3 (fr
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Shahid Mian
Ahmed MOHAMEDEN
Ibraheim ASHANKYTY
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University Of Ha'il
Smith, Stephen Edward
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • 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
    • G01N33/57426—Specifically defined cancers leukemia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to novel biomarkers, and signatures comprising the same, for identifying individuals with Hodgkin's lymphoma who are responsive or resistant to treatment with chemotherapeutic agents.
  • HL Hodgkin's lymphoma
  • the present invention seeks to provide novel biomarkers for use in predicting the responsiveness of a patient with Hodgkin's lymphoma to chemotherapeutic drug treatment.
  • the invention provides methods of gene expression analysis in which a novel biomarker 'signature' is obtained to predict the responsiveness of a Hodgkin's lymphoma patient to chemotherapy, wherein the signature corresponds to quantitative information about the amount of a plurality of proteins (or mRNA encoding the same) which have been identified as characteristic of the responsiveness of said patient.
  • a first aspect of the invention provides an in vitro method for determining the responsiveness of an individual with Hodgkin's lymphoma to chemotherapeutic drug treatment, the method comprising the steps of:
  • Table B lists eighty-six biomarkers previously known or suggested in the art as being of potential diagnostic value in differentiating chemotherapy-responsive from chemotherapy-resistant Hodgkin's lymphoma patients (see ref [34], in particular Table S5 of supplementary appendix therein; the disclosures of which are incorporated herein by reference).
  • a positive log-fold change indicates increased expression in chemotherapy-responsive versus chemotherapy-resistant Hodgkin's lymphoma patients
  • a negative log-fold change indicates increased expression in chemotherapy-resistant versus chemotherapy-responsive Hodgkin's lymphoma patients.
  • the individual being tested is typically a human. However, it will be appreciated that the methods may also be used for the diagnosis of any domestic or farm mammal (such as a horse, pig, cow, sheep, dog or cat).
  • any domestic or farm mammal such as a horse, pig, cow, sheep, dog or cat.
  • chemotherapeutic drug treatment we include any of the chemotherapeutic drug regimes commonly used clinically in the treatment of Hodgkin's lymphoma.
  • ABVD chemotherapy contains the drugs adriamycin (doxorubicin), bleomycin, vinblastine and dacarbazine.
  • doxorubicin doxorubicin
  • bleomycin bleomycin
  • vinblastine bleomycin
  • dacarbazine dacarbazine
  • advanced stage Hodgkin's lymphoma some people have ABVD for up to 8 cycles.
  • chemotherapeutic drug combinations include:
  • responsiveness in the context of chemotherapeutic drug treatment of an individual with Hodgkin's lymphoma we include the therapeutic effectiveness of the treatment with respect to Hodgkin's lymphoma.
  • responsiveness includes the ability of chemotherapeutic drug treatment to reduce and most preferably prevent a clinically significant deficit in the activity, function and response of the individual with Hodgkin's lymphoma.
  • the measure of responsiveness may encompass the effect of the chemotherapeutic drug treatment on one or more of the following:
  • Step (a) of the methods of the invention comprises providing a protein or mRNA sample from the individual to be tested.
  • the sample is a lymph node tumour biopsy sample (which may have been excised from the individual previously, for example at the time of diagnosis).
  • the sample may be a blood or serum sample. It will be appreciated by persons skilled in the art that the samples may be fresh-frozen or formalin-fixed.
  • step (b) comprises measuring the presence and/or amount in the sample of at least three proteins selected from the group identified in Table A, and/or mRNA encoding the same, for example at least four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more proteins selected from the group identified in Table A, and/or mRNA encoding the same.
