WO2014023808A2 - Procédé d'évaluation de l'aptitude d'un patient cancéreux à répondre à une thérapie - Google Patents

Procédé d'évaluation de l'aptitude d'un patient cancéreux à répondre à une thérapie Download PDF

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WO2014023808A2
WO2014023808A2 PCT/EP2013/066662 EP2013066662W WO2014023808A2 WO 2014023808 A2 WO2014023808 A2 WO 2014023808A2 EP 2013066662 W EP2013066662 W EP 2013066662W WO 2014023808 A2 WO2014023808 A2 WO 2014023808A2
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six1
plod2
seq
jak1
pcdha1
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PCT/EP2013/066662
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English (en)
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WO2014023808A3 (fr
Inventor
Céline SEVENO
Pascal Jezequel
Loïc Campion
Philippe Juin
Sophie BARILLE-NION
Mario CAMPONE
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Institut National De La Sante Et De La Recherche Medicale (Inserm)
Universite De Nantes
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Priority to EP13745701.6A priority Critical patent/EP2883053A2/fr
Publication of WO2014023808A2 publication Critical patent/WO2014023808A2/fr
Publication of WO2014023808A3 publication Critical patent/WO2014023808A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention concerns a method for evaluating a cancer patient for propensity to respond to therapy.
  • the invention further concerns a method of monitoring efficiency of a treatment of cancer.
  • Taxanes paclitaxel and docetaxel
  • pathologic complete response rates for single-agent taxanes are reduced.
  • Some signatures are as good or better than that achieved with clinical parameters alone (tumor size, nodal status, estrogen receptor (ER), progesterone receptor (PR), HER2, etc).
  • Model cell lines do not fully reflect the biology of breast tumors. Firstly, because those immortalized cells generally derive from metastasis and not from tumor cells. Additionally, because of the large diversity of tumor cells, numerous tumor breast cell types are not represented by any model cell line. Finally, the use of immortalized cells as biological model of cancer cells is biased in that during cell culture, immortalized cells may acquire mutations not present in original cancer cell.
  • Tumoral epithelial cells interact with stromal cells or with the extracellular matrix. It has been demonstrated that stromal cells play a crucial role in tumor sensitivity or resistance to chemotherapeutic drugs.
  • the invention concerns a method for predicting whether a cancer patient will respond to therapy, said method comprising determining the level of expression of at least one gene selected from the group consisting of procollagen-lysine, 2-oxoglutarate 5- dioxygenase 2 (PLOD2); imprinted maternally expressed transcript (H19); SIX homeobox 1 (SIX1 ); protocadherin alpha 1 (PCDHA1 ); S100 calcium binding protein A1 (S100A1 ); mitochondrial ribosomal protein S16 (MRPS16); thymidine kinase 2 (TK2); long intergenic non-protein coding RNA 589 (C8orf75); Cadherin 4 (CDH4); LOC100131756; zinc finger CCCH-type containing 12B (ZC3H12B); cation transport regulator homolog 2 (CHAC2); eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2); protocadherin beta 15 (PCDHB
  • the invention also concerns a method of monitoring efficiency of cancer therapy comprising:
  • CDH4 LOC100131756; ZC3H12B; CHAC2; EIF2AK2; PCDHB15; VGLL4; JAK1 ;
  • TAP2 in a biological sample from a patient undergoing said therapy
  • step b) repeating step a) on another biological sample from the same patient taken at a later point in time
  • a method of prognosing or classifying the outcome of cancer in a patient undergoing a therapy comprising a treatment with a taxane comprises the step of determining the level of expression of at least one gene selected from the group consisting of SIX1 ; PLOD2; H19; PCDHA1 ; S100A1 ; MRPS16; TK2; C8orf75; CDH4; LOC100131756; ZC3H12B; CHAC2; EIF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6; ST8SIA4; CCNO; PCDHB14; ITGA4; PCDHB18; PPIF; RHOU; TMEM63A; RPS6KL1 ; CSPP1 ; FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf
  • the invention also concerns a method for determining a therapeutic regimen suitable for treating a subject suffering from a cancer, wherein said method comprises the steps of:
  • a panel of cancer therapy markers comprising or consisting of at least one marker selected from the group consisting of SIX1 ; PLOD2; H19; PCDHA1 ; S100A1 ; MRPS16; TK2; C8orf75; CDH4; LOC100131756; ZC3H12B; CHAC2; EIF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6; ST8SIA4; CCNO; PCDHB14; ITGA4; PCDHB18; PPIF; RHOU; TMEM63A; RPS6KL1 ; CSPP1 ; FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf39; TRD@ and TAP2.
