[go: up one dir, main page]

WO2011058367A2 - Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase - Google Patents

Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase Download PDF

Info

Publication number
WO2011058367A2
WO2011058367A2 PCT/GB2010/051888 GB2010051888W WO2011058367A2 WO 2011058367 A2 WO2011058367 A2 WO 2011058367A2 GB 2010051888 W GB2010051888 W GB 2010051888W WO 2011058367 A2 WO2011058367 A2 WO 2011058367A2
Authority
WO
WIPO (PCT)
Prior art keywords
parp
biomarker
expression
cancer
protein
Prior art date
Application number
PCT/GB2010/051888
Other languages
English (en)
Other versions
WO2011058367A3 (fr
Inventor
Jonathan Richard Dry
Christopher George Harbron
Darren Richard Hodgson
Alan Yin Kai Lau
Mark James O'connor
John Edward Prime
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
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 Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2011058367A2 publication Critical patent/WO2011058367A2/fr
Publication of WO2011058367A3 publication Critical patent/WO2011058367A3/fr

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
    • 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
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6816—Hybridisation assays characterised by the detection means
    • 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
    • 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
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91091—Glycosyltransferases (2.4)
    • G01N2333/91142—Pentosyltransferases (2.4.2)
    • 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
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/924—Hydrolases (3) acting on glycosyl compounds (3.2)
    • 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 invention relates generally to methods for treating cancer and to methods of predicting the responsiveness of a cancer cell to therapeutic treatment.
  • the invention provides the identities of biomarkers (genes) that may be used to identify populations or individuals of cancer sufferers that are likely to respond favourably to treatment with PARP inhibitors, such as olaparib (4-[3-(4- cyclopropanecarbonyl-piperazine-1 -carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1 - one).
  • PARP inhibitors such as olaparib (4-[3-(4- cyclopropanecarbonyl-piperazine-1 -carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1 - one).
  • This invention also relates to the use of particular biomarkers to assess or determine the suitability of certain cells, in particular cancer cells, to treatment with a Poly(ADP-Ribose) polymerase (PARP) inhibitor.
  • PARP Poly(A
  • PARP Poly(ADP-Ribose) polymerase
  • BER Base Excision Repair
  • WO2005/012524 (The University of Sheffield) teach that cells deficient in homologous recombination (HR) are hypersensitive to PARP inhibitors as compared to wild type cells, and thus that PARP inhibitors are useful in the treatment of cancer cells defective in the expression of a gene involved in HR.
  • HR genes identified therein include XRCC1 , ADPRT (PARP-1 ), ADPRTL2 (PARP-2), CTPS, RPA, RPA1 , RPA2, RPA3, XPD, ERCC1 , XPF, MMSI9, RAD51 , RAD51 B, RAD51 C, RAD51 D, DMC1 , XRCC2, XRCC3, BRCA1 , BRCA2, RAD52, RAD54, RAD50, MRE 1 1 , NBS 1 , WRN, BLM, Ku70, Ku80, ATM, ATR, CHEK1 , CHEK2, FANCA, FANCB, FANCC, FANCD1 , FANCD2, FANCE, FANCF, FANCG, RAD1 , RAD9, FEN-1 , Mus81 , Emel, DSS1 and BARD.
  • the components of the HR dependent DNA DSB repair pathway listed include ATM (NM_000051 ), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3
  • NM_005732 MRE1 1 A (NM_005590) and NBN (NM_002485), as well as regulatory factors such as EMSY.
  • WO 2008/147418, US2007/0292883 and US2008/0262062 (BiPAR Sciences Inc.) relates to methods of treating a PARP mediated disease comprising measuring the level of PARP in a sample from a patient and if the level of PARP is up- regulated treating the patient with a PARP modulator, e.g. PARP inhibitor.
  • a PARP modulator e.g. PARP inhibitor.
  • the present invention relates to the identification and use of biomarker expression patterns (or profiles or signatures) which are correlated with cancer cells that are responsive to PARP inhibitor treatment, and which can therefore serve as a diagnostic personalised healthcare test to select patients that will likely respond favourably to PARP inhibitor therapy and deselect those that are unlikely to respond to PARP inhibitor therapy.
  • the patterns may thus be used in diagnostic or prognostic methods or assays in the clinic to determine the appropriate treatment following identification of cancer in a patient.
  • the present invention provides methods of treating cancer in a subject/patient and methods of selecting cancer patients for such treatment.
  • the method of selection involves determining the expression level of PARP-1 in a cancer cell containing sample from the patient and if the PARP-1 expression level is not low, identifying or selecting the patient for treatment with a PARP inhibitor.
  • the method of treating cancer includes determining the expression level of PARP-1 in a cancer cell containing sample from the subject and if the PARP-1 expression level is not low, administering to the subject an effective amount of a PARP inhibitor.
  • the present invention provides methods of treating cancer in a subject/patient and methods of selecting cancer patients for such treatment.
  • the method of selection involves determining the expression level of MUTYH in a cancer cell containing sample from the patient and if the MUTYH expression level is not low, identifying or selecting the patient for treatment with a PARP inhibitor.
  • the method of treating cancer includes determining the expression level of MUTYH in a cancer cell containing sample from the subject and if the MUTYH expression level is not low, administering to the subject an effective amount of a PARP inhibitor.
  • the expression level of one or more genes involved in homologous recombination repair as listed in Table 2 is also measured; and selecting the patient for treatment with a PARP inhibitor if the expression profile of the biomarkers identifies the patient as being a likely responder to treatment with the PARP inhibitor.
  • a patient whose cancer cells do not express low levels of PARP-1 or MUTYH but do express low levels of any of the homologous recombination repair genes selected from the group consisting of: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1 A is selected for treatment and/or treated with the PARP inhibitor compound.
  • the invention provides a method for selecting a cancer patient for treatment with a PARP inhibitor comprising measuring the expression level of at least one base excision repair biomarker as listed in Table 1 , at least one homologous recombination biomarker as listed in Table 2 and at least one proliferation biomarker as listed in Table 3, in a cancer cell containing sample obtained from the patient and selecting the patient for treatment with a PARP inhibitor if the expression profile of the at least three biomarkers identifies the patient as being a likely responder to treatment with the PARP inhibitor.
  • the biomarker(s) from Table 1 are selected from PARP-1 , MUTYH, POLD1 and POLE3.
  • recombination biomarker from Table 2 is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1 A.
  • the homologous recombination biomarker from Table 2 is selected from: MCM2, XRCC3, BRCA1 , MDC1 , ATM, ATR, NBN, RAD51 and MRE1 1 A.
  • the proliferation biomarker from Table 3 is selected from AURKA, SMARCD3, ZIC1 , SSX2IP and BOC.
  • a method of treating cancer comprising measuring the expression level of at least one base excision repair biomarker from Table 1 , at least one homologous recombination biomarker from Table 2 and at least one proliferation biomarker from Table 3, in a cancer cell containing sample obtained from the patient and if the expression profile of the biomarkers identifies the patient as being a likely responder to treatment with the PARP inhibitor, administering to said patient an effective amount of a PARP inhibitor.
  • the biomarker(s) from Table 1 is selected from PARP-1 and MUTYH.
  • the homologous recombination biomarker from Table 2 is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and
  • MRE1 1 A In another embodiment the homologous recombination biomarker from Table 2 is selected from: MCM2, XRCC3, BRCA1 , MDC1 , ATM, ATR, NBN, RAD51 and MRE1 1A.
  • the proliferation biomarker from Table 3 is selected from AURKA, SMARCD3, ZIC1 , SSX2IP, BOC, POLH, TP53BP2, SCMH1 , SMARCA5, MRAS, IP6K2, GTF2H4, MBD1 , RASA3, ZMYM4, PHF13, ARNT, KDM4A, PCBP4, TLR4, NUDT1 , PMS1 and ZMYM6.
  • a suitable PARP inhibitor compound that the methods of the invention can be applied to is olaparib.
  • Figure 1 shows PARP-1 gene and protein expression levels for each of the cell lines in the KU95 panel and the correlation with olaparib response.
  • A Scatter plots comparing PARP-1 mRNA expression (normalised to the average of 3 housekeeping genes - PPIA, PGK1 and TBP) on the x-axis and olaparib IC50 on the y-axis.
  • the solid line represents a simple straight line fit between all data points.
  • the hatched lines are cut-off levels for mean normalised gene expression (0; x-axis) or olaparib sensitivity (0; less than 1 ⁇ ; y-axis).
  • FIG. 2 shows BRCA1 gene expression for each of the cell lines in the KU95 panel and the correlation with olaparib response. Scatter plots comparing BRCA1 mRNA expression (normalised to the average of 3 housekeeping genes) on the x- axis and olaparib IC50 on the y-axis. The solid line represents a simple straight line fit between all data points.
  • Figure 3 shows the ROC curve demonstrating the increased predictive power of using PARP-1 and ATM over and above either biomarker alone
  • Figure 4 shows the identification of two main clusters within the 426 Affymetrix genes: the lower (smaller) cluster is a DNA repair cluster containing primarily genes associated with BER and HR, the other genes associated with cell proliferation function.
  • Figure 5 shows the three main functional groups of biomarkers for predicting olaparib sensitivity and how they were identified.
  • Figure 6 shows a ROC curve that illustrates the improved predictive power of the combination of PARP-1 (BER), BRCA1 (HR) and AURKA (proliferation)
  • Figure 7 shows a ROC curve that illustrates the improved predictive power of the combination of MUTYH (BER), BRCA1 (HR) and SMARCD3 (proliferation) biomarkers to predict olaparib response.
  • Figure 8 shows a ROC curve that illustrate the improved predictive power of the combination of MUTYH (BER), ATM (HR) and ZIC1 (proliferation) biomarkers to predict olaparib response.
  • Figure 9 shows a ROC curve that illustrates the improved predictive power of the combination of POLD1 , (BER), ATM (HR) and SSX2IP (proliferation) biomarkers to predict olaparib response.
  • Figure 10 shows a ROC curve that illustrates the improved predictive power of the combination of POLE3 (BER), BRCA1 (HR) and BOC1 (proliferation) biomarkers to predict olaparib response.
  • biomarker in the context of the present invention encompasses, without limitation, a gene (e.g. nucleic acid) including its encoded protein or polypeptide as disclosed in any of Tables 1 , 2 or 3, as well as polymorphisms thereof. Biomarkers can also include mutated proteins or mutated nucleic acids.
  • a gene e.g. nucleic acid
  • Biomarkers can also include mutated proteins or mutated nucleic acids.
  • a "gene” is a polynucleotide that encodes a discrete product, whether RNA or proteinaceous in nature. It is appreciated that more than one polynucleotide may be capable of encoding a discrete product.
  • the term includes alleles and polymorphisms of a gene that encodes the same product, or a functionally associated (including gain, loss, or modulation of function) analog thereof, based upon chromosomal location and ability to recombine during normal mitosis.
  • a biomarker (gene) expression “pattern” or “profile” or “signature” refers to the relative expression of one or more biomarkers (genes) between different cells, which expression is correlated with being able to distinguish between cancer cells that will respond favourably or not to treatment with a PARP inhibitor.
  • a “sequence” or “gene sequence” as used herein is a nucleic acid molecule or polynucleotide composed of a discrete order of nucleotide bases.
  • the term includes the ordering of bases that encodes a discrete product (i.e. "coding region"), whether RNA or proteinaceous in nature, as well as the ordered bases that precede or follow a "coding region". Non-limiting examples of the latter include 5' and 3' untranslated regions of a gene. It is appreciated that more than one polynucleotide may be capable of encoding a discrete product. It is also
  • alleles and polymorphisms of the disclosed sequences may exist and may be used in the practice of the invention to identify the expression level(s) of the disclosed sequences or the allele or polymorphism. Identification of an allele or polymorphism depends in part upon chromosomal location and ability to recombine during mitosis.
  • correlate refers to an association between the expression of one or more genes and the response to treatment with olaparib.
  • correlation refers to an association between the expression of one or more genes and the response to treatment with olaparib.
  • correlation are used more broadly than simply a Pearson or Spearman correlation to refer to an association or relationship which can take one of many forms, as demonstrated in the examples. Correlations may be positive such that high levels of expression are associated with large or positive responses, and low levels of expression are associated with small or negative responses, or negatively correlated, such that high levels of expression are associated with small or negative responses, and low levels of expression are associated with large or positive responses.
  • Expression data may be generated by one or more of a range of gene or protein expression measuring techniques, for example but not limited to, RT-PCR, Affymetrix whole genome microarray profiling for gene expression or IHC or Western Blotting for protein expression. Normalisation is typically applied to the raw data generated from these techniques to remove any artefactual inter-subject differences arising from sample processing or sample quality. Data from RT-PCR is typically normalised by subtracting the average expression of one or more normalisation genes from the observed expression levels of the gene of interest for each sample. Data from Affymetrix whole genome microarrays is typically normalised by the RMA algorithm or one of a number of alternative algorithms including but not limited to MAS5, PLIER, GC-RMA.
  • increases in gene expression can be indicated by ratios of or about 1 .1 , of or about 1 .2, of or about 1 .3, of or about 1 .4, of or about 1 .5, of or about 1 .6, of or about 1 .7, of or about 1 .8, of or about 1 .9, of or about 2, of or about 2.5, of or about 3, of or about 3.5, of or about 4, of or about 4.5, of or about 5, of or about 5.5, of or about 6, of or about 6.5, of or about 7, of or about 7.5, of or about 8, of or about 8.5, of or about 9, of or about 9.5, of or about 10, of or about 15, of or about 20, of or about 30, of or about 40, of or about 50, of or about 60, of or about 70, of or about 80, of or about 90, of or about 100, of or about 150, of or about 200, of or about 300, of or about 400, of or about 500, of or about 600, of or about 700, of or about 800, of or about 900
  • a ratio of 2 is a 100% (or a two-fold) increase in expression.
  • Decreases in gene expression can be indicated by ratios of or about 0.9, of or about 0.8, of or about 0.7, of or about 0.6, of or about 0.5, of or about 0.4, of or about 0.3, of or about 0.2, of or about 0.1 , of or about 0.05, of or about 0.01 , of or about 0.005, of or about 0.001 , of or about 0.0005, of or about 0.0001 , of or about 0.00005, of or about 0.00001 , of or about 0.000005, or of or about 0.000001 .
  • a number of different statistical algorithms can be applied in order to generate a mathematical model combining together the expression levels of two or more genes or proteins with a cut-off to classify subjects as predicted olaparib responders. These include, but are not limited to logistic regression, multiple regression, Cox proportional hazard models, random forests, recursive
  • partitioning random survival forests, partial least squares, partial least squares discriminant analysis, Support Vector Machines, neural networks.
  • amplify is used in the broad sense to mean creating an amplification product, which for example, can be made enzymatically with DNA or RNA polymerases.
  • Amplification generally refers to the process of producing multiple copies of a desired sequence, particularly those of a sample.
  • Multiple copies mean at least 2 copies.
  • a “copy” does not necessarily mean perfect sequence complementarity or identity to the template sequence.
  • Methods for amplifying mRNA are generally known in the art, and include reverse transcription PCR (RT-PCR) and those described in U.S. patent application Ser. No. 10/062,857 (filed on Oct. 25, 2001 ), as well as U.S.
  • RNA may be directly labelled as the corresponding cDNA by methods known in the art.
  • a "microarray” is a linear or two-dimensional array of preferably discrete regions, each having a defined area, formed on the surface of a solid support such as, but not limited to, glass, plastic, or synthetic membrane.
  • the density of the discrete regions on a microarray is determined by the total numbers of immobilized polynucleotides to be detected on the surface of a single solid phase support, for example at least about 50/cm 2 , at least about 100/cm 2 , at least about 500/cm 2 , but preferably below about 1 ,000/cm 2 .
  • the arrays contain less than about 500, about 1000, about 1500, about 2000, about 2500, or about 3000 immobilized polynucleotides in total.
  • a DNA microarray is an array of oligonucleotides or polynucleotides placed on a chip or other surfaces used to hybridize to amplified or cloned polynucleotides from a sample. Since the position of each particular group of primers in the array is known, the identities of a sample polynucleotides can be determined based on their binding to a particular position in the microarray.