  • step (b) may comprise measuring the presence and/or amount in the sample of at least 20 proteins selected from the group identified in Table A, and/or mRNA encoding the same, for example at least 30, 40, 50, 100, 200, 500, 1000, or more proteins selected from the group identified in Table A, and/or mRNA encoding the same
  • the proteins and/or mRNA encoding the same measured in step (b) are selected from one of the following sub-groups defined in Table A:
  • step (b) may comprise measuring the presence and/or amount in the sample of biomarker nos. 1 to 10 in Table A (i.e. the first ten biomarkers listed in Table A) and/or mRNA encoding the same
  • step (b) comprises measuring the presence and/or amount in the sample of at least one protein, and/or mRNA encoding the same, selected from the group consisting of:
  • Zinc finger protein 644 (a) Zinc finger protein 644 (ZNF644) ;
  • DC-STAMP domain containing 2 DCST2
  • (b) may comprise measuring the presence and/or amount in the sample of all of biomarkers 'a' to ⁇ ' above, and/or mRNA encoding the same (see Table C).
  • Table C lists all of the biomarkers identified herein as being differentially expressed (i.e. having an adjusted 'p'-value ['q'-value] of less than 0.05 in patients; see Example A) in all chemotherapy-responsive versus chemotherapy-resistant Hodgkin's lymphoma patients (see Example A below).
  • biomarkers 'a' to ⁇ ' above are measured at the mRNA level using the probe sets ("Probe ID's") identified in Table A (from the Affymetrix GeneChip Human Genome U133 Plus 2.0 array, from Affymetrix Inc, Santa Clara, USA).
  • probe sets (“Probe ID's") identified in Table A (from the Affymetrix GeneChip Human Genome U133 Plus 2.0 array, from Affymetrix Inc, Santa Clara, USA).
  • mRNA levels for heat shock 70kDa protein 5 may be determined using Affymetrix probe set 21 1936 at.
  • step (b) comprises measuring the presence and/or amount in the sample of mRNA encoding the proteins selected from the group identified in Table A.
  • measuring the presence and/or amount in the sample of the mRNA may be performed using binding agents capable of binding to the said mRNA, for example using oligonucleotides with a nucleotide sequence complementary to the target mRNA in a hybridisation assay.
  • step (b) comprises measuring the presence and/or amount in the sample of the proteins selected from the group identified in Table A, for example using binding agents capable of binding to said proteins.
  • Suitable binding agents may comprise or consist of an antibody or an antigen-binding fragment thereof, such as intact antibodies, Fv fragments (e.g. single chain Fv and disulphide-bonded Fv), Fab-like fragments (e.g. Fab fragments, Fab' fragments and F(ab) 2 fragments), single variable domains (e.g. V H and V L domains) and domain antibodies (dAbs, including single and dual formats [i.e. dAb-linker-dAb]).
  • Fv fragments e.g. single chain Fv and disulphide-bonded Fv
  • Fab-like fragments e.g. Fab fragments, Fab' fragments and F(ab) 2 fragments
  • single variable domains e.g. V H and V L domains
  • dAbs including single and dual formats [i.e
  • Suitable assays for detecting proteins include enzyme linked immunosorbent assays (ELISA), radioimmunoassay (RIA), immunoradiometric assays (IRMA) and immunoenzymatic assays (IEMA), including sandwich assays using monoclonal and/or polyclonal antibodies.
  • ELISA enzyme linked immunosorbent assays
  • RIA radioimmunoassay
  • IRMA immunoradiometric assays
  • IEMA immunoenzymatic assays
  • sandwich assays are described by David et al in US Patent Nos. 4,376,110 and 4,486,530, hereby incorporated by reference.
  • Antibody staining of cells on slides may be used in methods well known in cytology laboratory diagnostic tests, as well known to those skilled in the art.
  • the presence and/or amount of the proteins selected from Table A may be determined by ELISA.
  • the binding agent comprises or consists of an antibody-like binding agent, for example an affibody or aptamer.
  • the proteins and/or mRNA in the sample may be labelled with a detectable moiety prior to performing step (b).
  • a suitable detectable moiety is selected from the group consisting of: a fluorescent moiety; a luminescent moiety; a chemiluminescent moiety; a radioactive moiety; an enzymatic moiety.