  • the invention further provides a kit for predicting responsiveness of a cancer patient to a therapy comprising a treatment with a taxane, said kit comprising means for detecting the panel of markers according to the invention.
  • the inventors have developed a reproducible method of analyzing tumoral fragments with the intent of identifying markers of response to taxane therapy. Said method provides representative results because, during the assay, the natural tumoral cell environment is preserved and cells can be cultured up to 48 hours, a duration long enough to study the biological response of tumoral cells to drug therapy. Using this method, the inventors have found that specific genes were deregulated in tumoral cells and that this deregulation is indicative of the resistance or sensitivity of tumoral cells to taxane therapy. The inventors have reported that 35 genes were deregulated in breast cancer cells sensitive to taxanes compared with breast cancer resistant cells.
  • the invention relates to a method for predicting whether a cancer patient will respond to therapy, said method comprising determining the level of expression of at least one gene selected from the group consisting of SIX1 ; PLOD2; H19; PCDHA1 ; S100A1 ; MRPS16; TK2; C8orf75; CDH4; LOC100131756; ZC3H12B; CHAC2; EIF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6; ST8SIA4; CCNO; PCDHB14; ITGA4; PCDHB18; PPIF; RHOU; TMEM63A; RPS6KL1 ; CSPP1 ; FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf39; TRD@ and TAP2 in a biological sample from the patient.
  • said method comprises determining the level of expression of at least PLOD2 and TK2; or at least
  • the agent used for therapy is preferably an antiproliferative and/or anti-angiogenic agent, for example a taxane.
  • taxane means paclitaxel, docetaxel, or other taxanes that may be either isolated from natural sources such as the Yew tree, or from cell culture, or chemically synthesized, such as 10-deacetylpaclitaxel, 7-epipaclitaxel, cephalomannine, 7-epi-cephalomannine, and N-debenzoyl-N-phenylacetylpaclitaxel.
  • the most preferred taxane is paclitaxel.
  • Paclitaxel refers to paclitaxel (CAS N ° 33069-62-4), analogues and derivatives thereof, including, for example, a natural or synthetic functional analogue of paclitaxel which has paclitaxel biological activity, as well as a fragment of paclitaxel having paclitaxel biological activity.
  • a compound which is a paclitaxel analogue refers to a compound which interferes with cellular mitosis by affecting microtubule formation and/or action, thereby producing antimitotic and anti-cellular proliferation effects. Methods of preparing paclitaxel and its analogues and derivatives are well-known in the art.
  • Paclitaxel, its analogues and derivatives are also available commercially. Synthetic paclitaxel, for example, can be obtained from Bristol-Myers Squibb Company, Oncology Division (Princeton, NJ), under the registered trademark Taxol®.
  • the method of the invention comprises the step of determining the level of expression of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35genes selected from the group consisting of PLOD2; H19; SIX1; PCDHA1; S100A1; MRPS16; TK2; C8orf75; CDH4; LOC100131756; ZC3H12B; CHAC2; IF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6; ST8SIA4; CCNO; PCDHB14; ITGA4; PCDHB18; PPIF; RHOU; TMEM63A; RPS6KL1; CSPP1; FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf39; TRD@ and TAP2 or one variant thereof.
  • the method of the invention comprises the step of determining the level of expression of at least PLOD2, JAK1, SIX1, TK2 and CDH4; or PLOD2, JAK1, SIX1, TK2 and LOC100131756; or PLOD2, JAK1, SIX1, TK2 and ZC3H12B; or PLOD2, JAK1, SIX1, TK2 and CHAC2; or PLOD2, JAK1, SIX1, TK2 and EIF2AK2; or PLOD2, JAK1, SIX1, TK2 and PCDHB15; or PLOD2, JAK1, SIX1, TK2 and VGLL4; or PLOD2, JAK1, SIX1, TK2 and H19; or PLOD2, JAK1, SIX1, TK2 and APOL6; or PLOD2, JAK1, SIX1, TK2 and ST8SIA4; or PLOD2, JAK1, SIX1, TK2 and CCNO; or PLOD2, JAK1, SIX1, TK2 and CC
  • the method of the invention comprises the step of determining the level of expression of at least TRD@, H19, SIX1, TK2 and CDH4; or TRD@, H19, SIX1, TK2 and LOC100131756; or TRD@, H19, SIX1, TK2 and ZC3H12B; or TRD@, H19, SIX1, TK2 and CHAC2; or TRD@, H19, SIX1, TK2 and EIF2AK2; or TRD@, H19, SIX1, TK2 and PCDHB15; or TRD@, H19, SIX1, TK2 and VGLL4; or TRD@, H19, SIX1, TK2 and JAK1; or TRD@, H19, SIX1, TK2 and APOL6; or TRD@, H19, SIX1 , TK2 and ST8SIA4; or TRD@, H19, SIX1, TK2 and CCNO; or TRD@, H19, SIX1, ,
  • the level of expression of said gene(s) is determined by detecting transcription product(s) and/or translation product(s) of said gene(s).