  • label refers to a composition capable of producing a detectable signal indicative of the presence of the labelled molecule. Suitable labels include radioisotopes, nucleotide chromophores, enzymes, substrates, fluorescent molecules, chemiluminescent moieties, magnetic particles, bioluminescent moieties, and the like. As such, a label is any composition detectable by
  • support refers to conventional supports such as beads, particles, dipsticks, fibres, filters, membranes and silane or silicate supports such as glass slides.
  • “Expression” and “gene expression” include transcription and/or translation of nucleic acid material.
  • Conditions that "allow” an event to occur or conditions that are “suitable” for an event to occur are conditions that do not prevent such events from occurring. Thus, these conditions permit, enhance, facilitate, and/or are conducive to the event.
  • Such conditions known in the art and described herein, depend upon, for example, the nature of the nucleotide sequence, temperature, and buffer conditions. These conditions also depend on what event is desired, such as hybridization, cleavage, strand extension or transcription.
  • Detection includes any means of detecting, including direct and indirect detection of gene expression and changes therein. For example, “detectably less” products may be observed directly or indirectly, and the term indicates any reduction (including the absence of detectable signal). Similarly, “detectably more” product means any increase, whether observed directly or indirectly.
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e. prophylaxis is also included.
  • efficacious it is meant that the treatment leads to stabilization in tumour size, a decrease in tumour size, or a decrease in metastatic potential of cancer in a subject.
  • BER genes refers to genes associated with Base Excision Repair, a form of DNA repair involved in dealing with DNA single-strand breaks that may occur endogenously or may be induced through various cancer therapies such as ionizing radiation or treatment with DNA damaging chemotherapies. There are a number of genes associated with BER including PARP-1 . Those genes associated with BER for the purpose of this application are listed in Table 1 . Table 1 .
  • complementation group 1 (includes
  • PRIM1 primase DNA, polypeptide 1 (49kDa) 5557 -1 0.0073004 polymerase (DNA directed), epsilon 2
  • GNL3 like 3 (nucleolar) 26354 1 0.0315160 tankyrase, TRF1 -interacting ankyrin-
  • ESPL1 (S. cerevisiae) 9700 0.0649566
  • PARG poly (ADP-ribose) glycohydrolase 8505
  • Recombination repair pathway a form of DNA repair involved in dealing with DNA double strand breaks that may occur endogenously or may be induced through various cancer therapies such as ionizing radiation or treatment with DNA damaging chemotherapies.
  • HR a number of genes associated with HR including BRCA1 , BRCA2, ATM, ATR, CHEK2, MDC1 and MRE1 1A. Those genes associated with HR for the purpose of this application are listed in Table 2.
  • TROAP trophinin associated protein 1002 0.0005769
  • GINS2 GINS complex subunit 2 (Psf2 homolog) 5165 0.002101 1
  • CALM3 calmodulin 3 (phosphorylase kinase, 808 0.0027420 delta)
  • proliferation genes refers to those genes involved in the control of cell cycle and proliferation and for the purpose of this application are listed in Table 3. Table 3.
  • EIF2C3 eukaryotic translation initiation factor 2C, 3 19266 0.0002213
  • AIFM2 apoptosis-inducing factor, mitochondrion- 84883 0.0007537 associated, 2
  • TBC1 D2 TBC1 domain family member 2 55357 -1 0.0007978
  • SAMD1 sterile alpha motif domain containing 1 90378 1 0.0010875
  • EIF2C1 eukaryotic translation initiation factor 2C, 1 26523 1 0.0013255
  • PIAS2 protein inhibitor of activated STAT 2 9063 1 0.0014305
  • MIB2 mindbomb homolog 2 (Drosophila) 14267 0.0018255
  • TIA1 TIA1 cytotoxic granule-associated RNA 7072 0.0022886 binding protein 1
  • ORMDL2 ORM1 -like 2 (S. cerevisiae) 29095 -1 0.0024889
  • PCDHAC2 protocadherin alpha subfamily C 2 56134 1 0.0027171
  • NUDT3 nudix (nucleoside diphosphate linked 1 1 165 0.0039702 moiety X)-type motif 3 1
  • ATAD2 ATPase family AAA domain containing 2 29028 -1 0.0042200
  • IL1 R1 interleukin 1 receptor type I 3554 1 0.0048077
  • NDUFA5 NADH dehydrogenase (ubiquinone) 1 4698 0.0060914
  • PHF21A PHD finger protein 21A 51317 1 0.0068604
  • TP53BP2 tumor protein p53 binding protein 2 7159 1 0.0101765
  • DIRAS3 DIRAS family GTP-binding RAS-like 3 9077 1 0.0193385
  • PRKCA protein kinase C alpha 5578 -1 0.0196635
  • SERPINE1 serpin peptidase inhibitor SERPINE1 serpin peptidase inhibitor, clade E (nexin, 5054 -1 0.021 1086 plasminogen activator inhibitor type 1 ),
  • HNRNPA2B heterogeneous nuclear ribonucleoprotein 3181 0.0215084 1 A2/B1
  • GLIPR1 GLI pathogenesis-related 1 1 1010 -1 0.0289794
  • NUDT1 nudix (nucleoside diphosphate linked 4521 -1 0.0353147 moiety X)-type motif 1
  • CASP1 caspase 1 apoptosis-related cysteine 834 0.0578672 peptidase (interleukin 1 , beta, convertase)
  • PSMB8 proteasome prosome, macropain
  • 5696 -1 0.0714354 subunit, beta type, 8 (large multifunctional
  • oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian)
  • "Directionality" values of -1 represent a biomarker for which a high level of expression was found to be associated with resistance or a low level of expression to be associated with sensitivity (e.g.
  • Values of +1 represent a biomarker for which a high level of expression was found to be associated with sensitivity or a low level of expression to be associated with resistance in Example 4.
  • the biomarkers without a direction are those that did have a strong association in one or more of the analyses, but did not always have a constant direction of association across the different analyses that were performed.
  • the p-value in these tables (also referred to as p.min) is the smallest of the 5 permutation p-values from the DEGNN, DEGTN, DESNG, DEGTG and DES analyses as described in Example 4.
  • NCBI National Center for Biotechnology Information
  • NCBI National Center for Biotechnology Information
  • An 'Entrez Genlnfo Identifier' (“Entrez Gene ID”) sequence identification number is a series of digits assigned consecutively to each sequence record processed by NCBI and is unique to a particular gene and associated DNA sequence
  • Entrez Gene ID refers to the Entrez Database accession number of a sequence of each gene, the sequences of which are hereby incorporated by reference in their entireties as they are available from
  • KU95 panel refers to the panel of 95 cancer cell lines as listed in Table 4 representing breast, ovarian, colorectal, lung, head & neck and pancreatic cancers, tested for their response to treatment with single agent olaparib.
  • IC50 refers to the concentration of olaparib (in ⁇ ) that results in 50% of the number of cell colonies that grow compared to the untreated control.
  • An individual having a cancer condition may comprise one or more cancer cells.
  • Cancer cells in general are characterised by abnormal proliferation relative to normal cells and typically form clusters or tumours in an individual having a cancer condition.
  • the cancer cells may possess a phenotype, which characterises the cancer condition. It is this phenotype that the present invention seeks to identify.
  • a method for selecting a cancer patient for treatment with a PARP inhibitor comprising determining the expression level of PARP-1 and/or MUTYH in a cancer cell containing sample from the patient and if the PARP-1 and/or MUTYH expression level is not low, identifying or selecting the patient for treatment with a PARP inhibitor.
  • a suitable PARP inhibitor is olaparib.
  • the expression levels of both PARP-1 and MUTYH are determined.
  • the expression level of one or more genes involved in homologous recombination repair as listed in Table 2 is also measured.
  • the patient is then identified or selected for treatment with a PARP inhibitor if the expression profile of the biomarkers identifies the patient as being a likely responder to treatment with the PARP inhibitor.
  • a patient whose cancer cells do not express low levels of PARP-1 or MUTYH but do express low levels of any of the homologous recombination repair genes selected from the group consisting of: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1 A is selected for treatment and/or treated with the PARP inhibitor compound.
  • the invention provides a method for selecting a cancer patient for PARP inhibitor based therapy comprising: measuring the amount of PARP-1 and at least one other biomarker selected from: ATM, BRCA1 , BRCA2, MRE1 1 A, ATR, CHEK2 and MDC1 , in a tumour cell containing sample from said cancer patient, comparing these amounts to reference values; and, selecting the patient for treatment with PARP inhibitor based therapy if, compared to the reference values, the level of PARP-1 is not low and the level of the other biomarker is reduced in the tumour cell containing sample from said cancer patient.
  • the invention provides a method for selecting a cancer patient for PARP inhibitor based therapy comprising: measuring the amount of MUTYH and at least one other biomarker selected from: ATM, BRCA1 , BRCA2, MRE1 1 A, ATR, CHEK2 and MDC1 , in a tumour cell containing sample from said cancer patient, comparing these amounts to reference values; and, selecting the patient for treatment with PARP inhibitor based therapy if, compared to the reference values, the level of MUTYH is not low and the level of the other biomarker is reduced in the tumour cell containing sample from said cancer patient.
  • the methods of the invention can be applied to testing colorectal or gastric cancers.
  • the measurement of PARP-1 and ATM and/or MRE1 1 A can be used to select or identify colorectal or gastric cancer patients for treatment with a PARP inhibitor as required.
  • a PARP inhibitor compound in the manufacture of a medicament for treating a patient suffering from colorectal cancer whose cancer cells are deficient in ATM and/or MRE1 1 A.
  • a method for selecting a colorectal cancer patient for PARP inhibitor based therapy comprising: measuring the amount of ATM and/or MRE1 1 A in a tumour cell containing sample from said cancer patient, comparing these amounts to reference values; and, selecting the patient for treatment with PARP inhibitor based therapy if, compared to the reference values, the level of ATM and/or MRE1 1A is low.
  • a PARP inhibitor compound in the manufacture of a medicament for treating a patient suffering from gastric cancer whose cancer cells are deficient in ATM.
  • a method for selecting a gastric cancer patient for PARP inhibitor based therapy comprising: measuring the amount of ATM in a tumour cell containing sample from said cancer patient, comparing these amounts to reference values; and, selecting the patient for treatment with PARP inhibitor based therapy if, compared to the reference values, the level of ATM is low.
  • a method for identifying whether an individual with cancer will likely be responsive to a treatment with a PARP inhibitor drug comprising:
  • a first gene expression profile which profile includes one or more genes from Table 1 such as PARP-1 , MUTYH, POLD1 and POLE3, at least one gene from Table 2 and at least one gene from Table 3;
  • the inventors have found that a multiplex diagnostic involving at least one gene from each of Tables 1 , 2 and 3, yields even greater statistically significant prediction of likely response to PARP inhibitor than either PARP-1 or an HR deficiency alone.
  • MUTYH was found to be extremely predictive (even when used alone) and examples were also identified where POLD1 or POLE3 could replace PARP-1 or MUTYH from the BER group of genes providing predictive value.
  • BER genes that were particularly useful include POLD1 and POLE3.
  • HR group of genes Table 2
  • Table 12 shows that each of AURKA, SMARCD3, ZIC1 , SSX2IP, BOC, POLH, TP53BP2, SCMH1 , SMARCA5, MRAS, IP6K2, GTF2H4, MBD1 , RASA3, ZMYM4, PHF13, ARNT, KDM4A, PCBP4, TLR4, NUDT1 , PMS1 and ZMYM6 increased the predictive value when combined with a gene from Table 1 and Table 2.
  • the invention provides a method for selecting a cancer patient for treatment with a PARP inhibitor comprising measuring the expression level of at least one BER biomarker from Table 1 , at least one homologous recombination biomarker from Table 2 and at least one proliferation biomarker from Table 3, in a cancer cell containing sample obtained from the patient and selecting the patient for treatment with a PARP inhibitor if the expression profile of the at least three biomarkers identifies the patient as being a likely responder to treatment with the PARP inhibitor.
  • the biomarker(s) from Table 1 is selected from PARP-1 and MUTYH, POLD1 or POLE3.
  • the homologous recombination biomarker from Table 2 is selected from: MCM2, XRCC3, BRCA1 , MDC1 , ATM, ATR, NBN, RAD51 and MRE1 1A.
  • the proliferation biomarker from Table 3 is selected from: AURKA, SMARCD3, ZIC1 , SSX2IP, BOC, POLH, TP53BP2, SCMH1 , SMARCA5, MRAS, IP6K2, GTF2H4, MBD1 , RASA3, ZMYM4, PHF13, ARNT, KDM4A, PCBP4, TLR4, NUDT1 , PMS1 and ZMYM6.
  • AURKA, SMARCD3, ZIC1 , SSX2IP and BOC is selected from: MCM2, XRCC3, BRCA1 , MDC1 , ATM, ATR, NBN, RAD51 and MRE1 1A.
  • the proliferation biomarker from Table 3 is selected from: AURKA, SMARCD3, Z
  • one or more, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the other biomarkers identified in Table 1 are also assessed for their expression level.
  • At least 2, at least 3, at least 4, at least 5 or more BER biomarkers from Table 1 are assessed. In certain other embodiments, when more than one BER biomarker is assessed, one of these is PARP-1 or MUTYH.
  • At least 2, such as 3, 4, 5, 6, 7, 8, 9, 10, or more of the other biomarkers identified in Table 2 are also assessed for their expression level.
  • at least one HR biomarker is selected from the first 20 biomarkers listed in Table 2.
  • at least 2, at least 3, at least 4, at least 5 or more HR biomarkers from Table 2 are assessed.
  • the HR biomarker is selected from the group consisting of: MCM2, XRCC3, BRCA1 , MDC1 , ATM, ATR, NBN, RAD51 and MRE1 1A.
  • At least 2, such as 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 or more of the other biomarkers identified in Table 3 are also assessed for their expression level.
  • the at least one proliferation biomarker is selected from the first 20 biomarkers listed in Table 3.
  • at least 2, at least 3, at least 4, at least 5 or more proliferation biomarkers from Table 3 are assessed.
  • the proliferation biomarker from Table 3 is selected from: AURKA, SMARCD3, ZIC1 , SSX2IP, BOC, POLH, TP53BP2, SCMH1 , SMARCA5, MRAS, IP6K2, GTF2H4, MBD1 , RASA3, ZMYM4, PHF13, ARNT, KDM4A, PCBP4, TLR4, NUDT1 , PMS1 and ZMYM6, in particular from AURKA, SMARCD3, ZIC1 , SSX2IP and BOC.
  • the combination of 1 biomarker from Table 1 , one from Table 2 and one from Table 3 is any of the combinations shown in Figures 6- 10. According to certain embodiments, the methods of the invention involve
  • the set of biomarkers may involve just the recited 3 biomarkers or it may also involve one or more additional biomarkers, which additional biomarker may be from Table 1 , 2 or 3.
  • the differential biomarker expression values thus provide a profile of expression for the particular cancer cells and a prediction of likely response to treatment with a PARP inhibitor.
  • the examples described herein assessed the expression levels of each of the biomarkers listed in Tables 1 , 2 and 3 in the 95 cancer cell lines and determined a p-value for the expression of the marker in olaparib sensitive cell lines, compared to resistant cell lines.
  • the highest ranked biomarkers are predicted to be those that will deliver the best predictive value either alone or when combined with the biomarkers from the other Tables. However, it will be appreciated that the most predictive biomarkers for a particular cancer type will likely differ from the most predictive biomarkers for a different cancer type.
  • the one or more biomarker(s), in addition to PARP-1 and/or MUTYH, from Table 1 that are measured are selected from: POLD1 and POLE3.
  • the one or more biomarkers that are measured are selected from the group consisting of MCM2, XRCC3, BRCA1 , MDC1 , ATM, ATR, NBN, RAD51 and MRE1 1 A.
  • the one or more biomarkers that are measured are selected from the first 20 listed in Table 3.
  • the one or more biomarkers that are measured are selected from the group consisting of: AURKA, SMARCD3, ZIC1 , SSX2IP, BOC, POLH, TP53BP2, SCMH1 , SMARCA5, MRAS, IP6K2, GTF2H4, MBD1 , RASA3, ZMYM4, PHF13, ARNT, KDM4A, PCBP4, TLR4, NUDT1 , PMS1 and ZMYM6, in particular from AURKA, SMARCD3, ZIC1 , SSX2IP and BOC.
  • diagnostic patient selection methods do not involve the actual step of isolating the cancer cell-containing sample. Rather they are carried out on samples that have previously been isolated and are thus ex vivo diagnostic tests.
  • An individual suitable for treatment or identification as described herein may include a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), a murine (e.g. a mouse), a canine (e.g. a dog), a feline (e.g. a cat), an equine (e.g. a horse), a primate, such as a simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, gibbon), or a human.
  • the various aspects of the invention are particularly suited for application to humans.
  • Biomarker expression patterns of the invention may be identified by analysis of gene expression in samples containing cancer cells, e.g. tumour biopsies or blood samples that contain circulating cancer cells.
  • the overall gene expression profile of a sample can be obtained through quantifying the expression levels of mRNA or protein corresponding to one or more of the genes (biomarkers) identified herein, that the inventors have found correlate with response to PARP inhibitor.
  • the correlated biomarkers may be used singly with significant accuracy or in combination to increase the ability to accurately predict favourable treatment with a PARP inhibitor, in particular olaparib.