  • measuring the presence and/or amount of the proteins, or mRNA encoding the same, in the sample is performed using a gene expression profiling array.
  • Suitable arrays include surface-based arrays and bead-based arrays, which may be macroarrays, microarrays or nanoarrays.
  • the gene expression profiling array is commercially available.
  • the GeneChip Human Genome U133 Plus 2.0 array from Affymetrix Inc, Santa Clara, USA.
  • the method of the first aspect of the invention further comprises step (c) of comparing the presence and/or amount of the proteins, or mRNA encoding the same, with one or more reference values for said proteins or mRNA.
  • reference value we mean a numerical value corresponding to the amount of a biomarker protein (or its mRNA) associated with a defined group of individuals.
  • the reference values correspond to the presence and/or amount of said proteins or mRNA in lymph node tissue from one or more individuals selected from a group consisting of healthy individuals, individuals diagnosed with Hodgkin's lymphoma who are responsive to chemotherapeutic drug treatment and individuals diagnosed with Hodgkin's lymphoma who are resistant to chemotherapeutic drug treatment.
  • the reference values may correspond to the amount of the biomarker proteins or mRNA associated with individuals from the GEO dataset (Expression series GSE17920) diagnosed with Hodgkin's lymphoma who are responsive to chemotherapeutic drug treatment and individuals from the GEO diagnosed with Hodgkin's lymphoma who are resistant to chemotherapeutic drug treatment (see Example A below).
  • step (b) the amount of the proteins, or mRNA encoding the same, obtained in step (b) and the reference values for said proteins or mRNA may be normalised prior to being compared.
  • the comparison in step (c) may be performed manually but more typically will be performed using computer-based tools.
  • step (c) comprises the use of a predictive model, such as a computer-implemented adaptive learning algorithm.
  • the adaptive learning algorithm is an artificial neural network, e.g. a multilayer perceptron (see Example A below).
  • an artificial neural network e.g. a multilayer perceptron (see Example A below).
  • a biomarker signature for determining the responsiveness of Hodgkin's lymphoma patients to chemotherapy is reported with a predictive accuracy (AUC) of 0.837 based on gene expression profile data from 130 Hodgkin's lymphoma patients (GEO expression series GSE17920), compared to a predictive accuracy of only 0.625 using a clinical model based on the International Prognostic Score.
  • AUC predictive accuracy
  • the methods of the invention utilize a predictive model having an accuracy of at least 90% for determining the responsiveness of Hodgkin's lymphoma patients to chemotherapy.
  • the predictive model may have an accuracy of at least 95% for such patient classification, and preferably at least 99%. It will be appreciated that such predictive accuracy may be determined relative to any given population of Hodgkin's lymphoma patients. In one embodiment, however, the predictive accuracy is determined relative to the 130 patients used in Example A (Expression series GSE17920 from the Gene Expression Omnibus [GEO] data repository).
  • Example A The studies detailed in Example A below reveal that some proteins exhibit increased expression in individuals with Hodgkin's lymphoma who are resistant to chemotherapeutic drug treatment whilst some proteins exhibit decreased expression in individuals with Hodgkin's lymphoma who are resistant to chemotherapeutic drug treatment (compared to the expression of said proteins in individuals with Hodgkin's lymphoma who are resistant to chemotherapeutic drug treatment).
  • ZNF644, EMID2, RLN1 , SPATA12, CLPS, EST tu05b03.x1 , PDE6D, GET 4 and/or DCST2 is indicative of the individual with Hodgkin's lymphoma being responsive to chemotherapeutic drug treatment.
  • EMID2, RLN1 , SPATA12, CLPS, EST tu05b03.x1 , PDE6D, GET 4 and/or DCST2 is indicative of the individual with Hodgkin's lymphoma being responsive to chemotherapeutic drug treatment.
  • HSPA5, PTX3, C1orf163, KTN1 , MAPK14 and/or EPOR is indicative of the individual with Hodgkin's lymphoma being resistant to chemotherapeutic drug treatment.