  • Level of expression of gene can be performed by methods which are well known to the person skilled in the art, including in particular quantitative methods involving reverse transcriptase PCR (RT-PCR), such as real-time quantitative RT-PCR (qRT-PCR), and methods involving the use of DNA arrays (macroarrays or microarrays) and In Situ hybridizations.
  • Level of expression of gene(s) may further be assessed by using immunologic methods such as detection using polyclonal or monoclonal antibodies. Suitable immunologic methods include enzyme linked immunoassays (ELISA), sandwich, direct, indirect, or competitive ELISA assays, enzyme linked immunospotassays (ELIspot), radio immunoassays (RIA), flow-cytometry assays (FACS), immunohistochemistry, Western Blot, fluorescence resonance energy transfer (FRET) assays, protein chip assays using for example antibodies, antibody fragments, receptor ligands or other agents binding the proteins coded by the genes of table 1 .
  • immunologic methods include enzyme linked immunoassays (ELISA), sandwich, direct, indirect, or competitive ELISA assays, enzyme linked immunospotassays (ELIspot), radio immunoassays (RIA), flow-cytometry assays (FACS), immunohistochemistry, Western Blot, fluorescence resonance energy transfer (FRET) assays, protein chip assays using for example antibodies
  • a "gene” refers to a nucleic acid that is transcribed.
  • the gene includes regulatory sequences involved in transcription, or message production or composition.
  • the gene comprises transcribed sequences that encode for a protein, polypeptide or peptide.
  • the gene comprises a nucleic acid, and/or encodes a polypeptide or peptide- coding sequences of a gene that is defective or mutated in a hematopoietic and lympho- hematopoietic disorder.
  • an "isolated gene” may comprise transcribed nucleic acid(s), regulatory sequences, coding sequences, or the like, isolated substantially away from other such sequences, such as other naturally occurring genes, regulatory sequences, polypeptide or peptide encoding sequences, etc.
  • the term “gene” is used for simplicity to refer to a nucleic acid comprising a nucleotide sequence that is transcribed, and the complement thereof.
  • the transcribed nucleotide sequence comprises at least one functional protein, polypeptide and/or peptide encoding unit.
  • this functional term "gene” includes both genomic sequences, RNA or cDNA sequences, or smaller engineered nucleic acid segments, including nucleic acid segments of a non-transcribed part of a gene, including but not limited to the non-transcribed promoter or enhancer regions of a gene. Smaller engineered gene nucleic acid segments may express, or may be adapted to express using nucleic acid manipulation technology, proteins, polypeptides, domains, peptides, fusion proteins, mutants and/or such like. For example, when the level of expression of said gene(s) is determined by detecting transcription product(s), said transcription product is a nucleic acid comprising a sequence or a sequence complementary to SEQ ID NO : 1 ; SEQ ID NO : 3
  • SEQ ID NO : 14 SEQ ID NO : 16
  • SEQ ID NO 18 SEQ ID NO : 19
  • SEQ ID NO : 23 SEQ ID NO : 25
  • SEQ ID NO 27 SEQ ID NO : 29
  • SEQ ID NO : 33 SEQ ID NO : 35 SEQ ID NO 37 SEQ ID NO : 39 SEQ ID NO : 41
  • SEQ ID NO : 63 SEQ ID NO : 65; SEQ ID NO : 66; or a variant or fragment thereof, preferably of said transcription product is a nucleic acid comprising a sequence or a sequence complementary to at least one, 2, 3 or 4 sequence(s) SEQ ID NO : 1 ; SEQ ID NO : 4; SEQ ID NO : 12; SEQ ID NO : 29; or a variant or fragment thereof.