  • the present invention thus provides means for correlating a molecular expression phenotype with likely outcome following PARP inhibitor treatment.
  • Expression of the biomarkers can be determined at the protein or nucleic acid level using any method known in the art. For example, at the nucleic acid level Northern hybridization analysis using probes which specifically recognize one or more of these sequences can be used to determine gene expression.
  • expression can be measured using reverse-transcription-based PCR assays, e.g., using primers specific for the differentially expressed sequence of genes.
  • the diagnostic methods of the invention are carried out on fresh samples, frozen samples or formalin-fixed, paraffin-embedded tissue samples.
  • An assay of the invention may utilize a means related to the expression level of a biomarker disclosed herein as long as the assay reflects, quantitatively or qualitatively, expression of the biomarker.
  • a quantitative assay is performed. The ability to discriminate is conferred by the identification of expression of the individual biomarkers as relevant and not by the form of the assay used to determine the actual level of expression.
  • An assay may utilize any identifying feature of an identified individual biomarker as disclosed herein as long as the assay reflects, quantitatively or qualitatively, expression of the biomarker. Identifying features include, but are not limited to, unique nucleic acid sequences used to encode (DNA), or express (RNA), said gene or epitopes specific to, or activities of, a protein encoded by said gene.
  • Alternative means include detection of nucleic acid amplification as indicative of increased expression levels and nucleic acid inactivation, deletion, or methylation, as indicative of decreased expression levels.
  • the invention may be practiced by assaying one or more aspect of the DNA template(s) underlying the expression of the disclosed sequence(s), of the RNA used as an intermediate to express the sequence(s), or of the
  • cancer cell-containing sample from the patient for analysis.
  • This can for example, be cells from a solid biopsy sample or may be circulating cancer (tumour) cells (CTCs).
  • any method known in the art may be utilized.
  • expression based on detection of mRNA, which hybridizes to the genes identified and disclosed herein is used. This is readily performed by any RNA detection or amplification+detection method known or recognized as equivalent in the art such as, but not limited to, reverse transcription-PCR, the methods disclosed in U.S. patent publication number US2003/0022194 (claiming priority from U.S. patent application Ser. No.
  • RNA stabilizing or destabilizing sequences 60/298,847 and 60/257,801 , and US regular application 10/062,857), and methods to detect the presence, or absence, of RNA stabilizing or destabilizing sequences.
  • the detection of gene expression from the samples may be by use of a single microarray able to assay gene expression of the genes disclosed herein.
  • the expression levels are determined by microarray analysis.
  • one embodiment of the invention involves determining expression by hybridization of mRNA, or an amplified or cloned version thereof, of a sample cell to a polynucleotide that is unique to a particular gene sequence.
  • one or more sequences capable of hybridising to one or more of the genes identified herein is immobilised on a solid support or microarray.
  • the immobilized gene(s) may be in the form of polynucleotides that are unique or otherwise specific to the gene(s) such that the polynucleotide would be capable of hybridizing to a DNA or RNA corresponding to the gene(s).
  • These polynucleotides may be the full length of the gene(s) or be short sequences of the genes (up to one nucleotide shorter than the full length sequence known in the art by deletion from the 5' or 3' end of the sequence) that are optionally minimally interrupted (such as by mismatches or inserted non-complementary base pairs) such that hybridization with a DNA or RNA corresponding to the gene(s) is not affected.
  • the polynucleotides used are from the 3' end of the gene, such as within about 350, about 300, about 250, about 200, about 150, about 100, or about 50 nucleotides from the polyadenylation signal or
  • Preferred polynucleotides contain at least about 18, at least about 20, at least about 22, at least about 24, at least about 26, at least about 28, at least about 30, or at least about 32, at least about 34, at least about 36, at least about 38, at least about 40, at least about 42, at least about 44, or at least about 46 consecutive base pairs of a gene sequence that is not found in other gene sequences.
  • the term "about” as used in the previous sentence refers to an increase or decrease of 1 from the stated numerical value.
  • the term "about” as used in the preceding sentence refers to an increase or decrease of 10% from the stated numerical value.
  • polynucleotides may also be referred to as polynucleotide probes that are capable of hybridizing to sequences of the genes, or unique portions thereof, described herein.
  • the sequences are those of mRNA encoded by the genes, the corresponding cDNA to such mRNAs, and/or amplified versions of such sequences.
  • the polynucleotide probes are immobilized on a microarray, other devices, or in individual spots that localize the probes on a support. Polynucleotides containing mutations relative to the sequences of the disclosed genes may also be used so long as the presence of the mutations still allows hybridization to produce a detectable signal.
  • all or part of a disclosed biomarker sequence may be amplified and detected by methods such as the polymerase chain reaction (PCR) and variations thereof, such as, but not limited to,
  • PCR polymerase chain reaction
  • Q-PCR quantitative PCR
  • RT-PCR reverse transcription PCR
  • real-time PCR including as a means of measuring the initial amounts of mRNA copies for each sequence in a sample
  • Q-PCR quantitative PCR
  • RT-PCR reverse transcription PCR
  • real-time PCR including as a means of measuring the initial amounts of mRNA copies for each sequence in a sample
  • Q-PCR quantitative PCR
  • RT-PCR reverse transcription PCR
  • real-time PCR including as a means of measuring the initial amounts of mRNA copies for each sequence in a sample
  • Q-PCR quantitative PCR
  • RT-PCR reverse transcription PCR
  • real-time PCR including as a means of measuring the initial amounts of mRNA copies for each sequence in a sample
  • Q-PCR quantitative PCR
  • RT-PCR reverse transcription PCR
  • real-time PCR including as a means of measuring the initial amounts of mRNA copies for each sequence in a sample
  • Q-PCR quantitative PCR
  • RT-PCR reverse transcription PCR
  • the expression level is determined by reverse phase polymerase chain reaction (RT-PCR).
  • RT-PCR reverse phase polymerase chain reaction
  • RNA is fragmented.
  • the nucleic acid derived from the sample cancer cell(s) may be preferentially amplified by use of appropriate primers such that only the genes to be analyzed are amplified to reduce contaminating background signals from other genes expressed in the cancer cell.
  • the nucleic acid from the sample may be globally amplified before hybridization to the immobilized polynucleotides.
  • RNA or the cDNA counterpart thereof may be directly labelled and used, without amplification, by methods known in the art.
  • the isolation and analysis of a cancer-cell containing sample may be performed as follows: (1 ) RNA is extracted from a tissue biopsy sample obtained from a cancer patient;
  • RNA is purified, amplified, and labelled
  • Binding of a probe to target nucleic acid may be measured using any of a variety of techniques at the disposal of those skilled in the art.
  • probes may be radioactively, fluorescently or enzymatically labelled.
  • Other methods not employing labelling of probe include examination of restriction fragment length polymorphisms, amplification using PCR, RN'ase cleavage and allele specific oligonucleotide probing.
  • Suitable selective hybridisation conditions for oligonucleotides of 17 to 30 bases include hybridization overnight at 42°C in 6X SSC and then washing in 6X SSC at a series of increasing temperatures from 42°C to 65°C.
  • probes may be washed in 6xSSC at 42 °C for 30 minutes then 6xSSC at 50°C for 45 mins then 2xSSC for 45 mins at 65°C.
  • Other suitable conditions and protocols are described in Molecular Cloning: a Laboratory Manual: 3rd edition, Sambrook & Russell (2001 ) Cold Spring Harbor Laboratory Press NY and Current Protocols in
  • gene expression may be determined at the protein level, e.g. by measuring the levels of peptides encoded by the gene products described herein, or activities thereof.
  • Such methods are well known in the art and include, e.g., any immunohistochemistry (IHC) based, blood based (especially for secreted proteins), antibody (including autoantibodies against the protein) based, ex foliate cell (from the cancer) based, mass spectroscopy based, and image (including used of labelled ligand) based method known in the art and recognized as appropriate for the detection of the protein.
  • the detection is via an immunoassay that uses one or more antibodies specific for one or more epitopes of individual gene products in a cell sample of interest. Any biological material can be used for the
  • a suitable method can be selected to determine the activity of proteins encoded by the marker genes according to the activity of each protein analyzed.
  • the biomarker proteins can be detected in any suitable manner, but are typically detected by contacting a sample from the patient with an antibody that binds the biomarker protein and then detecting the presence or absence of a reaction product. Such as, by use of labelled antibodies against cell surface markers followed by fluorescence activated cell sorting (FACS). Such antibodies are preferably labelled to permit their easy detection after binding to the gene product.
  • Detection methodologies suitable for use in the practice of the invention include, but are not limited to, immunohistochemistry of cell containing samples or tissue, enzyme linked immunosorbent assays (ELISAs) including antibody sandwich assays of cell containing tissues or blood samples, mass spectroscopy, and immuno-PCR.
  • the antibody may be monoclonal, polyclonal, chimeric, or a fragment of the foregoing, as discussed in detail above, and the step of detecting the reaction product may be carried out with any suitable immunoassay.
  • the sample from the subject is typically a solid tissue sample, e.g. a biopsy, as described above, but may be a cancer cell containing biological fluid, e.g. blood or serum sample.
  • the sample may be in the form of a tissue specimen from a patient where the specimen is suitable for immunohistochemistry in a variety of formats such as paraffin-embedded tissue, frozen sections of tissue, and freshly isolated tissue.
  • the immunodetection methods are antibody-based but there are numerous additional techniques that allow for highly sensitive determinations of binding to an antibody in the context of a tissue. Those skilled in the art will be familiar with various immunohistochemistry strategies.
  • Immunoassays carried out in accordance with the present invention may be homogeneous assays or heterogeneous assays.
  • the immunological reaction usually involves the specific antibody (e.g., anti- biomarker protein antibody), a labelled analyte, and the sample of interest.
  • the signal arising from the label is modified, directly or indirectly, upon the binding of the antibody to the labelled analyte.
  • Both the immunological reaction and detection of the extent thereof are carried out in a homogeneous solution.
  • Immunochemical labels that may be employed include free radicals, radioisotopes, fluorescent dyes, enzymes, bacteriophages, or coenzymes.
  • the reagents are usually the sample, the antibody, and means for producing a detectable signal.
  • Samples as described above may be used.
  • the antibody is generally immobilized on a support, such as a bead, plate or slide, and contacted with the specimen suspected of containing the antigen in a liquid phase.
  • the support is then separated from the liquid phase and either the support phase or the liquid phase is examined for a detectable signal employing means for producing such signal.
  • the signal is related to the presence of the analyte in the sample.
  • Means for producing a detectable signal include the use of radioactive labels, fluorescent labels, or enzyme labels.
  • an antibody which binds to that site can be conjugated to a detectable group and added to the liquid phase reaction solution before the separation step.
  • the presence of the detectable group on the solid support indicates the presence of the antigen in the test sample.
  • suitable immunoassays are radioimmunoassays, immunofluorescence methods, chemiluminescence methods, electrochemiluminescence or enzyme-linked immunoassays.
  • Antibodies may be conjugated to a solid support suitable for a diagnostic assay (e.g., beads, plates, slides or wells formed from materials such as latex or polystyrene) in accordance with known techniques, such as passive binding.
  • a diagnostic assay e.g., beads, plates, slides or wells formed from materials such as latex or polystyrene
  • Antibodies as described herein may likewise be conjugated to detectable groups such as radiolabels (e.g., 35 S, 125 I, 131 I), enzyme labels (e.g., horseradish peroxidase, alkaline phosphatase), and fluorescent labels (e.g., fluorescein) in accordance with known techniques.
  • radiolabels e.g., 35 S, 125 I, 131 I
  • enzyme labels e.g., horseradish peroxidase, alkaline phosphatase
  • fluorescent labels e.g., fluorescein
  • nucleic acid probes e.g., oligonucleotides, aptamers, siRNAs against any of the biomarkers in Tables 1 , 2 or 3.
  • the present invention may be practised with any subset of the genes, as disclosed herein.
  • 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 15 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more or all the genes provided in Table 1 , 2 or 3 below may be used in combination to increase the accuracy of the method.
  • the invention thus specifically contemplates the use of a multiplex assay system employing a number of biomarkers from each of Tables 1 , 2 and 3 for use as a subset in the identification of whether a cancer sample is one that will respond favourably to treatment with a PARP inhibitor.
  • a number of different statistical algorithms can be applied in order to generate a mathematical model combining together the expression levels of two or more genes or proteins with a cut-off to classify subjects as predicted olaparib responders. These include, but are not limited to logistic regression, multiple regression, Cox proportional hazard models, random forests, recursive
  • partitioning random survival forests, partial least squares, partial least squares discriminant analysis, Support Vector Machines, neural networks.
  • Increases and decreases in expression of the disclosed sequences can be determined based upon percent or fold changes over expression in normal cells, reference cells or normalised against one or more housekeeping genes. Increases may be of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200% relative to expression levels in normal cells. Alternatively, fold increases may be of 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 fold over expression levels in normal cells.
  • Decreases may be of 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 99 or 100% relative to expression levels in normal cells. For example, a 2-fold increase or decrease is a useful measure for determining whether or not the expression level is low or high.
  • the actual level of expression of any biomarker used according to the invention to predict response to a PARP inhibitor will need to be determined empirically using clinical samples and an appropriate algorithm as described further herein.
  • kits comprising agents for the detection of expression of the disclosed genes for determining susceptibility to treatment with a PARP inhibitor.
  • a kit may comprise separate containers, each with one or more of the various reagents (typically in concentrated form) utilized in the methods, e.g., The kit may contain in separate containers one or more nucleic acids or antibodies (either already bound to a solid matrix or packaged separately with reagents for binding them to the matrix), control formulations (positive and/or negative), and/or a detectable label, as well as other reagents such as buffers, nucleotide
  • kits packaged together in the form of a kit.
  • Instructions e.g., written, or on electronic medium, e.g. CD-ROM, etc.
  • the assay may for example be in the form of a Northern hybridization or a sandwich ELISA as known in the art.
  • Suitable cancer cell(s) for use in the described methods may be obtained from an individual in a tissue sample for example a biopsy from a cancerous tissue or a blood sample that contains circulating tumour cells.
  • the cancer can be any cancer.
  • the cancer is selected from the group consisting of breast cancer, colorectal cancer, head and neck cancer, lung cancer, gastric cancer, prostate, haematological cancers, pancreatic cancer and ovarian cancer.
  • the expression level of the biomarker(s) can be compared to that detected in control cell(s), which may be obtained from non-cancerous tissue from the same or a different individual.
  • Suitable controls include non-cancer cells from the same tissue or lineage. Comparison can be performed on test and reference samples measured concurrently or at temporally distinct times. An example of the latter is the use of compiled expression information, e.g., a sequence database, which assembles information about expression levels of the biomarker(s). If the reference sample, e.g., a control sample is from cells that are sensitive to a therapeutic compound then a similarity in the amount of the biomarker proteins in the test sample and the reference sample indicates that treatment with that therapeutic compound will be efficacious.