  • step (c) comprises identifying the individual as exhibiting atypical gene expression.
  • atypical gene expression we mean that the gene expression profile for the dataset (e.g. patient group or sub-group) is qualitatively and/or quantitatively different from the gene expression profile most commonly observed in that dataset.
  • the presence and/or amount of one or more proteins (or their respective mRNAs) may be quantitatively different from the presence and/or amount of said proteins or mRNAs most commonly observed in that dataset.
  • the presence and/or amount of one or more (e.g. all) proteins in Table C may be atypical for a given subgroup of those patients (e.g. patients responsive or resistant to chemotherapy). Having identified a given patient as falling within the "outlier" subgroup, a different biomarker signature may be used to determiner whether said patient is responsive or resistant to chemotherapy.
  • the methods of the invention may further comprise step (d) of determining the presence and/or amount in the sample of at least two proteins selected from the group identified in Table D, and/or of mRNA encoding the same.
  • Table D lists all of the biomarkers identified herein as being differentially expressed (i.e. having an adjusted 'p'-value ['q'-value] of less than 0.05 in patients exhibiting an atypical or "outlier" gene expression profile; see Example A) in chemotherapy- responsive versus chemotherapy-resistant Hodgkin's lymphoma patients (see Example A below).
  • step (d) it will be appreciated by persons skilled in that art that the methods described above in relation to step (b) may be used in step (d).
  • step (d) comprises measuring the presence and/or amount in the sample of at least three proteins selected from the group identified in Table D, and/or mRNA encoding the same, for example at least four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more proteins selected from the group identified in Table D, and/or mRNA encoding the same.
  • step (d) may comprise measuring the presence and/or amount in the sample of at least 20 proteins selected from the group identified in Table A, and/or mRNA encoding the same, for example at least 30, 40, 50, 100, 200, 500, 1000, or more proteins selected from the group identified in Table D, and/or mRNA encoding the same.
  • the proteins, and/or mRNA encoding the same, measured in step (d) are selected from one of the following groups defined in Table D:
  • Biomarker nos. 1 to 10 (b) Biomarker nos. 1 to 20;
  • Biomarker nos. 1 to 1000 wherein the biomarker number is shown in first column of Table D ("No.”).
  • step (d) may comprise measuring the presence and/or amount in the sample of at least one protein, and/or mRNA encoding the same, selected from the group consisting of
  • Cytoglobin (e) Cytoglobin (CYGB);
  • Zinc finger DHHC-type containing 9 (ZDHHC9).
  • Step (d) comprises measuring the presence and/or amount in the sample of all of the following proteins, and/or mRNA encoding the same:
  • the method further comprises step (e) of comparing the presence and/or amount of the proteins, or mRNA encoding the same, with one or more reference values for said proteins or mRNA.
  • the reference values may correspond to the presence and/or amount of said proteins or mRNA in lymph node tissue from one or more individuals selected from a group consisting of healthy individuals, individuals diagnosed with Hodgkin's lymphoma who are responsive to chemotherapeutic drug treatment and individuals diagnosed with Hodgkin's lymphoma who are resistant to chemotherapeutic drug treatment.
  • step (e) the amount of the proteins, or mRNA encoding the same, obtained in step (e) and the reference values for said proteins or mRNA may be normalised prior to being compared.
  • the method further comprises the step of determining the medical history of the individual.
  • the medical history of the individual may comprise determining whether the patient has taken any HIV drug therapies prior to providing the sample.
  • a second aspect of the invention provides a method for treating an individual with Hodgkin's lymphoma comprising:
  • step (b) administering a chemotherapeutic drug to the individual identified in step (a).
  • Suitable chemotherapeutic drug regimes effective in the treatment of Hodgkin's lymphoma are known to those skilled in the art.
  • the individual may be administered 2 to 4 cycles of ABVD chemotherapy, which contains the drugs adriamycin (doxorubicin), bleomycin, vinblastine and dacarbazine.
  • ABVD chemotherapy contains the drugs adriamycin (doxorubicin), bleomycin, vinblastine and dacarbazine.