  • nucleic acid will generally refer to at least one molecule or strand of DNA, RNA or a derivative or mimic thereof, comprising at least one nucleobase, such as, for example, a naturally occurring purine or pyrimidine base found in DNA (e.g., adenine "A,” guanine “G,” thymine “T,” and cytosine “C”) or RNA (e.g. A, G, uracil “U,” and C).
  • nucleic acid encompasses the terms “oligonucleotide” and “polynucleotide.”
  • oligonucleotide refers to at least one molecule of between about 3 and about 100 nucleobases in length.
  • polynucleotide refers to at least one molecule of greater than about 100 nucleobases in length. These definitions generally refer to at least one single-stranded molecule, but in specific embodiments will also encompass at least one additional strand that is partially, substantially or fully complementary to the at least one single-stranded molecule. Thus, a nucleic acid may encompass at least one double- stranded molecule or at least one triple-stranded molecule that comprises one or more complementary strand(s) or "complement(s)" of a particular sequence comprising a strand of the molecule.
  • a nucleic acid may be made by any technique known to one of ordinary skill in the art.
  • Non-limiting examples of synthetic nucleic acid, particularly a synthetic oligonucleotide include a nucleic acid made by in vitro chemical synthesis using phosphotriester, phosphite or phosphoramidite chemistry and solid phase techniques such described by Froehler et at., 1986 via deoxynucleoside H-phosphonate intermediates.
  • a non-limiting example of enzymatically produced nucleic acid include one produced by enzymes in amplification reactions such as PCRTM or the synthesis of oligonucleotides.
  • a non-limiting example of a biologically produced nucleic acid includes recombinant nucleic acid production in living cells (see for example, Sambrook et al. 2000).
  • a nucleic acid may be purified on polyacrylamide gels, cesium chloride centrifugation gradients, or by any other means known to one of ordinary skill in the art (see for example, Sambrook et al. 2000).
  • the nucleic acid molecule is preferably isolated, which means that it is essentially free of other nucleic acids. Essentially free from other nucleic acids means that the nucleic acid molecule is at least about 90%, preferably at least about 95% and, more preferably at least about 98% free of other nucleic acids.
  • the molecule is essentially pure, which means that the molecule is free not only of other nucleic acids, but also of other materials used in the synthesis and isolation of the molecule.
  • Materials used in synthesis include, for example, enzymes.
  • Materials used in isolation include, for example, gels, such as SDS-PAGE.
  • the molecule is at least about 90% free, preferably at least about 95% free and, more preferably at least about 98% free of other nucleic acids and such other materials.
  • the translation product is a polypeptide of sequence SEQ ID NO : 2 ; SEQ ID NO : 5 ; SEQ ID NO : 7 ; SEQ ID NO : 9 ; SEQ ID NO
  • SEQ ID NO 34 SEQ ID NO : 36 ; SEQ ID NO 38 SEQ ID NO 40 ; SEQ ID NO :
  • SEQ ID NO 54 SEQ ID NO : 56 ; SEQ ID NO 58 SEQ ID NO 60 ; SEQ ID NO :
  • the translation product is at least 1 , 2, 3, 4 polypeptide(s) of sequence SEQ ID NO : 2; SEQ ID NO : 5; SEQ ID NO : 13; SEQ ID NO : 30 ; or a variant or fragment thereof.
  • polypeptide refers to any chain of amino acids linked by peptide bonds, regardless of length or post-translational modification.
  • Polypeptides include natural proteins, synthetic or recombinant polypeptides and peptides (i.e. polypeptides of less than 50 amino acids) as well as hybrid, post-translationally modified polypeptides, and peptidomimetic.
  • amino acid refers to the 20 standard alpha-amino acids as well as naturally occurring and synthetic derivatives.
  • a polypeptide may contain L or D amino acids or a combination thereof.
  • variants includes protein and nucleic acid variants.
  • Variant proteins may be naturally occurring variants, such as splice variants, alleles and isoforms, or they may be produced by recombinant means.
  • Variations in amino acid sequence may be introduced by substitution, deletion or insertion of one or more codons into the nucleic acid sequence encoding the protein that results in a change in the amino acid sequence of the protein.
  • the variation is by substitution of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids with any other amino acid in the protein. Amino acid substitutions may be conservative or non-conservative.