  • a change in the amount of the biomarker in the test sample and the reference sample indicates treatment with that compound will result in a less favourable clinical outcome or prognosis.
  • the reference sample e.g., a control sample is from cells that are resistant to a therapeutic compound
  • a similarity in the amount of the biomarker proteins in the test sample and the reference sample indicates that the treatment with that compound will result in a less favourable clinical outcome or prognosis.
  • a change in the amount of the biomarker in the test sample and the reference sample indicates that treatment with that therapeutic compound will be efficacious.
  • the pattern of biomarker expression in the test sample is measured and then may be normalised against one or more control genes.
  • control genes against which the biomarker expression levels can be normalised include, but are not limited to: ACTB (ACTB 60), B2M (B2M 567), GAPDH (GAPDH 2597), GUSB (GUSB 2990), HMBS (HMBS 3145), HPRT1 (HPRT1 3251 ), IPO8 (IPO8 10526), PGK1 (PGK1 5230), POLR2A (POLR2A 5430), PPIA (PPIA 5478), RPLP0 (RPLP0 6175), TBP (TBP 6908), TFRC (TFRC 7037), UBC (UBC 7316), YWHAZ (YWHAZ 7534);
  • the Entrez gene IDs are in brackets. Another commonly used housekeeping gene is 18s rRNA (Genbank accession number is X03205).
  • a mathematical algorithm which has been pre-determined by the analysis of preclinical or historical clinical data cane then be applied to the expression measures to give a prediction of the sensitivity to olaparib.
  • the methods provided by the present invention may also be automated in whole or in part. All aspects of the present invention may also be practiced such that they consist essentially of a subset of the disclosed genes to the exclusion of material irrelevant to the identification of cells treatable with a PARP inhibitor.
  • the diagnostic methods permit the identification of which patient or patient populations are likely to be responsive to treatment with a PARP inhibitor, such as olaparib. Accordingly, the present invention also opens up the possibility of treating the patient or patient populations identified as likely to be responsive to a PARP inhibitor.
  • a method of treating a patient suffering from cancer comprising determining whether or not the patient will respond favourably to a PARP inhibitor according the method as claimed in any of claims, and administering an effective amount of a PARP inhibitor to said patient if they are identified as likely to be responsive to treatment with a PARP inhibitor.
  • a method of treating cancer comprising determining the expression level of PARP-1 in a cancer cell containing sample from the subject and if the PARP-1 expression level is not low, administering to the subject an effective amount of a PARP inhibitor.
  • the PARP inhibitor is olaparib.
  • a method of treating cancer comprising determining the expression level of PARP-1 and/or MUTYH and one or more genes involved in homologous recombination repair as listed in Table 2 in a cancer cell containing sample from a patient, and administering an effective amount of a PARP inhibitor compound to a patient whose cancer cells do not express low levels of PARP-1 or MUTYH but do express differences in expression in any of the homologous recombination repair genes according to Table 2, and in particular the directionality shown therein.
  • the PARP inhibitor is olaparib.
  • the homologous recombination repair gene is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1 A.
  • a method of treating cancer comprising measuring the expression level of at least one base excision repair biomarker from Table 1 , at least one homologous recombination biomarker from Table 2 and at least one proliferation biomarker from Table 3, in a cancer cell containing sample obtained from the patient and if the expression profile of the biomarkers identifies the patient as being a likely responder to treatment with the PARP inhibitor, administering to said patient an effective amount of a PARP inhibitor.
  • the PARP inhibitor is olaparib.
  • the biomarker(s) from Table 1 is selected from PARP-1 and MUTYH.
  • the homologous recombination biomarker from Table 2 is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1A.
  • the proliferation biomarker from Table 3 is selected from AURKA, SMARCD3, ZIC1 , SSX2IP, BOC, POLH, TP53BP2, SCMH1 , SMARCA5, MRAS, IP6K2, GTF2H4, MBD1 , RASA3, ZMYM4, PHF13, ARNT, KDM4A, PCBP4, TLR4, NUDT1 , PMS1 and ZMYM6.
  • a method for selecting a cancer patient for treatment with a PARP inhibitor comprising: measuring the expression level of at least three biomarker RNA transcripts or their products in a cancer cell containing sample obtained from said patient, wherein at least one of the biomarkers is selected from Table 1 , at least one of the biomarkers is selected from Table 2; and, at least one of the biomarkers is selected from Table 3, comparing the level of each measured biomarker in the sample to a reference level; and selecting a patient for treatment with a PARP inhibitor based on the biomarker levels present in the sample, with the proviso that PARP-1 represents one biomarker from Table 1 whose expression level is measured.
  • a PARP inhibitor for use in the treatment of a cancer patient whose cancer cells have been identified as not expressing low levels of PARP-1 .
  • the PARP inhibitor is olaparib.
  • a PARP inhibitor for use in the treatment of a cancer patient whose cancer cells have been identified as not expressing low levels of MUTYH.
  • the PARP inhibitor is olaparib.
  • a PARP inhibitor for use in the treatment of a cancer patient whose cancer cells have been identified as not expressing low levels of MUTYH do express differences in expression in any of the homologous recombination repair genes according to Table 2, and in particular differences in the directionality shown in Table 2.
  • the PARP inhibitor is olaparib.
  • the homologous recombination repair gene is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1A.
  • a PARP inhibitor for use in the treatment of a cancer patient whose cancer cells have been identified as being likely to be responsive to treatment with the PARP inhibitor according to the expression profile generated by measuring the expression levels of PARP-1 and/or MUTYH and at least one homologous recombination repair gene from Table 2.
  • BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1 A is selected for treatment and/or treated with the PARP inhibitor compound.
  • a PARP inhibitor for use in the treatment of a cancer patient whose cancer cells have been identified as being likely to respond to treatment with the PARP inhibitor according to the gene expression profile generated by measuring the expression level of at least one base excision repair biomarker from Table 1 , at least one homologous recombination biomarker from Table 2 and at least one proliferation biomarker from Table 3, in a cancer cell containing sample obtained from the patient .
  • the PARP inhibitor is olaparib.
  • the biomarker(s) from Table 1 is selected from PARP-1 and MUTYH.
  • the homologous recombination biomarker from Table 2 is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1 A.
  • the proliferation biomarker from Table 3 is selected from AURKA, SMARCD3, ZIC1 , SSX2IP, BOC, POLH, TP53BP2, SCMH1 , SMARCA5, MRAS, IP6K2, GTF2H4, MBD1 , RASA3, ZMYM4, PHF13, ARNT, KDM4A, PCBP4, TLR4, NUDT1 , PMS1 and ZMYM6.
  • a PARP inhibitor in the manufacture of a medicament for treating a cancer patient whose cancer cells have been identified as not expressing low levels of PARP-1 .
  • the PARP inhibitor is olaparib.
  • a PARP inhibitor in the manufacture of a medicament for treating a cancer patient whose cancer cells have been identified as not expressing low levels of MUTYH.
  • the PARP inhibitor is olaparib.
  • a PARP inhibitor in the manufacture of a medicament for treating a cancer patient whose cancer cells have been identified as being likely to be responsive to treatment with the PARP inhibitor according to the expression profile generated by measuring the expression levels of PARP-1 and/or MUTYH and at least one homologous recombination repair gene from Table 2.
  • the cancer cells are identified as being likely to be responsive to treatment with the PARP inhibitor if the cancer cells do not express low levels of PARP-1 and/or MUTYH but do express low levels of any of the homologous recombination repair genes from Table 2.
  • the PARP inhibitor is olaparib.
  • the cancer cells are identified as being likely to be responsive to treatment with the PARP inhibitor if the cancer cells do not express low levels of PARP-1 and/or MUTYH but do express low levels of any of the homologous recombination repair genes from Table 2.
  • the PARP inhibitor is olaparib.
  • homologous recombination repair gene is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1 A.
  • a PARP inhibitor in the manufacture of a medicament for treating a cancer patient whose cancer cells have been identified as not expressing low levels of PARP-1 and/or MUTYH but do express differences in expression in any of the homologous recombination repair genes according to Table 2, and in particular according to the directionality in Table 2.
  • the PARP inhibitor is olaparib.
  • the homologous recombination repair gene is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1 A.
  • a PARP inhibitor in the manufacture of a medicament for treating a cancer patient whose cancer cells have been identified as not expressing low levels of PARP-1 and/or MUTYH but do express differences in expression in any of the homologous recombination repair genes according to Table 2, and in particular according to the directionality in Table 2.
  • a PARP inhibitor in the manufacture of a medicament for treating a cancer patient whose cancer cells have been tested for expression level of at least one base excision repair biomarker from Table 1 , at least one homologous recombination biomarker from Table 2 and at least one proliferation biomarker from Table 3, and the expression profile of the biomarkers has identified the patient as being a likely responder to treatment with the PARP inhibitor.
  • the PARP inhibitor is olaparib.
  • the biomarker(s) from Table 1 is selected from PARP-1 and MUTYH.
  • the homologous recombination biomarker from Table 2 is selected from: BRCA1 , BRCA2, MDC1 , ATM, ATR, CHEK2 and MRE1 1A.
  • the proliferation biomarker from Table 3 is selected from AURKA, SMARCD3, ZIC1 , SSX2IP, BOC, POLH, TP53BP2, SCMH1 , SMARCA5, MRAS, IP6K2, GTF2H4, MBD1 , RASA3, ZMYM4, PHF13, ARNT, KDM4A, PCBP4, TLR4, NUDT1 , PMS1 and ZMYM6.
  • a treatment regimen comprising administration of a PARP inhibitor to a patient may be designed for an individual identified according to the present invention.
  • a suitable PARP inhibitor may be selected and the dosage and schedule of administration established for the individual using appropriate medical criteria.
  • the methods described herein may be particularly useful in identifying cohorts of cancer patients, for example for clinical trials of PARP inhibitor compounds.
  • 'PARP' refers to PARP-1 (EC 2.4.2.30, Genbank No: M32721 .1 Gl: 190266, D'Amours et al, (1999) Biochem. J. 342: 249-268; Ame et al., BioEssays (2004) 26 882-893) and/or PARP2 (Ame et al., J. Biol. Chem.
  • PARP inhibition may be determined using conventional methods, including for example dot blots (Affar EB et al., Anal Biochem. 1998; 259(2):280-3), and BER assays that measure the direct activity of PARP to form poly ADP-ribose chains for example by using radioactive assays with tritiated substrate NAD or specific antibodies to the polymer chains formed by PARP activity (K.J. Dillon et al, Journal of Biomolecular Screening, 8(3): 347-352 (2003). Examples of suitable methods for determining PARP activity are described below.
  • Examples of compounds which are known PARP inhibitors and which may be used in accordance with the invention include:
  • Nicotinamides such as 5-methyl nicotinamide and O-(2-hydroxy-3- piperidino-propyl)-3-carboxylic acid amidoxime, and analogues and derivatives thereof.
  • Benzamides including 3-substituted benzamides such as 3- aminobenzamide, 3-hydroxybenzamide, 3-nitrosobenzamide, 3- methoxybenzamide and 3-chloroprocainamide, and 4-aminobenzamide, 1 , 5-di[(3- carbamoylphenyl)aminocarbonyloxy] pentane, and analogues and derivatives thereof.
  • Isoquinolinones and Dihydroisoquinolinones including 2H-isoquinolin-1 -ones, 3H-quinazolin-4-ones, 5-substituted dihydroisoquinolinones such as 5-hydroxy dihydroisoquinolinone, 5-methyl dihydroisoquinolinone, and 5-hydroxy
  • Benzimidazoles and indoles including benzoxazole-4-carboxamides, benzimidazole-4-carboxamides, such as 2-substituted benzoxazole 4- carboxamides and 2-substituted benzimidazole 4-carboxamides such as 2-aryl benzimidazole 4-carboxamides and 2-cycloalkylbenzimidazole-4-carboxamides including 2-(4-hydroxphenyl) benzimidazole 4-carboxamide,
  • Phthalazin-1 (2H)-ones and quinazolinones such as 4-hydroxyquinazoline, phthalazinone, 5-methoxy-4-methyl-1 (2) phthalazinones, 4-substituted
  • phthalazinones 4-(1 -piperazinyl)-1 (2H)-phthalazinone, tetracyclic benzopyrano[4, 3, 2-de] phthalazinones and tetracyclic indeno [1 , 2, 3-de] phthalazinones and 2- substituted quinazolines, such as 8-hydroxy-2-methylquinazolin-4-(3H) one, tricyclic phthalazinones and 2-aminophthalhydrazide, and analogues and derivatives thereof.
  • Phenanthridines and phenanthhdinones such as 5[H]phenanthhdin-6-one, substituted 5[H] phenanthridin-6-ones, especially 2-, 3- substituted 5[H]
  • 6(5H)phenanthhdinones thieno[2, 3-c]isoquinolones such as 9-annino thieno[2, 3- c]isoquinolone and 9-hydroxythieno[2, 3-c]isoquinolone, 9-methoxythieno[2, 3- c]isoquinolone, and N-(6-oxo-5, 6-dihydrophenanthridin-2-yl]-2-(N,N- dimethylannino ⁇ acetannide, substituted 4,9-dihydrocyclopenta[lmn]phenanthridine- 5-ones, and analogues and derivatives thereof.
  • Benzopyrones such as 1 , 2-benzopyrone, 6-nitrosobenzopyrone, 6-nitroso 1 , 2- benzopyrone, and 5-iodo-6-aminobenzopyrone, and analogues and derivatives thereof.
  • Unsaturated hydroximic acid derivatives such as O-(3-piperidino-2-hydroxy- 1 -propyl)nicotinic amidoxime, and analogues and derivatives thereof.
  • Pyridazines including fused pyridazines and analogues and derivatives thereof.
  • the PARP inhibitor is selected from the group consisting of: benzamide, quinolone, isoquinolone, benzopyrone, methyl 3,5-diiodo-4-(4'-methoxyphenoxy)benzoate, and methyl-3,5-diiodo-4-(4'-methoxy- 3',5'-diiodo-phenoxy)benzoate, cyclic benzamide, benzimidazole and indole.
  • a PARP inhibitor includes phthalazinones such as 1 (2H)- phthalazinone and derivatives thereof, as described in WO02/36576, which is incorporated herein by reference.
  • a PARP inhibitor may be a compound of the formula (I):
  • RC is represented by -L-RL, where L is of formula:
  • RL is optionally substituted C5-20 aryl
  • RN is selected from hydrogen, optionally substituted C1 -7 alkyl, C3-20
  • heterocyclyl and C5-20 aryl, hydroxy, ether, nitro, amino, amido, thiol, thioether, sulfoxide and sulfone.
  • a preferred compound may have the formula (I) wherein:
  • RC is -CH2-RL
  • RL is optionally substituted phenyl
  • RN is hydrogen
  • Suitable PARP inhibitors are described in WO 2004/080976, which is incorporated herein by reference, and may have the formula (III):
  • X can be NRX or CRXRY
  • RX is selected from the group consisting of H, optionally substituted C1 -20 alkyl, C5-20 aryl, C3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups;
  • RY is selected from H, hydroxy, amino;
  • RX and RY may together form a spiro-C3-7 cycloalkyl or heterocyclyl group;
  • RC1 and RC2 are both hydrogen, or when X is CRXRY, RC1 , RC2, RX and RY, together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and
  • R1 is selected from H and halo.
  • PARP poly(ADP-ribose)polymerase
  • X and Y are selected from CH and CH, CF and CH, CH and CF and N and CH respectively;
  • R c is selected from H, Ci -4 alkyl
  • R 1 is selected from Ci -7 alkyl, 03-20 heterocyclyl and C 5- 2o aryl, which groups are optionally substituted; or
  • R c and R 1 together with the carbon and oxygen atoms to which they are attached form a spiro-C 5-7 oxygen-containing heterocyclic group, which is optionally substituted or fused to a C 5-7 aromatic ring.
  • a suitable compound, from this patent publication, that can be used according to the present invention is 4-(4-Fluoro-3-(4-methoxypiperidine-1 - carbonyl)benzyl)phthalazin-1 (2H)-one.
  • Other examples of suitable PARP inhibitors are described in WO2008/122810, which is incorporated herein by reference, and have the formula (I):
  • X is selected from H and F;
  • R 1 and R 2 are independently selected from H and methyl
  • R N1 is selected from H and optionally substituted Ci -7 alkyl
  • R N2 is selected from H, optionally substituted Ci -7 alkyl, C3-7 heterocylyl and C 5- 6 aryl;
  • R N1 and R N2 and the nitrogen atom to which they are bound form an optionally substituted nitrogen containing C 5-7 heterocyclic group.
  • R represents one or more optional substituents on the fused cyclohexene ring;
  • R x is selected from the group consisting of H, optionally substituted alkyl, optionally substituted C 5- 2o aryl, optionally substituted 03-20 heterocyclyl, optionally substituted amido, optionally substituted thioamido, optionally substituted ester, optionally substituted acyl, and optionally substituted sulfonyl groups;
  • R x is selected from the group consisting of H, optionally substituted alkyl, optionally substituted C 5- 2o aryl, optionally substituted 03-20 heterocyclyl, optionally substituted amido, optionally substituted thioamido, optionally substituted sulfonamino, optionally substituted ether, optionally substituted ester, optionally substituted acyl, optionally substituted acylamido and optionally substituted sulfonyl groups and R Y is selected from H, hydroxy, optionally substituted amino, or R x and R Y may together form an optionally substituted spiro-C3-7 cycloalkyl or heterocyclyl group;
  • R C1 and R C2 are both hydrogen, or when X is CR X R Y , R C1 , R C2 , R x and R Y , together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring;
  • R 1 is selected from H and halo.