  • doxorubicin doxorubicin
  • bleomycin bleomycin
  • vinblastine dacarbazine
  • dacarbazine dacarbazine
  • Other possible chemotherapeutic drug combinations include:
  • a related, third aspect of the invention provides a method for treating an individual with Hodgkin's lymphoma comprising:
  • step (b) administering a therapeutic agent other than a chemotherapeutic drug to the individual identified in step (a).
  • Suitable non-chemotherapeutic treatment regimes effective in the treatment of Hodgkin's lymphoma are known to those skilled in the art, for example radiotherapy.
  • a fourth aspect of the invention provides a method for treating an individual with Hodgkin's lymphoma comprising:
  • step (c) administering said effective therapeutic agent identified in step (b) to the individual.
  • a fifth aspect of the invention provides an array for use in a method according to the first aspect of the invention the array comprising binding agents for two or more of the proteins identified in Table A and/or D, or mRNA encoding the same.
  • Arrays per se are well known in the art. Typically they are formed of a linear or two- dimensional structure having spaced apart (i.e. discrete) regions ("spots"), each having a finite area, formed on the surface of a solid support.
  • An array can also be ad structure where each bead can be identified by a molecular code or colour code or identified in a continuous flow. Analysis can also be performed sequentially where the sample is passed over a series of spots each adsorbing the class of molecules from the solution.
  • the solid support is typically glass or a polymer, the most commonly used polymers being cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.
  • the solid supports may be in the form of tubes, beads, discs, silicon chips, microplates, polyvinylidene difluoride (PVDF) membrane, nitrocellulose membrane, nylon membrane, other porous membrane, non-porous membrane (e.g. plastic, polymer, perspex, silicon, amongst others), a plurality of polymeric pins, or a plurality of microtitre wells, or any other surface suitable for immobilising proteins, polynucleotides and other suitable molecules and/or conducting an immunoassay.
  • PVDF polyvinylidene difluoride
  • binding processes are well known in the art and generally consist of cross-linking covalently binding or physically adsorbing a protein molecule, polynucleotide or the like to the solid support.
  • affinity coupling of the probes via affinity-tags or similar constructs may be employed.
  • contact or non-contact printing, masking or photolithography the location of each spot can be defined.
  • the array is a microarray.
  • microarray we include the meaning of an array of regions having a density of discrete regions of at least about 100/cm 2 , and preferably at least about 1000/cm 2 .
  • the regions in a microarray have typical dimensions, e.g. diameter, in the range of between about 10-250 ⁇ , and are separated from other regions in the array by about the same distance.
  • the array may alternatively be a macroarray or a nanoarray.
  • the array comprises binding agents for fewer then 1000 different proteins, or mRNA coding the same, for example fewer than 500, 400, 300, 200, 100, 50, 25, or 20 different proteins, or mRNA coding the same.
  • the array comprises binding agents for all of the proteins defined in Table 1 , or mRNA encoding the same.
  • the array may comprise:
  • the binding agents are immobilised.
  • the array is a surface-based array or bead-based array.
  • the array is suitable for use with high-throughput screening methods of gene profiling.
  • a sixth aspect of the invention provides a kit for performing a method according to the first aspect of the invention comprising:
  • kits further comprises one or more reagents for use in a method according to the first aspect of the invention.
  • kits further comprises a positive control sample and/or a negative control sample.
  • a seventh aspect of the invention provides a computer-implemented method for classifying a sample from an individual with Hodgkin's lymphoma, comprising:
  • step (c) classifying said sample according to the output of said analytical process wherein one or more of the at least two proteins selected from the group defined in Table A is not identified in Table B. and wherein in step (c) the sample is classified as from an individual with Hodgkin's lymphoma who is responsive to chemotherapeutic drug treatment or from an individual with Hodgkin's lymphoma who is resistant to chemotherapeutic drug treatment.