  • substitutions are conservative substitutions, in which one amino acid is substituted for another amino acid with similar structural and/or chemical properties.
  • the variation may be by addition or deletion of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids within the protein.
  • Amino acid substitutions may be conservative or non-conservative.
  • substitutions are conservative substitutions, in which one amino acid is substituted for another amino acid with similar structural and/or chemical properties. Exemplary conservative substitutions are listed below.
  • Variant proteins may include proteins that have at least about 80% amino acid sequence identity with a polypeptide sequence disclosed herein.
  • a variant protein will have at least about 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% amino acid sequence identity to a full-length polypeptide sequence or a fragment of a polypeptide sequence as disclosed herein.
  • Amino acid sequence identity is defined as the percentage of amino acid residues in the variant sequence that are identical with the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Sequence identity may be determined over the full length of the variant sequence, the full length of the reference sequence, or both.
  • sequence alignment and determination of sequence identity are well known in the art, for example using publicly available computer software such as BioPerl, BLAST, BLAST-2, CS-BLAST, FASTA, ALIGN, ALIGN-2, LALIGN, Jaligner, matcher or Megalign (DNASTAR) software and alignment algorithms such as the Needleman-Wunsch and Smith-Waterman algorithms.
  • the percentage of identity may be calculated by performing a pairwise global alignment based on the Needleman-Wunsch alignment algorithm to find the optimum alignment (including gaps) of two sequences along their entire length, for instance using Needle, and using the BLOSUM62 matrix with a gap opening penalty of 10 and a gap extension penalty of 0.5.
  • the percentage identity may be calculated by performing a pairwise global alignment based on the Needleman-Wunsch alignment algorithm to find the optimum alignment (including gaps) of two sequences along their entire length, for instance using Needle, and using the BLOSUM62 matrix with a gap opening penalty of 10 and a gap extension penalty of 0.5.
  • fragments of the proteins and variant proteins disclosed herein are also encompassed by the invention. Such fragments may be truncated at the N-terminus or C- terminus, or may lack internal residues, for example, when compared with a full length protein. Certain fragments lack amino acid residues that are not essential for enzymatic activity. Preferably, said fragments are at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 150, 250, 300, 350, 400, 450, 500 or more amino acids in length.
  • Variant nucleic acid sequences include sequences capable of specifically hybridizing to the sequence of SEQ ID NO : 1 ; SEQ ID NO : 3; SEQ ID NO : 4; SEQ ID NO : 6; SEQ ID NO : 8; SEQ ID NO : 10; SEQ ID NO : 12; SEQ ID NO : 14; SEQ ID NO : 16; SEQ ID NO : 18; SEQ ID NO : 19; SEQ ID NO : 21 ; SEQ ID NO : 23; SEQ ID NO : 25 SEQ ID NO : 27 SEQ ID NO : 29 SEQ ID NO : 31 SEQ ID NO : 33 SEQ ID NO : 35 SEQ ID NO : 37 SEQ ID NO : 39 SEQ ID NO : 41 SEQ ID NO : 43 SEQ ID NO : 45 SEQ ID NO : 47 SEQ ID NO : 49 SEQ ID NO : 51 SEQ ID NO : 53 SEQ ID NO : 55 SEQ ID NO : 57 SEQ ID NO : 59
  • Stringent conditions or high stringency conditions may be identified by those that: (1 ) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1 % sodium dodecyl sulfate at 50 °C; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1 % bovine serum albumin/0.1 % Ficoll/0.1 % polyvinylpyrrolidone/5 OmM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42 °C; or (3) employ 50% formamide, 5 x SSC (0.75 M NaCI, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1 % sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 Mg/ml), 0.1 % SDS, and 10% dextran sul
  • Moderately stringent conditions may be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and %SDS) less stringent that those described above.
  • washing solution and hybridization conditions e.g., temperature, ionic strength and %SDS
  • moderately stringent conditions is overnight incubation at 37°C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCI, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 x Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1 x SSC at about 37-50 ⁇ .
  • Variant nucleic acid sequences may include nucleic acid sequences that have at least about 80% nucleic acid sequence identity with a nucleic acid sequence disclosed herein.
  • a variant nucleic acid sequence will have at least about 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% nucleic acid sequence identity to a full-length nucleic acid sequence or a fragment of a nucleic acid sequence as disclosed herein.
  • Nucleic acid sequence identity can be calculated by methods well-known to one of skill in the art.