  • the present invention can be applied to any compound disclosed and/or exemplified in these patent publications.
  • the PARP inhibitor may be a compound selected from the group consisting of: 3-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1 - ylmethyl)-phenyl]-5-methyl-imidazolidine-2,4-dione; 3-[3-(5,8-difluoro-4-oxo-3,4- dihydro-phthalazin-1 -ylmethyl)-phenyl]-5-methyl-imidazoline-2,4-dione; 5-chloro- 2- ⁇ 1 -[3-([1 ,4]diazepane-1 -carbonyl)-4-fluoro-phenyl]-ethoxy ⁇ -benzamide; 2- ⁇ 3-[2- fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1 -yl methyl )-phenyl]-5-methyl-2,4-dioxo- imidazolidin-1 -yl ⁇
  • the PARP inhibitor may have a greater potency than the potency of 3-aminobenzamide (IC50 ⁇ 20uM), preferably 5-fold or greater, 10-fold or greater, 50-fold or greater, 100 fold or greater or 1000-fold or greater than the potency of 3-aminobenzamide.
  • Suitable PARP inhibitors are either commercially available or may be synthesized by known methods from starting materials that are known (see, for example, Suto et al. Anticancer Drug Des. 6:107-17, 1991 ).
  • an active PARP inhibitor compound While it is possible for an active PARP inhibitor compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g., formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or
  • compositions comprising a PARP inhibitor and/or a kinase- mediated cellular pathway inhibitor as defined above, for example, an inhibitor admixed or formulated together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein, may be used in the methods described herein.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g., human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well-known in the art of pharmacy. Such methods include the step of bringing the active compound into association with a carrier, which may constitute one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
  • the inhibitor(s) or pharmaceutical composition comprising the inhibitor(s) may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g.
  • vaginal parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
  • a tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free- flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropyl methyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica);
  • binders e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropyl methyl cellulose
  • fillers or diluents e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate
  • lubricants
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • concentration of the active compound in the solution is from about 1 ng/ml to about 10 ⁇ g ml, for example, from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.
  • appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day.
  • the active compound is a salt, an ester, prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • a cross tumor-type panel of 95 cell lines was tested for sensitivity to olaparib.
  • Baseline (untreated) gene expression profiles were generated using Affymetrix genome-wide U133A 2.0 arrays for each cell line.
  • Current state-of-the- art has suggested that sensitivity to PARP inhibitors can be correlated with high levels of PARP expression (WO 2008/147418, US2007/0292883 and
  • Example 1 Analysis of 95 cancer cell lines (KU95 panel) for their response to olaparib
  • a panel of 95 cancer cell lines representing six tumour types were assessed for their response to single agent olaparib using long-term 2-D colony-formation assays (CFA; clonogenic) with continual exposure to the drug.
  • CFA colony-formation assays
  • Each cell line was plated at an appropriate pre-determined concentration (-150-200 colonies/well in vehicle alone wells) into three 6-well plates and allowed to attach overnight.
  • Olaparib was added to triplicate wells at 0 (vehicle alone), 0.123, 0.370, 1 .1 1 1 , 3.333, 10 ⁇
  • Cellular IC 5 o values were calculated using a dose response curve plotted using XLFit, set with the curve fit 4 Parameter Logistic Model (IDBS XLFit model 205) for each cell line.
  • the baseline mRNA expression levels of HR factors (ATM, ATR, BRCA1 , BRCA2, CHEK2, MDC1 and MRE1 1A), PARP-1 (a BER factor) and ABCB1 (a drug transporter gene) were determined for each cell line in the KU95 cell line panel (see Table 4). Exponentially growing cell lines were grown in 15 cm dishes then washed in ice-cold Ca/Mg-free PBS (Invitrogen), scraped into centrifuge tubes and cells pelleted at 300 x g at a temperature of 4°C for 2 minutes. Supernatants were discarded and cell pellets snap frozen in LN 2 and stored at -80°C until use.
  • HR factors ATM, ATR, BRCA1 , BRCA2, CHEK2, MDC1 and MRE1 1A
  • PARP-1 a BER factor
  • ABCB1 a drug transporter gene
  • Quantitative real-time PCR was performed using well established commercial TaqMan gene expression primer assays and master mix (Applied Biosystems) utilising FAM- MGB fluorescent dye-labelled probes and detection on a StepOnePlus real-time PCR system (Applied Biosystems). Normalised gene expression of ATM, ATR, BRCA1 , BRCA2, CHEK2, MDC1 , MRE1 1 A, PARP-1 and ABCB1 relative to the average of 3 endogenous control genes (PPIA, PGK1 , TBP) was calculated (ACT) for each cell line. Relative gene expression across all 95 cell lines was calculated using 2 _AACT method as described previously (Livak and Schmittgen Methods 25:402-408, 2001 ).
  • the baseline protein expression levels of ATM, ATR, CHEK2, MDC1 , MRE1 1A and PARP-1 were determined for each cell line in the KU95 cell line panel using western blotting with commercially available antibodies and densitometry quantification.
  • Total protein concentration for each extract was determined using the well-known reduction of Cu 2+ to Cu 1+ bicinchoninic acid (BCA) method in the form of commercial BCA Protein Assay Reagent kit from Pierce.
  • Primary antibodies were diluted to an appropriate concentration in MTBS-T buffer (5% skimmed milk powder, 0.05% Tween- 20 in Tris-buffered saline (TBS)) and incubated with the membranes for 2.5 hours at room temperature. Proteins were detected using standard electrochemiluminescent (ECL) reagent methods. Images and protein band intensity were quantified on a LAS- 3000 luminescent image analyser and associated AIDA software (Fujifilm).
  • the term "sensitive" in the context of this Example refers to those cancer cell lines in the KU95 panel that have an IC50 value of less than 1 ⁇ . 1 uM has been found by the applicant to be a pharmacologically relevant concentration for which tumour exposure has been demonstrated for tolerable doses of olaparib in a phase 1 biopsy study clinical trial in man.
  • resistant in the context of this Example refers to those cancer cell lines in the KU95 panel that have an IC50 value of more than 4 ⁇ , which is the concentration just above that achieved in any sample within the phase 1 biopsy trial referred to above.
  • Table 4 lists the KU95 panel of cancer cell lines analysed along with their olaparib IC50 data as determined by 2D-colony formation assays.
  • HR gene mutation black boxes
  • the black boxes in the IC50 column indicate cell lines that demonstrated significant sensitivity to olaparib with IC50 values less than 1 .0 ⁇ (clinically achievable doses).
  • the grey boxes represent cell lines with olaparib sensitivity between 1 .0 and 1 .2 ⁇ .
  • Olaparib IC50 was determined by 2D-colony formation assays.
  • HR gene mutation data were obtained from literature or online public databases. Quantification of mRNA for HR genes (ATM, ATR, BRCA1 , BRCA2, CHEK2, MRE1 1A, MDC1 ), ABCB1 (P-gp drug transporter) and PARP-1 were determined by Taqman RT- PCR and relative expression levels (to mean of KU95 cell panel) calculated using 2- ⁇ me thod. HR gene expression was classified as low if relative mRNA levels were less than 50%. PARP-1 BER gene expression was classified as low if relative mRNA levels less than 50% or classified as high if relative mRNA levels were greater than 200%.
  • ABCB1 gene expression was classified as low if relative mRNA expression levels were up to 100%, moderate if relative expression between 100% and 200% or high if greater than 200%.
  • a number of cell lines that demonstrated high PARP-1 expression levels e.g. BT474, HCC-38 were not sensitive to olaparib.
  • Figure 1 shows plots of both PARP-1 gene and protein expression levels against cell line IC50 data.
  • the data in Figure 1 clearly show that higher levels of PARP cannot distinguish between those cell lines that are responsive to olaparib and those that are not.
  • these data do demonstrate that there are hardly any cell lines with low levels of PARP-1 expression that are sensitive to olaparib (see lower left quadrant), indicating that low levels of PARP-1 may be a useful biomarker to exclude those cancer cells unlikely to respond to PARP inhibition.
  • BRCA deficiencies are notably associated with breast and ovarian cancers but not all cancers, raising the possibility that different HR deficiencies may be more common in some tumour types than others. Consistent with this idea are the observations that up to 50% of head and neck cancers are associated with chromosome 1 1 q deletions that remove the ATM gene (Parikh et al. Genes Chromosomes & Cancer 46:761-775, 2007) and 30% of non-small cell lung cancers that are associated with MDC1 deficiencies (Bartkova et al. Oncogene 26:7414-7422, 2007).
  • Table 5 shows PARP and HR biomarker correlation with breast cancer cell line response to olaparib. Quantification of mRNA for HR genes (ATM, ATR, BRCA1 , BRCA2, CHEK2, MRE1 1A, MDC1 ) and PARP-1 were determined by Taqman RT- PCR and relative expression levels (to mean of breast cell panel) calculated using 2- ⁇ me thod.
  • Relative HR gene expression levels are shown as less that 50% (- 2; black), between 50% and 67% (-0.5), between 67% and 150% (0), between 150% and 200% (0.5) and greater than 200% (2). HR gene expression was classified as low if relative mRNA levels were less than 50% (-2). Relative PARP- 1 gene expression is shown as either low (less than 50%; grey) or high (greater than 200%).
  • Table 6 shows PARP and HR biomarker correlation with colorectal cancer cell line response to olaparib.
  • PARP inhibitor (olaparib) IC50 was determined by 2D- colony formation assays.
  • MSI Microsatelite instability
  • MRE1 1 A gene mutation data were obtained from literature or online public databases.
  • HR gene expression was classified as low (black boxes) if relative mRNA levels were less than 50%.
  • ABCB1 P-gp drug transporter gene expression was classified as low if relative mRNA expression levels were up to 100%, moderate if relative expression between 100% and 200% or high if greater than 200% (grey).
  • Table 7 shows PARP and HR biomarker correlation with gastric cancer cell line response to olaparib.
  • PARP inhibitor (olaparib) IC50 was deternnined by 2D- colony formation assays. The black boxes indicate cell lines that demonstrated sensitivity to olaparib with IC50 values less than 1 .0 ⁇ . The grey boxes represent cell lines with olaparib sensitivity between 1 .0 and 1 .2 ⁇ .
  • ATM gene mutation data were obtained from literature or online public databases. Cell lines with DNA mutations are shown in grey. ATM and PARP-1 protein expression was
  • Protein expression analysis was performed using the methods outlined above in Example 1 using antibodies against ATM, ATR, MDC1 , MRE1 1 A and PARP-1 .
  • a striking correlation was observed between the most sensitive gastric cancer cell lines and ATM expression levels (Table 7). Expression levels of ATM were termed low when less than 50% expression was observed relative to the mean ATM expression of the gastric cell line panel.
  • Immunohistochemistry using the following method.
  • IHC staining for ATM was performed using 4 ⁇ formalin fixed paraffin wax embedded (FFPE) sections of human tissue (mounted on slides) and microscopic interpretation. Slides were heated at 60°C for 30 min then rehydrated by sequential immersion in Xylene (Standard laboratory grade; 2 changes, 10 min each), alcohol (Industrial methylated, iso-propyl alcohol; 2 changes, 5 min each), 70% v/v alcohol in pure water (5 min) and in running tap water for 5 min.
  • Target antigen retrieval was performed using 1 X target retrieval solution pH 9 (DAKO S2367) in a boiling domestic pressure cooker for 5 minutes.
  • ATM staining was run using a Labvision automated IHC autostainer using the following incubation programme: Rinse slides in wash buffer (DAKO S3306), Peroxidase blocking solution (DAKO S2001 ) 5 min, wash slides in wash buffer twice, Protein blocking solution (DAKO X0909) 5min, Blow off, primary ATM antibody (Epitomics 1549-1 ) in diluent (DAKO S0809) 60min, wash slides in wash buffer twice, HRP labelled rabbit/mouse polymer (DAKO K5007) 30min, wash slides in wash buffer twice, Diaminobenzidene solution (DAKO K3468) 10min and wash slides in water. For negative control sections the ATM antibody was replaced with negative control rabbit IgG (DAKO X0903).
  • lymphocyte staining was acceptable then the tumour cells were identified and the presence or absence of nuclear staining and its intensity scored as:
  • Table 8 shows ATM protein expression level analysis by immunohistochemistry (IHC) on tumour and adjacent normal tissue samples from Chinese gastric cancer patients.
  • RNAi expression vectors were created for each of the HR knockdown clones using the pSilencer 3.1 -H1 neo vector and RNAi knockdown system (Ambion/Applied biosystems).
  • the RNAi target sequences for each HR gene clone was inserted into the pSilencer 3.1 -H1 neo vector between the BamHI and Hind 111 restriction enzyme sites according to the manufacturers' recommended conditions.
  • Nonspecific (NS) negative control constructs acting as controls were also generated from standard non-coding sequences (Ambion/Applied Biosystems).
  • the CAL51 breast cell line was transfected with each HR gene RNAi expression vector or nonspecific control vector using the Lipofectamine-2000 lipid transfection reagent (Invitrogen) according to the manufacturers' recommendation instructions.
  • Transfected cells were plated out into multiple dishes and incubated in RPMI1640 + 10% foetal bovine serum (FBS) media containing 300 g/ml Geneticin
  • Proteomic identification of differentially expressed proteins for each HRD knockdown cell line compared to HR-proficient control cells were undertaken using two-dimensional difference gel electrophoresis (2D-DIGE) method (Gharbi et al 2002).
  • Proteomic profiles for each HRD knockdown cell lines were compared with their wild type (CAL51 WT) or non-specific control (CAL51 NS control) cells.
  • For each cell line either nuclear protein extraction or phospho-protein enrichment was performed to reduce protein complexity and aid data analysis. Standard nuclear protein enrichment method was used involving the gentle lysis of the cells by repeated freeze/thawing in a Hypotonic buffer. A high salt buffer was then added and the samples underwent centrifugation to pellet the nuclear fraction. The supernatant containing the cytoplasmic fraction was removed and the nuclear pellet resuspended in the proteomics lysis buffer (Gharbi et al., Mol. Cell.
  • the two-dimensional difference gel electrophoresis (2D-DIGE) method used was peformed essentially as previously described (Gharbi et al., Mol. Cell. Proteomics. 1 : 91-98, 2002). 200pmol of CyDye fluor were used to label 50pg of protein, samples were IEF focussed on 24cm pH4-7 IEF strips using an IPGphor II with an IPGphor manifold (GE healthcare, Little Chalfont, Bucks) at 20°C, ⁇ /strip.
  • Focussing conditions were 300V for3hrs, then increased in a linear gradient to 1 000V over the following 6 hours, then increased to 8000V again in a l inear gradient over 3 hours and finally continued at 8000V for a further 4 hours and 40 minutes. Total volt hours were approximately 55000 hours.
  • IEF focussed strips were run in the 2 nd dimension on 26cm X 21 cm format 10-20% gradient gels. The gels were run overnight on an Ettan Dalt II system (GE healthcare, Little Chalfont, Bucks). Running conditions were 5W/gel for the first 15-60 minutes, then 1 - 1 .5W/gel overnight at 25°C until the dye front ran off the bottom of the gel.
  • Protein IDs for each protein spot of interest was determined as follows. Preparative 2D gels loaded with 500- 1 000 g protein/gel were run and subsequently fixed and stained with an appropriate fluorescent stain (Sypro Ruby or Deep Purple Total Protein Stain [GE healthcare, Little Chalfont, Bucks]). These preparative gels were then scanned and spots matched to those previously identified as those containing proteins of interest. These were then selected for processing and identification by mass spectrometry using peptide mass fingerprinting and protein sequencing.
  • Results from these analyses were cross-compared with those from a gene expression analysis of the cell lines along with pertinent data from other sources.
  • journal publications were identified disclosing genelists representing mRNA expression changes following dynamic activation or inhibition of core BER (PARP-1 ) or HR (BRCA1 , BRCA2, ATM, ATR, MRE1 1 A, CHEK2 or MDC1 ) genes, listed here by PubMed ID:
  • Table 11 shows the expanded list of 498 HR genes identified through proteomic and genomic analysis of isogenic cancer cell lines with HR deficiencies.
  • DEGs Differentially expressed genes between Core HR knockdown and isogenic wild-type cell lines as discovered through 2D-DIGE proteomics and Affymet gene expression array analysis.
  • GABA protein homolog 1 diazepam binding inhibitor
  • DCI isomerase (3,2 trans-enoyl-Coenzyme 1632
  • polypeptide 3 X-linked 1 dihydrolipoamide S-
  • DSTN destrin actin depolymerizing factor 11034 1 dynein, cytoplasmic 1, intermediate
  • subunit 2 beta 38kDa 1 eukaryotic translation initiation factor
  • TSFM (includes Ts translation elongation factor
  • twinfilin actin-binding protein
  • U2AF2 (includes U2 small nuclear RNA auxiliary
  • ADM adrenomedullin 133 1 anterior gradient homolog 3 (Xenopus
  • GPR177 G protein-coupled receptor 177 79971 1
  • GPR137C G protein-coupled receptor 137C 283554 1 phosphodiesterase 3A, cGMP-
  • subunit beta type, 10 1
  • RBP1 retinol binding protein 1 cellular 5947 1
  • Rho-related BTB domain containing 1 9886 1 roundabout, axon guidance receptor