  • the dataset in step (a) comprises quantitative data for zinc finger protein 644 (ZNF644) and/or heat shock 70kDa protein 5 (HSPA5), and/or mRNA encoding the same.
  • the dataset in step (a) comprises quantitative data for at least three proteins selected from the group identified in Table A, and/or mRNA encoding the same, for example at least four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more proteins selected from the group identified in Table A, and/or mRNA encoding the same.
  • the dataset in step (a) may comprise quantitative data for at least 20 proteins selected from the group identified in Table A, and/or mRNA encoding the same, for example at least 30, 40, 50, 100, 200, 500, 1000, or more proteins selected from the group identified in Table A, and/or mRNA encoding the same.
  • the proteins, and/or mRNA encoding the same, for which quantitative data are provided in step (a) are selected from one of the following groups defined in Table A: (a) Biomarker nos. 1 to 10
  • none of the at least two proteins selected from the group identified in Table A are identified in Table B.
  • the dataset in step (a) may comprise quantitative data for at least one protein, and/or mRNA encoding the same, selected from the group consisting of: (a) Zinc finger protein 644 (ZNF644) ;
  • the dataset in step (a) may comprise quantitative data for all of biomarkers 'a' to 'o' above, and/or mRNA encoding the same.
  • the dataset in step (a) comprises quantitative data for biomarkers 'a' to ⁇ ' above as measured at the mRNA level using the probe sets ("Probe ID's") identified in Table A (from the Affymetrix GeneChip Human Genome U133 Plus 2.0 array, from Affymetrix Inc, Santa Clara, USA).
  • probe sets ("Probe ID's") identified in Table A (from the Affymetrix GeneChip Human Genome U133 Plus 2.0 array, from Affymetrix Inc, Santa Clara, USA).
  • mRNA levels for heat shock 70kDa protein 5 may be determined using Affymetrix probe set 211936_at.
  • the dataset in step (a) comprises quantitative data for at least two proteins selected from the group identified in Table D, and/or of mRNA encoding the same.
  • the dataset in step (a) comprises quantitative data for at least three proteins selected from the group identified in Table D, and/or mRNA encoding the same, for example at least four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more proteins selected from the group identified in Table D, and/or mRNA encoding the same.
  • the dataset in step (a) comprises quantitative data for at least 20 proteins selected from the group identified in Table A, and/or mRNA encoding the same, for example at least 30, 40, 50, 100, 200, 500, 1000, or more proteins selected from the group identified in Table D, and/or mRNA encoding the same.
  • the proteins, and/or mRNA encoding the same, for which quantitative data are provided in step (a) are selected from one of the following groups defined in Table D:
  • the dataset in step (a) comprises quantitative data for at least one protein, and/or mRNA encoding the same, selected from the group consisting of:
  • Cytoglobin (e) Cytoglobin (CYGB);
  • step (j) Zinc finger, DHHC-type containing 9 (ZDHHC9).
  • the dataset in step (a) may comprise quantitative data for all of biomarkers 'a' to 'j' above, and/or mRNA encoding the same.
  • the dataset in step (a) comprises quantitative data for all of the following proteins, and/or mRNA encoding the same:
  • the dataset in step (a) may comprises quantitative data for biomarkers 'a' to 'j' above as measured at the mRNA level using the probe sets ("Probe ID's") identified in Table A (from the Affymetrix GeneChip Human Genome U133 Plus 2.0 array, from Affymetrix Inc, Santa Clara, USA).
  • said analytical process in step (b) comprises the use of a predictive model based on the one or more reference datasets.
  • step (b) may comprise the use of a Linear Discriminant Analysis (LDA) model, a support vector machine classification algorithm, a recursive feature elimination model, a prediction analysis of microarray model, a Logistic Regression model, a CART algorithm, a FlexTree algorithm, a LART algorithm, a random forest algorithm, a MART algorithm, or a Machine Learning algorithm.