  • the percentage of identity may be calculated by performing a pairwise global alignment based on the Needleman-Wunsch alignment algorithm to find the optimum alignment (including gaps) of two sequences along their entire length, for instance using Needle, and using the BLOSUM62 matrix with a gap opening penalty of 10 and a gap extension penalty of 0.5.
  • the method for predicting whether a cancer patient will respond to therapy additionally comprises the steps of:
  • similar level of expression means that there is no or little difference in the level of expression of at least one gene of table 1 between a first sample as compared with a second sample (such as a control sample). There is a similar level of expression of at least one gene of table 1 between two samples when there is no statistically significant difference in the level of expression of said genes.
  • An alteration of the expression of at least one gene of table 1 by comparing its level of expression in the patient biological sample to the one of a control sample is indicative that the patient is sensitive or resistant to therapy.
  • alteration of the expression a gene of table 1 refers to a statistically significant difference in the level of expression of said gene measured between two samples such as for example, the patient biological sample and the control sample.
  • the alteration of the expression can be compared using the ratio of the level of expression of a given gene or gene(s) as compared with the expression level of the given gene or gene(s) of another sample, wherein the ratio is not equal to 1 .
  • there is an alteration of the expression of a gene if the ratio of the level of expression in a first sample as compared with a second sample is greater than or less than 1 .0.
  • the alteration of the expression is measured using p-value. For instance, when using p-value, an alteration of the expression of a gene is as between a first sample and a second sample or a control sample when the p-value is less than 0.1 , preferably less than 0.05, more preferably less than 0.01 , even more preferably less than 0.005, the most preferably less than 0.001 .
  • the "alteration of the expression” means an increase (over-expression) or a decrease (under-expression) of the level of expression of a gene of table 1 by comparing its level of expression between two samples such as for example, by comparing a biological sample of a patient to a control sample.
  • TMEM63A TMEM63A; RPS6KL1 ; FUT6; SIDT2 ; C5orf4 ; CES3; C14orf39 or one variant thereof and preferably, SIX1 and/or TK2 or one variant thereof, compared to the control sample is indicative of a patient that responds to therapy wherein the control sample is a biological sample of a cancer patient or a group of cancer patients that does not respond or has reduced response to said therapy.
  • control value when the method of the invention involves comparing the level of expression of a gene of table 1 with that of a control sample obtained from an individual (healthy subject or cancer patients) or a group of individuals (a group of healthy subjects or a group of cancer patients), the level of expression of said gene in said control sample is called a "control value".
  • the control value can be any number of statistical measures to distinguish therapy-sensitive and/or therapy-resistant levels, including Mean and Median expression levels, and/or cut-off or threshold gene expression or fold change values as determined in an individual or a group of individuals.
  • control values for at least 2, 3 or 4 genes selected from the group consisting of PLOD2; H19; SIX1 ; PCDHA1 ; S100A1 ; MRPS16; TK2; C8orf75; CDH4; LOC100131756; ZC3H12B; CHAC2; IF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6; ST8SIA4; CCNO; PCDHB14; ITGA4; PCDHB18; PPIF; RHOU; TMEM63A; RPS6KL1 ; CSPP1 ; FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf39; TRD@ and TAP2 or one variant thereof define a gene expression signature.
  • the control values for at least 2, 3 or 4 genes selected from the group consisting of PLOD2; SIX1 ; TK2; JAK1 or one variant thereof define a gene expression signature.
  • control values for at least 2, 3 or 4 genes selected from the group consisting of PLOD2; SIX1 ; TK2; JAK1 or one variant thereof as determined in a biological sample from a cancer patient or a group of cancer patients that responds to therapy define a therapy- resistant gene expression signature or a therapy-sensitive gene expression signature.
  • a cancer patient is evaluated for the presence of one or more of the gene of table 1 , by scoring or classifying the patient expression level against the gene expression signature (therapy- sensitive gene expression signature or therapy-resistant gene expression signature).
  • Various classification schemes are known for classifying samples between two or more classes or groups, and these include, without limitation: Principal Components Analysis, Naive Bayes, Support Vector Machines, Nearest Neighbors, Decision Trees, Logistic, Artificial Neural Networks, and Rule-based schemes.
  • the predictions from multiple models can be combined to generate an overall prediction.
  • the control sample is a biological sample obtained from an individual or a group of individuals.
  • a "biological sample” encompasses a variety of sample types obtained from an individual and can be used in a diagnostic or monitoring assay.