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Food Science & Technology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicinal Chemistry (AREA)
  • Cell Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne d'une manière générale des procédés pour traiter un cancer et des procédés de prédiction de la sensibilité d'une cellule cancéreuse à un traitement thérapeutique. En particulier, l'invention concerne les identités de gènes (biomarqueurs) qui peuvent être utilisés pour identifier des populations de personnes souffrant d'un cancer ou des individus souffrant d'un cancer qui sont susceptibles d'une réponse favorable à un traitement par un inhibiteur de poly(ADP-ribose) polymérase (PARP).
PCT/GB2010/051888 2009-11-13 2010-11-11 Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase WO2011058367A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US26093409P 2009-11-13 2009-11-13
US61/260,934 2009-11-13

Publications (2)

Publication Number Publication Date
WO2011058367A2 true WO2011058367A2 (fr) 2011-05-19
WO2011058367A3 WO2011058367A3 (fr) 2011-08-18

Family

ID=43500036

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2010/051888 WO2011058367A2 (fr) 2009-11-13 2010-11-11 Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase

Country Status (1)

Country Link
WO (1) WO2011058367A2 (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012156501A1 (fr) * 2011-05-18 2012-11-22 Centre National De La Recherche Scientifique (Cnrs) Signature pour le diagnostic d'agressivité et d'instabilité génétique d'un cancer
WO2013133876A1 (fr) * 2011-12-07 2013-09-12 The Regents Of The University Of California Biomarqueurs destinés à la prédiction de la réponse à une inhibition de parp dans le cancer du sein
US20140045853A1 (en) * 2012-08-06 2014-02-13 The Institute Of Cancer Research: Royal Cancer Hospital Materials, methods, and systems for treating cancer
WO2014138101A1 (fr) * 2013-03-04 2014-09-12 Board Of Regents, The University Of Texas System Signature génique pour prédire un cancer déficient pour la recombinaison homologue (rh)
WO2014190090A1 (fr) * 2013-05-21 2014-11-27 Dignity Health Signature génétique de la vulnérabilité aux inhibiteurs de la réparation par excision des bases (ber) en oncologie
WO2014205105A1 (fr) * 2013-06-19 2014-12-24 The Regents Of The University Of California Biomarqueurs de réponse à l'inhibition de poly(adp-ribose) polymérase (parp) dans un cancer
WO2015042570A1 (fr) 2013-09-23 2015-03-26 The University Of Chicago Procédés et compositions concernant une thérapie anticancéreuse au moyen d'agents endommageant l'adn
WO2015168544A1 (fr) * 2014-05-02 2015-11-05 Emory University Traitements sélectifs de chimiothérapie et méthodes de diagnostic associées à ceux-ci
WO2018161081A1 (fr) * 2017-03-03 2018-09-07 Board Of Regents, The University Of Texas System Signatures géniques permettant de prédire la réponse à un médicament contre le cancer
EP3415915A1 (fr) * 2012-02-23 2018-12-19 Children's Medical Center Corporation Procédés de prédiction de réponse anticancéreuse
WO2019219759A1 (fr) * 2018-05-15 2019-11-21 Oncology Venture ApS Procédés de prédiction de la réponse aux médicaments chez des patients cancéreux
US10577662B2 (en) 2010-08-24 2020-03-03 Dana-Farber Cancer Institute, Inc. Methods for predicting anti-cancer response
CN111801117A (zh) * 2017-12-27 2020-10-20 特沙诺有限公司 治疗癌症的方法
CN111868265A (zh) * 2017-09-30 2020-10-30 浙江数问生物技术有限公司 Dna重组修复功能评分rds在癌症治疗中的用途
US10823738B2 (en) * 2015-12-07 2020-11-03 George Mason Research Foundation, Inc. Methods for breast cancer treatment
US20210093730A1 (en) * 2019-10-01 2021-04-01 Immunomedics, Inc. Biomarkers for antibody-drug conjugate monotherapy or combination therapy
CN114934120A (zh) * 2022-06-20 2022-08-23 柳州市人民医院 一种快速鉴定早期结直肠癌的环状rna标志物的应用及诊断试剂盒
WO2022185260A1 (fr) * 2021-03-04 2022-09-09 Otsuka Pharmaceutical Co., Ltd. Biomarqueurs pour la thérapie anticancéreuse utilisant des antagonistes de mdm2
US11596637B2 (en) 2017-04-10 2023-03-07 Sierra Oncology, Inc. CHK1 (SRA737)/PARPi combination methods of inhibiting tumor growth
WO2024009946A1 (fr) * 2022-07-08 2024-01-11 国立大学法人東海国立大学機構 Procédé de test de l'efficacité d'un inhibiteur de parp contre le cancer de l'ovaire
RU2842422C1 (ru) * 2024-09-11 2025-06-26 Федеральное государственное бюджетное образовательное учреждение высшего образования "Курский государственный медицинский университет" Министерства здравоохранения Российской Федерации Способ генотипирования однонуклеотидного варианта rs3219472 (C>T) гена MUTYH человека методом полимеразно-цепной реакции в режиме реального времени
US12383542B2 (en) 2016-06-29 2025-08-12 Tesaro, Inc. Methods of treating ovarian cancer