  • LDA Linear Discriminant Analysis
  • said one or more reference datasets comprise quantitative data obtained from one or more individuals selected from a group consisting of healthy individuals, individuals diagnosed with Hodgkin's lymphoma who are responsive to chemotherapeutic drug treatment and individuals diagnosed with Hodgkin's lymphoma who are resistant to chemotherapeutic drug treatment.
  • the analytical process in step (b) comprises use of an adaptive learning algorithm, such as an artificial neural network.
  • the artificial neural network may be a multilayer perceptron.
  • the predictive model has an accuracy of at least 90% for determining the responsiveness of Hodgkin's lymphoma patients to chemotherapy.
  • the predictive model may have an accuracy of at least 95% for such patient classification, and preferably at least 99%.
  • An eighth aspect of the invention provides a computer system for performing a computer- implemented method according to the seventh aspect of the invention, wherein the system comprises a digital computer and computer readable program means for enabling the computer to perform said computer-implemented method.
  • the computer readable program may be contained within the internal or external memory of the computer system, for example on a RAM chip, hard- drive, CD-ROM, DVD-ROM, USB memory pen and the like.
  • the computer system further comprises a computer-readable storage medium comprising reference datasets (i.e. from step 'b' of the computer- implemented method of the invention).
  • a ninth aspect of the invention provides a computer-readable storage medium comprising computer readable program means for enabling the computer to perform a computer-implemented method according to the seventh aspect of the invention.
  • the computer-readable storage medium further comprises reference datasets (i.e. from step 'b' of the computer-implemented method of the invention).
  • the black boxes ( ⁇ ) represent the median value and suggests that the data are median centred and therefore appropriate for comparative analyses. Low and high part of the box represents the 25th and 75th percentile respectively. Minimum and maximum values are shown by the vertical thin lines.
  • Figure 2 A general overview of a multi-layer perceptron back propagation network. Input signals are fed forward in a unidirectional manner (through weighted links) and transformed by an activation function into a predicted classification result. Error in classification is back propagated resulting in incremental changes to the weighted links and a minimisation of classification error.
  • FIG. 3 Receiver Operating Characteristic (ROC) curve for 100 models retained after training for run 5 (sample seed variation). Plots represent the values obtained from all predictions made within training, testing and validation datasets.
  • the true positive class represents patients who responded to treatment (i.e. chemo-sensitive).
  • the true negative class are indicative of patients who did not respond to treatment (i.e. chemo-resistant).
  • A Average predictive accuracy (%) for each sample.
  • the mean value represents an average taken from 100 models per run with a total of 10 runs.
  • a random sample seed with fixed network seed values were used to select training, testing and validation datasets and to initialise the network respectively.
  • Chemotherapy failure patients are listed between sample numbers 1-38 and chemotherapy sensitive patients between sample numbers 39-130 respectively. Confidence intervals are shown at p ⁇ 0.05 two-tail t-distribution and 9 degrees of freedom (based upon 10 runs (generating 20,000 models per run)).
  • the mean value represents an average taken from 100 models per run with a total of 10 runs.
  • a fixed sample seed with random network seed values were used to select training, testing and validation datasets and to initialise the network respectively.
  • Chemotherapy failure patients are listed between sample numbers 1-38 and chemotherapy sensitive patients between sample numbers 39-130 respectively. Confidence intervals are shown at p ⁇ 0.05 two-tail t- distribution and 9 degrees of freedom (based upon 10 runs (generating 20,000 models per run)).
  • Figure 5 Average predictive accuracy for outlier samples.
  • the mean value represents an average taken from 100 models per run with a total of 10 runs.
  • a random sample seed with fixed network seed values were used to select training/testing/validation datasets and to initialise the network respectively.
  • Chemotherapy failure patients (class F) and chemotherapy sensitive patients (class S) from "Sequential" and "Randomised” sample presentation are listed respectively. Confidence intervals are shown at p ⁇ 0.05 two-tail t- distribution and 9 degrees of freedom (based upon 10 runs (generating 20,000 models per run)).
  • Figure 6 Number of genes with reported back from GE02R as having adjusted p-values ("q-values") with FDR ⁇ 0.05.