Citations (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4230767A (en) 1978-02-08 1980-10-28 Toyo Boseki Kabushiki Kaisha Heat sealable laminated propylene polymer packaging material
US4233402A (en) 1978-04-05 1980-11-11 Syva Company Reagents and method employing channeling
US4275149A (en) 1978-11-24 1981-06-23 Syva Company Macromolecular environment control in specific receptor assays
US4376110A (en) 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies
US4659678A (en) 1982-09-29 1987-04-21 Serono Diagnostics Limited Immunoassay of antigens
US4727022A (en) 1984-03-14 1988-02-23 Syntex (U.S.A.) Inc. Methods for modulating ligand-receptor interactions and their application
JPH0314319A (ja) 1989-06-13 1991-01-23 Anritsu Corp ラダー抵抗回路
WO1994026730A2 (fr) 1993-05-12 1994-11-24 Octamer, Inc. Nouveaux composes aromatiques nitro et nitroso et leurs metabolites, aptes a etre utilises comme agents antiviraux et antitumoraux
WO1995024379A1 (fr) 1994-03-09 1995-09-14 Newcastle University Ventures Limited Analogues de benzamides utiles en tant qu'inhibiteurs de l'enzyme parp (adp-ribosyltransferase, adprt) de reparation de l'adn
US5587384A (en) 1994-02-04 1996-12-24 The Johns Hopkins University Inhibitors of poly(ADP-ribose) synthetase and use thereof to treat NMDA neurotoxicity
WO2000042040A1 (fr) 1999-01-11 2000-07-20 Agouron Pharmaceuticals, Inc. Inhibiteurs tricycliques de poly(adp-ribose) polymerases
WO2001012199A2 (fr) 1999-08-13 2001-02-22 Case Western Reserve University Effet synergique de la methoxyamide sur l'activite anticancereuse de la temozolomide
WO2001016136A2 (fr) 1999-08-31 2001-03-08 Agouron Pharmaceuticals, Inc. Inhibiteurs tricycliques de poly(adp-ribose) polymerases
WO2001021615A1 (fr) 1999-09-17 2001-03-29 Yamanouchi Pharmaceutical Co., Ltd. Dérivés de benzimidazole
WO2001023390A2 (fr) 1999-09-28 2001-04-05 Basf Aktiengesellschaft Derives d'azepinoindol, preparation et utilisation desdits derives
WO2001057038A1 (fr) 2000-02-01 2001-08-09 Basf Aktiengesellschaft Composes heterocycliques et leur utilisation comme inhibiteurs de parp
US6285701B1 (en) 1998-08-06 2001-09-04 Lambda Physik Ag Laser resonator for improving narrow band emission of an excimer laser
WO2001079184A1 (fr) 2000-04-18 2001-10-25 Sumitomo Pharmaceuticals Company, Limited Composes de piperazine substitues
WO2001085686A2 (fr) 2000-05-09 2001-11-15 Cephalon, Inc. Nouveaux composes multicycliques et leur utilisation
WO2001085687A1 (fr) 2000-05-11 2001-11-15 Basf Ag Indoles substitues en tant qu'inhibiteurs de parp
WO2001090077A1 (fr) 2000-05-19 2001-11-29 Guilford Pharmaceuticals, Inc. Derives de sulfonamide et de carbamide de 6(5h) phenanthridinones et utilisations de ceux-ci
WO2002036599A1 (fr) 2000-10-31 2002-05-10 Smithkline Beecham P.L.C. Thieno[2,3-c]isoquinolines utilises en tant qu'inhibiteurs de parp
WO2002036576A1 (fr) 2000-10-30 2002-05-10 Kudos Pharmaceuticals Limited Derives de phtalazinone
WO2002052031A2 (fr) 2000-12-22 2002-07-04 Arcturus Engineering, Inc. Amplification d'acide nucleique
US6426415B1 (en) 1997-09-03 2002-07-30 Guilford Pharmaceuticals Inc. Alkoxy-substituted compounds, methods and compositions for inhibiting parp activity
WO2002068407A1 (fr) 2001-02-28 2002-09-06 Yamanouchi Pharmaceutical Co., Ltd. Compose benzimidazole
US6476048B1 (en) 1999-12-07 2002-11-05 Inotek Pharamaceuticals Corporation Substituted phenanthridinones and methods of use thereof
WO2002094790A1 (fr) 2001-05-23 2002-11-28 Mitsubishi Pharma Corporation Compose heterocyclique condense et son utilisation medicale
WO2003007959A1 (fr) 2001-07-16 2003-01-30 Fujisawa Pharmaceutical Co., Ltd. Derives de quinoxaline ayant une action inhibitrice sur parp
US6514983B1 (en) 1997-09-03 2003-02-04 Guilford Pharmaceuticals Inc. Compounds, methods and pharmaceutical compositions for treating neural or cardiovascular tissue damage
WO2003051879A1 (fr) 2001-12-14 2003-06-26 Altana Pharma Ag 4,5-dihydro-imidazo[4,5,1-ij]quinoline-6-ones connues et nouvelles utilisees en tant qu'inhibiteurs de la poly(adp-ribose)polymerase
WO2003055865A1 (fr) 2001-12-24 2003-07-10 Fujisawa Pharmaceutical Co., Ltd. Derives de quinazolinone
WO2003057145A2 (fr) 2001-12-31 2003-07-17 Guilford Pharmaceuticals Inc. 4,9-dihydrocyclopenta[imn]phenanthridine-5-ones substitues, leurs derives et leurs utilisations
WO2003070707A1 (fr) 2002-02-19 2003-08-28 Ono Pharmaceutical Co., Ltd. Composes condenses derives de la pyridazine et medicaments contenant lesdits composes comme ingredients actifs
WO2003080581A1 (fr) 2002-03-26 2003-10-02 Fujisawa Pharmaceutical Co., Ltd. Phenanthridinones utilisees comme inhibiteurs de parp
US6635642B1 (en) 1997-09-03 2003-10-21 Guilford Pharmaceuticals Inc. PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same
WO2004014873A1 (fr) 2002-08-09 2004-02-19 Kyorin Pharmaceutical Co., Ltd. Derive de quinazoline-8-carboxyamide substitue en 4 et sel d'addition pharmaceutiquement acceptable de celui-ci
WO2004024694A1 (fr) 2002-09-10 2004-03-25 Kyorin Pharmaceutical Co., Ltd. Derive de 4-(aryle substitue)-5-hydroxyisoquinolinone
WO2004048339A1 (fr) 2002-11-22 2004-06-10 Mitsubishi Pharma Corporation Composes d'isoquinolinone et leur utilisation a des fins medicinales
WO2004080976A1 (fr) 2003-03-12 2004-09-23 Kudos Pharmaceuticals Limited Derives de phtalazinone
WO2004087713A1 (fr) 2003-03-31 2004-10-14 Pfizer Inc. Sels d'inhibiteurs tricycliques de poly(adp-ribose) polymerases
WO2004096779A1 (fr) 2003-04-30 2004-11-11 Suemegi Balazs Derives de quinazolinone et utilisation de ceux-ci dans la preparation de compositions pharmaceutiques possedant des effets inhibiteurs d'enzyme
WO2004096793A1 (fr) 2003-04-28 2004-11-11 Hideg Kalman Nouveaux 4-carboxamido-benzimidazoles alicycliques substitues par une amine utilises comme inhibiteurs de parp et comme antioxydants
US20040229895A1 (en) 2003-02-28 2004-11-18 Inotek Pharmaceuticals Corporation Tetracyclic benzamide derivatives and methods of use thereof
WO2004105700A2 (fr) 2003-05-28 2004-12-09 Guildford Pharmaceuticals, Inc. Composes, procedes et compositions pharmaceutiques destines a l'inhibition de la parp
WO2004108723A1 (fr) 2003-06-04 2004-12-16 Altana Pharma Ag 4,5-dihydro-imidazo(4,5,1-ij)quinolin-6-ones utilisees comme inhibiteurs de parp
WO2005012524A1 (fr) 2003-07-25 2005-02-10 The University Of Sheffield Utilisation d'arni inhibiteur de l'activite parp pour la fabrication d'un medicament pour le traitement du cancer
WO2005012305A2 (fr) 2003-07-25 2005-02-10 Cancer Research Technology Limited Composes therapeutiques
US20050054631A1 (en) 2003-09-04 2005-03-10 Aventis Pharmaceuticals Inc. Substituted indoles as inhibitors of poly (ADP-ribose) polymerase (PARP)
WO2005054209A1 (fr) 2003-11-20 2005-06-16 Janssen Pharmaceutica N.V. 2-quinolinones et 2 quinoxalinones a substitution 7-phenylalkyl tenant lieu d'inhibiteurs de poly(adp-ribose) polymerase inhibitors
WO2005054201A1 (fr) 2003-11-20 2005-06-16 Janssen Pharmaceutica N.V. 2-quinolinones et 2-quinoxalinones substituees par 6-alcenyle et 6-phenylalkyle utilisees comme inhibiteurs de la poly(adp-ribose) polymerase (parp)
WO2005054210A1 (fr) 2003-12-05 2005-06-16 Janssen Pharmaceutica N.V. 2-quinolinones 6-substituees et 2-quinoxalinones utilisees comme inhibiteurs de la poly(adp-ribose) polymerase
WO2005053662A1 (fr) 2003-12-01 2005-06-16 Kudos Pharmaceuticals Limited Inhibiteurs de réparation d'adn endommagé pour le traitement du cancer
WO2005058843A1 (fr) 2003-12-10 2005-06-30 Janssen Pharmaceutica N.V. 2-quinolinones substitues 6-cyclohexylalkyl substitues et 2-quinoxalinones utilises en tant qu'inhibiteurs de la poly(adp-ribose) polymerase
WO2005097750A1 (fr) 2004-03-30 2005-10-20 Aventis Pharmaceuticals Inc. Pyridones substitues inhibiteurs de la poly(adp-ribose) polymerase (parp)
WO2005123687A1 (fr) 2004-06-16 2005-12-29 Sanofi-Aventis Deutschland Gmbh Derives substitues de tetrahydro-2h-isoquinolein-1-one, leur procede de production, et leur utilisation en tant que medicaments
WO2006003147A1 (fr) 2004-06-30 2006-01-12 Janssen Pharmaceutica N.V. Derives de phtalazine utilises comme inhibiteurs de parp
WO2006003146A1 (fr) 2004-06-30 2006-01-12 Janssen Pharmaceutica N.V. Derives de quinazolinone en tant qu'inhibiteurs de parp
WO2006003148A1 (fr) 2004-06-30 2006-01-12 Janssen Pharmaceutica N.V. Derives de quinazolinedione utilises comme inhibiteurs de parp
WO2006024545A1 (fr) 2004-09-03 2006-03-09 Stichting Voor De Technische Wetenschappen Composes bicycliques naturels condenses et utilisation de ceux-ci comme inhibiteurs de parp et des processus inflammatoires a mediation parp
DE102004050196A1 (de) 2004-10-15 2006-04-20 Sanofi-Aventis Deutschland Gmbh Substituierte 2-Pyridon-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Medikament
WO2006078711A2 (fr) 2005-01-19 2006-07-27 Mgi Gp, Inc. Composes de diazabenzo[de]anthracene-3-one et utilisation dans l'inhibition de parp
WO2006078503A2 (fr) 2005-01-07 2006-07-27 Arqule, Inc. Compositions pour moduler une parp et procedes pour la cribler
US20060229289A1 (en) 2005-04-11 2006-10-12 Gui-Dong Zhu 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors
US20070292883A1 (en) 2006-06-12 2007-12-20 Ossovskaya Valeria S Method of treating diseases with PARP inhibitors
WO2008084261A1 (fr) 2007-01-10 2008-07-17 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Indazoles à substitution amide utilisés comme inhibiteurs de la poly(adp-ribose)polymérase (parp)
WO2008122810A1 (fr) 2007-04-10 2008-10-16 Kudos Pharmaceuticals Limited Dérivés de phthalazinone et leur utilisation en tant que médicaments destinés à traiter le cancer
US20080262062A1 (en) 2006-11-20 2008-10-23 Bipar Sciences, Inc. Method of treating diseases with parp inhibitors
WO2009004356A1 (fr) 2007-07-05 2009-01-08 Astrazeneca Ab Dérivés de phtalazinone comme inhibiteurs de parp-1
WO2009093032A1 (fr) 2008-01-23 2009-07-30 Astrazeneca Ab Dérivés de phtalazinone
WO2009121031A1 (fr) 2008-03-27 2009-10-01 Vascular Biosciences, Inc. Procédé d'identification de nouveaux candidats thérapeutiques via l'analyse d'expression génique dans les maladies d'origine vasculaire

Patent Citations (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4230767A (en) 1978-02-08 1980-10-28 Toyo Boseki Kabushiki Kaisha Heat sealable laminated propylene polymer packaging material
US4233402A (en) 1978-04-05 1980-11-11 Syva Company Reagents and method employing channeling
US4275149A (en) 1978-11-24 1981-06-23 Syva Company Macromolecular environment control in specific receptor assays
US4376110A (en) 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies
US4659678A (en) 1982-09-29 1987-04-21 Serono Diagnostics Limited Immunoassay of antigens
US4727022A (en) 1984-03-14 1988-02-23 Syntex (U.S.A.) Inc. Methods for modulating ligand-receptor interactions and their application
JPH0314319A (ja) 1989-06-13 1991-01-23 Anritsu Corp ラダー抵抗回路
WO1994026730A2 (fr) 1993-05-12 1994-11-24 Octamer, Inc. Nouveaux composes aromatiques nitro et nitroso et leurs metabolites, aptes a etre utilises comme agents antiviraux et antitumoraux
US5587384A (en) 1994-02-04 1996-12-24 The Johns Hopkins University Inhibitors of poly(ADP-ribose) synthetase and use thereof to treat NMDA neurotoxicity
WO1995024379A1 (fr) 1994-03-09 1995-09-14 Newcastle University Ventures Limited Analogues de benzamides utiles en tant qu'inhibiteurs de l'enzyme parp (adp-ribosyltransferase, adprt) de reparation de l'adn
US6426415B1 (en) 1997-09-03 2002-07-30 Guilford Pharmaceuticals Inc. Alkoxy-substituted compounds, methods and compositions for inhibiting parp activity
US6514983B1 (en) 1997-09-03 2003-02-04 Guilford Pharmaceuticals Inc. Compounds, methods and pharmaceutical compositions for treating neural or cardiovascular tissue damage
US6635642B1 (en) 1997-09-03 2003-10-21 Guilford Pharmaceuticals Inc. PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same
US6285701B1 (en) 1998-08-06 2001-09-04 Lambda Physik Ag Laser resonator for improving narrow band emission of an excimer laser
WO2000042040A1 (fr) 1999-01-11 2000-07-20 Agouron Pharmaceuticals, Inc. Inhibiteurs tricycliques de poly(adp-ribose) polymerases
WO2001012199A2 (fr) 1999-08-13 2001-02-22 Case Western Reserve University Effet synergique de la methoxyamide sur l'activite anticancereuse de la temozolomide
WO2001016136A2 (fr) 1999-08-31 2001-03-08 Agouron Pharmaceuticals, Inc. Inhibiteurs tricycliques de poly(adp-ribose) polymerases
WO2001021615A1 (fr) 1999-09-17 2001-03-29 Yamanouchi Pharmaceutical Co., Ltd. Dérivés de benzimidazole
WO2001023390A2 (fr) 1999-09-28 2001-04-05 Basf Aktiengesellschaft Derives d'azepinoindol, preparation et utilisation desdits derives
US6476048B1 (en) 1999-12-07 2002-11-05 Inotek Pharamaceuticals Corporation Substituted phenanthridinones and methods of use thereof
WO2001057038A1 (fr) 2000-02-01 2001-08-09 Basf Aktiengesellschaft Composes heterocycliques et leur utilisation comme inhibiteurs de parp
WO2001079184A1 (fr) 2000-04-18 2001-10-25 Sumitomo Pharmaceuticals Company, Limited Composes de piperazine substitues
WO2001085686A2 (fr) 2000-05-09 2001-11-15 Cephalon, Inc. Nouveaux composes multicycliques et leur utilisation
WO2001085687A1 (fr) 2000-05-11 2001-11-15 Basf Ag Indoles substitues en tant qu'inhibiteurs de parp
WO2001090077A1 (fr) 2000-05-19 2001-11-29 Guilford Pharmaceuticals, Inc. Derives de sulfonamide et de carbamide de 6(5h) phenanthridinones et utilisations de ceux-ci
WO2002036576A1 (fr) 2000-10-30 2002-05-10 Kudos Pharmaceuticals Limited Derives de phtalazinone
WO2002036599A1 (fr) 2000-10-31 2002-05-10 Smithkline Beecham P.L.C. Thieno[2,3-c]isoquinolines utilises en tant qu'inhibiteurs de parp
US20030022194A1 (en) 2000-12-22 2003-01-30 Erlander Mark G. Nucleic acid amplification
WO2002052031A2 (fr) 2000-12-22 2002-07-04 Arcturus Engineering, Inc. Amplification d'acide nucleique
US6794141B2 (en) 2000-12-22 2004-09-21 Arcturus Bioscience, Inc. Nucleic acid amplification
WO2002068407A1 (fr) 2001-02-28 2002-09-06 Yamanouchi Pharmaceutical Co., Ltd. Compose benzimidazole
WO2002094790A1 (fr) 2001-05-23 2002-11-28 Mitsubishi Pharma Corporation Compose heterocyclique condense et son utilisation medicale
WO2003007959A1 (fr) 2001-07-16 2003-01-30 Fujisawa Pharmaceutical Co., Ltd. Derives de quinoxaline ayant une action inhibitrice sur parp
WO2003051879A1 (fr) 2001-12-14 2003-06-26 Altana Pharma Ag 4,5-dihydro-imidazo[4,5,1-ij]quinoline-6-ones connues et nouvelles utilisees en tant qu'inhibiteurs de la poly(adp-ribose)polymerase
WO2003055865A1 (fr) 2001-12-24 2003-07-10 Fujisawa Pharmaceutical Co., Ltd. Derives de quinazolinone
WO2003057145A2 (fr) 2001-12-31 2003-07-17 Guilford Pharmaceuticals Inc. 4,9-dihydrocyclopenta[imn]phenanthridine-5-ones substitues, leurs derives et leurs utilisations
WO2003070707A1 (fr) 2002-02-19 2003-08-28 Ono Pharmaceutical Co., Ltd. Composes condenses derives de la pyridazine et medicaments contenant lesdits composes comme ingredients actifs
WO2003080581A1 (fr) 2002-03-26 2003-10-02 Fujisawa Pharmaceutical Co., Ltd. Phenanthridinones utilisees comme inhibiteurs de parp
WO2004014873A1 (fr) 2002-08-09 2004-02-19 Kyorin Pharmaceutical Co., Ltd. Derive de quinazoline-8-carboxyamide substitue en 4 et sel d'addition pharmaceutiquement acceptable de celui-ci
WO2004024694A1 (fr) 2002-09-10 2004-03-25 Kyorin Pharmaceutical Co., Ltd. Derive de 4-(aryle substitue)-5-hydroxyisoquinolinone
WO2004048339A1 (fr) 2002-11-22 2004-06-10 Mitsubishi Pharma Corporation Composes d'isoquinolinone et leur utilisation a des fins medicinales
US20040229895A1 (en) 2003-02-28 2004-11-18 Inotek Pharmaceuticals Corporation Tetracyclic benzamide derivatives and methods of use thereof
WO2004080976A1 (fr) 2003-03-12 2004-09-23 Kudos Pharmaceuticals Limited Derives de phtalazinone
WO2004087713A1 (fr) 2003-03-31 2004-10-14 Pfizer Inc. Sels d'inhibiteurs tricycliques de poly(adp-ribose) polymerases
WO2004096793A1 (fr) 2003-04-28 2004-11-11 Hideg Kalman Nouveaux 4-carboxamido-benzimidazoles alicycliques substitues par une amine utilises comme inhibiteurs de parp et comme antioxydants
WO2004096779A1 (fr) 2003-04-30 2004-11-11 Suemegi Balazs Derives de quinazolinone et utilisation de ceux-ci dans la preparation de compositions pharmaceutiques possedant des effets inhibiteurs d'enzyme
WO2004105700A2 (fr) 2003-05-28 2004-12-09 Guildford Pharmaceuticals, Inc. Composes, procedes et compositions pharmaceutiques destines a l'inhibition de la parp
WO2004108723A1 (fr) 2003-06-04 2004-12-16 Altana Pharma Ag 4,5-dihydro-imidazo(4,5,1-ij)quinolin-6-ones utilisees comme inhibiteurs de parp
WO2005012524A1 (fr) 2003-07-25 2005-02-10 The University Of Sheffield Utilisation d'arni inhibiteur de l'activite parp pour la fabrication d'un medicament pour le traitement du cancer
WO2005012305A2 (fr) 2003-07-25 2005-02-10 Cancer Research Technology Limited Composes therapeutiques
US20050054631A1 (en) 2003-09-04 2005-03-10 Aventis Pharmaceuticals Inc. Substituted indoles as inhibitors of poly (ADP-ribose) polymerase (PARP)
WO2005054209A1 (fr) 2003-11-20 2005-06-16 Janssen Pharmaceutica N.V. 2-quinolinones et 2 quinoxalinones a substitution 7-phenylalkyl tenant lieu d'inhibiteurs de poly(adp-ribose) polymerase inhibitors
WO2005054201A1 (fr) 2003-11-20 2005-06-16 Janssen Pharmaceutica N.V. 2-quinolinones et 2-quinoxalinones substituees par 6-alcenyle et 6-phenylalkyle utilisees comme inhibiteurs de la poly(adp-ribose) polymerase (parp)
WO2005053662A1 (fr) 2003-12-01 2005-06-16 Kudos Pharmaceuticals Limited Inhibiteurs de réparation d'adn endommagé pour le traitement du cancer
WO2005054210A1 (fr) 2003-12-05 2005-06-16 Janssen Pharmaceutica N.V. 2-quinolinones 6-substituees et 2-quinoxalinones utilisees comme inhibiteurs de la poly(adp-ribose) polymerase
WO2005058843A1 (fr) 2003-12-10 2005-06-30 Janssen Pharmaceutica N.V. 2-quinolinones substitues 6-cyclohexylalkyl substitues et 2-quinoxalinones utilises en tant qu'inhibiteurs de la poly(adp-ribose) polymerase
WO2005097750A1 (fr) 2004-03-30 2005-10-20 Aventis Pharmaceuticals Inc. Pyridones substitues inhibiteurs de la poly(adp-ribose) polymerase (parp)
WO2005123687A1 (fr) 2004-06-16 2005-12-29 Sanofi-Aventis Deutschland Gmbh Derives substitues de tetrahydro-2h-isoquinolein-1-one, leur procede de production, et leur utilisation en tant que medicaments
WO2006003147A1 (fr) 2004-06-30 2006-01-12 Janssen Pharmaceutica N.V. Derives de phtalazine utilises comme inhibiteurs de parp
WO2006003146A1 (fr) 2004-06-30 2006-01-12 Janssen Pharmaceutica N.V. Derives de quinazolinone en tant qu'inhibiteurs de parp
WO2006003148A1 (fr) 2004-06-30 2006-01-12 Janssen Pharmaceutica N.V. Derives de quinazolinedione utilises comme inhibiteurs de parp
WO2006024545A1 (fr) 2004-09-03 2006-03-09 Stichting Voor De Technische Wetenschappen Composes bicycliques naturels condenses et utilisation de ceux-ci comme inhibiteurs de parp et des processus inflammatoires a mediation parp
DE102004050196A1 (de) 2004-10-15 2006-04-20 Sanofi-Aventis Deutschland Gmbh Substituierte 2-Pyridon-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Medikament
WO2006078503A2 (fr) 2005-01-07 2006-07-27 Arqule, Inc. Compositions pour moduler une parp et procedes pour la cribler
WO2006078711A2 (fr) 2005-01-19 2006-07-27 Mgi Gp, Inc. Composes de diazabenzo[de]anthracene-3-one et utilisation dans l'inhibition de parp
US20060229289A1 (en) 2005-04-11 2006-10-12 Gui-Dong Zhu 1H-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent PARP inhibitors
US20070292883A1 (en) 2006-06-12 2007-12-20 Ossovskaya Valeria S Method of treating diseases with PARP inhibitors
WO2008147418A1 (fr) 2006-06-12 2008-12-04 Bipar Sciences, Inc. Procédé permettant de traiter des maladies avec des inhibiteurs de parp
US20080262062A1 (en) 2006-11-20 2008-10-23 Bipar Sciences, Inc. Method of treating diseases with parp inhibitors
WO2008084261A1 (fr) 2007-01-10 2008-07-17 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Indazoles à substitution amide utilisés comme inhibiteurs de la poly(adp-ribose)polymérase (parp)
WO2008122810A1 (fr) 2007-04-10 2008-10-16 Kudos Pharmaceuticals Limited Dérivés de phthalazinone et leur utilisation en tant que médicaments destinés à traiter le cancer
WO2009004356A1 (fr) 2007-07-05 2009-01-08 Astrazeneca Ab Dérivés de phtalazinone comme inhibiteurs de parp-1
WO2009093032A1 (fr) 2008-01-23 2009-07-30 Astrazeneca Ab Dérivés de phtalazinone
WO2009121031A1 (fr) 2008-03-27 2009-10-01 Vascular Biosciences, Inc. Procédé d'identification de nouveaux candidats thérapeutiques via l'analyse d'expression génique dans les maladies d'origine vasculaire