  • Group 130 includes all 130 samples from the original study.
  • Group 114 includes 114 samples with outlier samples removed.
  • Group 16 includes the original 16 outlier samples only.
  • Group 130, Group 114 and Group 16 contain both chemotherapy sensitive and resistant patient samples.
  • Figure 7 Receiver Operating Characteristic (ROC) curve for 100 models for Group 130 samples using top 4 predictors identified as having the most significant adjusted p-values for Group 16 outlier samples. Plots represent the values obtained from all predictions made within training, testing and validation datasets.
  • the true positive class (sensitivity) represents patients who responded to treatment (i.e. chemo-sensitive).
  • the true negative class (specificity) are indicative of patients who did not respond to treatment (i.e. chemo- resistant).

Abstract

L'invention concerne un procédé in vitro de détermination de la sensibilité d'un individu atteint de lymphome de Hodgkin à un traitement par médicament chimiothérapeutique, le procédé comprenant les étapes de fourniture d'une protéine ou d'un échantillon d'ARNm provenant d'un ganglion lymphatique de l'individu à tester, puis de détermination de la présence et/ou de la quantité dans les échantillons d'au moins deux protéines choisies dans le groupe identifié dans le Tableau A, et/ou d'ARNm codant pour ces dernières, la présence et/ou la quantité dans l'échantillon des protéines choisies dans le groupe défini dans le Tableau A, ou de l'ARNm codant pour ces dernières, indiquent la sensibilité de l'individu atteint de lymphome de Hodgkin au traitement par médicament chimiothérapeutique. L'invention concerne en outre des gammes et des trousses à utiliser dans ce dernier.
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WO2016141375A1 (fr) * 2015-03-05 2016-09-09 Case Western Reserve University Arn régulé par her2 à utiliser en tant que cibles diagnostiques et thérapeutiques dans le cancer du sein her2 positif
US10961589B2 (en) 2015-03-05 2021-03-30 Case Western Reserve University HER2-regulated RNA as a diagnostic and therapeutic targets in HER2+ breast cancer
CN107217105A (zh) * 2017-07-27 2017-09-29 江苏省原子医学研究所 一种癌症联合诊断标记物及其用途
CN107217105B (zh) * 2017-07-27 2020-10-20 江苏省原子医学研究所 一种癌症联合诊断标记物及其用途
EP3578981A1 (fr) * 2018-06-06 2019-12-11 Technische Universität Dresden Traitement anticancéreux de sujets présélectionnée et procédés de criblage permettant d'identifier des sujets prédisposés
WO2019233779A1 (fr) * 2018-06-06 2019-12-12 Technische Universität Dresden Traitement anticancéreux de sujets présélectionnés et procédés de criblage pour identifier des sujets sensibles
RU2688313C1 (ru) * 2018-10-02 2019-05-21 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр онкологии имени Н.Н. Петрова" Министерства здравоохранения Российской Федерации Способ прогнозирования инфертильности после риск-адаптированного лечения лимфомы ходжкина у детей и подростков
CN111235269A (zh) * 2018-11-28 2020-06-05 中国科学院大连化学物理研究所 Plin2及定量检测plin2的试剂的应用和试剂盒
CN111228289A (zh) * 2018-11-28 2020-06-05 中国科学院大连化学物理研究所 Plin2抑制剂的应用和治疗肿瘤药物混合物
WO2021005002A1 (fr) * 2019-07-05 2021-01-14 Intellexon Gmbh Procédés de diagnostic de l'efficacité d'un traitement anti-tumoral
EP3909600A1 (fr) 2020-05-12 2021-11-17 International Centre For Genetic Engineering And Biotechnology - ICGEB Protéine emid2 en tant que traitement anticancéreux
WO2021228817A1 (fr) 2020-05-12 2021-11-18 International Centre For Genetic Engineering And Biotechnology - Icgeb Protéine emid2 utilisèe en tant que traitement anticancéreux

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