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Current Protocols in Molecular Biology", 1992, JOHN WILEY & SONS
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
AFFAR EB ET AL., ANAL BIOCHEM., vol. 259, no. 2, 1998, pages 280 - 3
ALTSCHUL ET AL., J. MOL. BIOL., vol. 215, 1990, pages 403 - 410
AME ET AL., BIOESSAYS, vol. 26, 2004, pages 882 - 893
AME ET AL., J. BIOL. CHEM., vol. 274, 1999, pages 15504 - 15511
BANASIK ET AL., J. BIOL. CHEM., vol. 267, no. 3, 1992, pages 1569 - 75
BANASIK ET AL., MOLEC. CELL. BIOCHEM., vol. 138, 1994, pages 185 - 97
BARTKOVA ET AL., ONCOGENE, vol. 26, 2007, pages 7414 - 7422
BOOM ET AL., J CLIN MICOBIOL, vol. 28, 1990, pages 495 - 503
BRYANT ET AL., NATURE, vol. 434, 2005, pages 913 - 917
COSI, EXPERT OPIN. THER. PATENTS, vol. 12, no. 7, 2002
D'AMOURS ET AL., BIOCHEM. J., vol. 342, 1999, pages 249 - 268
E. MAGGIO: "Enzyme-Immunoassay", 1980, CRC PRESS, INC.
FARMER H ET AL., NATURE, vol. 434, 2005, pages 917 - 21
GHARBI ET AL., MOL. CELL. PROTEOMICS, vol. 1, 2002, pages 91 - 98
IRIZARRY ET AL., BIOSTAT., vol. 4, 2003, pages 249 - 264
K.J. DILLON ET AL., JOURNAL OF BIOMOLECULAR SCREENING, vol. 8, no. 3, 2003, pages 347 - 352
LIVAK; SCHMITTGEN, METHODS, vol. 25, 2001, pages 402 - 408
MCCABE ET AL., CANCER BIOLOGY & THERAPY, vol. 4, no. 9, 2005, pages 934 - 936
MCCABE ET AL., CANCER RES., 2006
PARIKH ET AL., GENES CHROMOSOMES & CANCER, vol. 46, 2007, pages 761 - 775
PUENTE ET AL., FEBS LETT., vol. 574, 2004, pages 138 - 44
SAMBROOK; RUSSELL: "Molecular Cloning: a Laboratory Manual", 2001, COLD SPRING HARBOR LABORATORY PRESS
SOUTHAN; SZABO, CURR MED CHEM, vol. 10, 2003, pages 321 - 340
SUTO ET AL., ANTICANCER DRUG DES., vol. 6, 1991, pages 107 - 17
TALLOEN ET AL., BIOINFORMATICS, vol. 23, no. 21, 1 November 2007 (2007-11-01), pages 2897 - 2902

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10577662B2 (en) 2010-08-24 2020-03-03 Dana-Farber Cancer Institute, Inc. Methods for predicting anti-cancer response
WO2012156501A1 (fr) * 2011-05-18 2012-11-22 Centre National De La Recherche Scientifique (Cnrs) Signature pour le diagnostic d'agressivité et d'instabilité génétique d'un cancer
WO2013133876A1 (fr) * 2011-12-07 2013-09-12 The Regents Of The University Of California Biomarqueurs destinés à la prédiction de la réponse à une inhibition de parp dans le cancer du sein
US20140364434A1 (en) * 2011-12-07 2014-12-11 The Regents Of The University Of California Biomarkers for Prediction of Response to PARP Inhibition in Breast Cancer
US11299782B2 (en) 2012-02-23 2022-04-12 Children's Medical Center Corporation Methods for predicting anti-cancer response
EP3415915A1 (fr) * 2012-02-23 2018-12-19 Children's Medical Center Corporation Procédés de prédiction de réponse anticancéreuse
US9512486B2 (en) * 2012-08-06 2016-12-06 The Institute Of Cancer Research: Royal Cancer Hospital Materials, methods, and systems for treating cancer
US20140045853A1 (en) * 2012-08-06 2014-02-13 The Institute Of Cancer Research: Royal Cancer Hospital Materials, methods, and systems for treating cancer
WO2014138101A1 (fr) * 2013-03-04 2014-09-12 Board Of Regents, The University Of Texas System Signature génique pour prédire un cancer déficient pour la recombinaison homologue (rh)
US9850542B2 (en) 2013-03-04 2017-12-26 Board Of Regents, The University Of Texas System Gene signature to predict homologous recombination (HR) deficient cancer
US20160102360A1 (en) * 2013-05-21 2016-04-14 The Translational Genomics Research Institute Genetic signature of vulnerability to inhibitors of base excision repair (ber) in cancer
US9637798B2 (en) 2013-05-21 2017-05-02 Dignity Health Genetic signature of vulnerability to inhibitors of base excision repair (BER) in cancer
WO2014190090A1 (fr) * 2013-05-21 2014-11-27 Dignity Health Signature génétique de la vulnérabilité aux inhibiteurs de la réparation par excision des bases (ber) en oncologie
WO2014205105A1 (fr) * 2013-06-19 2014-12-24 The Regents Of The University Of California Biomarqueurs de réponse à l'inhibition de poly(adp-ribose) polymérase (parp) dans un cancer
CN105793437B (zh) * 2013-09-23 2020-12-15 芝加哥大学 关于dna损伤制剂用于癌症治疗的方法和组合物
CN105793437A (zh) * 2013-09-23 2016-07-20 芝加哥大学 关于dna损伤制剂用于癌症治疗的方法和组合物
WO2015042570A1 (fr) 2013-09-23 2015-03-26 The University Of Chicago Procédés et compositions concernant une thérapie anticancéreuse au moyen d'agents endommageant l'adn
EP3543353A1 (fr) * 2013-09-23 2019-09-25 The University of Chicago Procédés et compositions concernant une thérapie anticancéreuse au moyen d'agents endommageant l'adn
EP3049536A4 (fr) * 2013-09-23 2017-08-02 The University of Chicago Procédés et compositions concernant une thérapie anticancéreuse au moyen d'agents endommageant l'adn
CN112592975A (zh) * 2013-09-23 2021-04-02 芝加哥大学 关于dna损伤制剂用于癌症治疗的方法和组合物
CN112522408A (zh) * 2013-09-23 2021-03-19 芝加哥大学 关于dna损伤制剂用于癌症治疗的方法和组合物
WO2015168544A1 (fr) * 2014-05-02 2015-11-05 Emory University Traitements sélectifs de chimiothérapie et méthodes de diagnostic associées à ceux-ci
US10823738B2 (en) * 2015-12-07 2020-11-03 George Mason Research Foundation, Inc. Methods for breast cancer treatment
US12383542B2 (en) 2016-06-29 2025-08-12 Tesaro, Inc. Methods of treating ovarian cancer
WO2018161081A1 (fr) * 2017-03-03 2018-09-07 Board Of Regents, The University Of Texas System Signatures géniques permettant de prédire la réponse à un médicament contre le cancer
US11447830B2 (en) 2017-03-03 2022-09-20 Board Of Regents, The University Of Texas System Gene signatures to predict drug response in cancer
US11596637B2 (en) 2017-04-10 2023-03-07 Sierra Oncology, Inc. CHK1 (SRA737)/PARPi combination methods of inhibiting tumor growth
CN111868265A (zh) * 2017-09-30 2020-10-30 浙江数问生物技术有限公司 Dna重组修复功能评分rds在癌症治疗中的用途
CN111868265B (zh) * 2017-09-30 2024-03-26 浙江数问生物技术有限公司 Dna重组修复功能评分rds在癌症治疗中的用途
CN111801117A (zh) * 2017-12-27 2020-10-20 特沙诺有限公司 治疗癌症的方法
WO2019219759A1 (fr) * 2018-05-15 2019-11-21 Oncology Venture ApS Procédés de prédiction de la réponse aux médicaments chez des patients cancéreux
US20210093730A1 (en) * 2019-10-01 2021-04-01 Immunomedics, Inc. Biomarkers for antibody-drug conjugate monotherapy or combination therapy
WO2022185260A1 (fr) * 2021-03-04 2022-09-09 Otsuka Pharmaceutical Co., Ltd. Biomarqueurs pour la thérapie anticancéreuse utilisant des antagonistes de mdm2
CN114934120A (zh) * 2022-06-20 2022-08-23 柳州市人民医院 一种快速鉴定早期结直肠癌的环状rna标志物的应用及诊断试剂盒
WO2024009946A1 (fr) * 2022-07-08 2024-01-11 国立大学法人東海国立大学機構 Procédé de test de l'efficacité d'un inhibiteur de parp contre le cancer de l'ovaire
JPWO2024009946A1 (fr) * 2022-07-08 2024-01-11
RU2842420C1 (ru) * 2024-09-05 2025-06-26 Федеральное государственное бюджетное образовательное учреждение высшего образования "Курский государственный медицинский университет" Министерства здравоохранения Российской Федерации Способ генотипирования однонуклеотидного варианта rs3219487 (C>T) гена MUTYH человека методом полимеразно-цепной реакции в режиме реального времени
RU2842422C1 (ru) * 2024-09-11 2025-06-26 Федеральное государственное бюджетное образовательное учреждение высшего образования "Курский государственный медицинский университет" Министерства здравоохранения Российской Федерации Способ генотипирования однонуклеотидного варианта rs3219472 (C>T) гена MUTYH человека методом полимеразно-цепной реакции в режиме реального времени

Also Published As

Publication number Publication date
WO2011058367A3 (fr) 2011-08-18

Similar Documents

Publication Publication Date Title
WO2011058367A2 (fr) Test de diagnostic pour prédire la sensibilité à un traitement par un inhibiteur de poly(adp-ribose) polymérase
Bott et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21. 1 losses in malignant pleural mesothelioma
Brough et al. Functional viability profiles of breast cancer
Hsu et al. Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer
CN102216775B (zh) 对hsp90-抑制剂的易感性
Müller et al. Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas
Grubach et al. Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia
US20090275608A1 (en) Methods of diagnosing and treating parp-mediated diseases
EP1945819B1 (fr) Profils d'expression genique et procedes d'utilisation
US20070065827A1 (en) Gene expression profiles and methods of use
US20080113874A1 (en) Gefitinib sensitivity-related gene expression and products and methods related thereto
WO2004066941A2 (fr) Profils d'expression destines au cancer du colon et procedes d'utilisation
Ibarrola-Villava et al. Deregulation of ARID1A, CDH1, cMET and PIK3CA and target-related microRNA expression in gastric cancer
WO2007059094A2 (fr) Procedes destines a predire et a pronostiquer un cancer, et suivi de la therapie du cancer
US20060240441A1 (en) Gene expression profiles and methods of use
WO2007123722A2 (fr) Procedes de prevision et de pronostic de cancer, et surveillance d'une therapie anticancereuse
Olar et al. Biomarkers classification and therapeutic decision-making for malignant gliomas
US20040191819A1 (en) Expression profiles for breast cancer and methods of use
US20120277110A1 (en) Parp and adjuvant cisplatin-based chemotherapy in non-small-cell lung cancer
Hickinson et al. Identification of biomarkers in human head and neck tumor cell lines that predict for in vitro sensitivity to gefitinib
WO2011146725A1 (fr) Biomarqueurs pour un inhibiteur à multiples kinases
JP2010505123A (ja) ｅＩＦ４Ｅレギュロン・ベースの診断薬
Kitamura et al. Tumor p16INK4 gene expression and prognosis in colorectal cancer
Wang et al. Contribution of PGAP3 co‐amplified and co‐overexpressed with ERBB2 at 17q12 involved poor prognosis in gastric cancer
JP2005034151A (ja) 癌を評価および治療する方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10782357

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10782357

Country of ref document: EP

Kind code of ref document: A2