  • the definition encompasses a clinical sample, solid tissue samples such as a biopsy specimen or tissue cultures, cells in culture, cell supernatants, cell lysates or cells derived there from and the progeny thereof, and also includes serum, plasma, blood and other liquid samples of biological origin.
  • the definition also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, purification or enrichment for certain components, such as polypeptides or nucleic acids.
  • control sample is a biological sample from "a healthy subject” "a group of healthy subjects"
  • the expression “healthy subject(s)” refers an individual or a reference group of individuals who are not suffering from or who did not develop a cancer.
  • control sample is a biological sample from "a cancer patient or a group of cancer patients that does not respond or has reduced response to said therapy" an individual or a reference group of individuals who are suffering from or who developed a cancer and have been diagnosed as resistant or as having reduced response to a therapy.
  • control sample is a biological sample from "a cancer patient or a group of cancer patients that responds to said therapy" an individual or a reference group of individuals who are suffering from or who developed a cancer and have been diagnosed as sensitive to a therapy.
  • the sample After comparing the patient's gene(s) level of expression to the gene expression signature, therapy-sensitive and/or therapy-resistant signature, the sample is classified as, or for example, given a probability of being, a therapy-sensitive patient or a therapy- resistant patient.
  • the classification may be determined computationally based upon known methods as described above.
  • the result of the computation may be displayed on a computer screen or presented in a tangible form, for example, as a probability (e.g., from 0 to 100%) of the patient responding to said therapy.
  • the method according the invention distinguishes a therapy-sensitive tumor from a therapy-resistant tumor with at least about 60%, 75%, 80%, 85%, 90% or greater accuracy.
  • the invention further relates to a method of monitoring efficiency of cancer therapy comprising:
  • CDH4 LOC100131756; ZC3H12B; CHAC2; EIF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6;
  • CSPP1 FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf39; TRD@ and TAP2 in a biological sample from a patient undergoing said therapy, b) repeating step a) on another biological sample from the same patient taken at a later point in time;
  • said therapy preferably comprises a treatment with a taxane
  • said method comprises determining the level of expression of at least PLOD2 and TK2; or at least PLOD2 and SIX1 ; or at least PLOD2 and JAK1 ; or at least TK2 and SIX1 ; or at least TK2 and JAK1 ; or at least SIX1 and JAK1 ; or at least SIX1 ; PLOD2 and TK2; or at least SIX1 , PLOD2 and JAK1 ; or at least SIX1 , TK2 and JAK1 ; or at least TK2, PLOD2 and JAK1 ; or at least SIX1 , PLOD2; TK2 and JAK1 ; or PLOD2, JAK1 and H19; or at least PLOD2, SIX1 and JAK1 ; or at least PLOD2, SIX1 and PCDHA1 ; or at least PLOD2, SIX1 and S100A1 ; or at least PLOD2, JAK1 and MRPS16; or
  • the "alteration of the expression” means an increase or a decrease of the level of expression of a gene by comparing its level of expression in a biological sample of the patient following treatment with the therapy to its level of expression in a biological sample of the patient prior to treatment with the therapy:
  • the method according to the invention will aid a physician in selecting a course of treatment for the cancer patient.
  • the patient will be determined to be a therapy-sensitive patient on the basis of a probability, and the patient will be subsequently treated with that therapy alone in combination with other chemotherapeutic drugs.
  • the patient will be determined to be therapy-resistant, thereby allowing the physician to exclude that candidate treatment for the patient, thereby sparing the patient the unnecessary toxicity.
  • the invention concerns, a method for determining a therapeutic regimen suitable for treating a subject suffering from a cancer, wherein said method comprises the steps of:
  • a method of prognosing or classifying the outcome of cancer in a patient undergoing a therapy comprising a treatment with a taxane comprises the step of determining the level of expression of at least one gene selected from the group consisting of PLOD2; H19; SIX1 ; PCDHA1 ; S100A1 ; MRPS16; TK2;
  • said method comprises determining the level of expression of PLOD2 and TK2; or at least PLOD2 and SIX1 ; or at least PLOD2 and JAK1 ; or at least TK2 and SIX1 ; or at least TK2 and JAK1 ; or at least SIX1 and JAK1 ; or at least SIX1 ; PLOD2 and TK2; or at least SIX1 , PLOD2 and JAK1 ; or at least SIX1 , TK2 and JAK1 ; or at least TK2, PLOD2 and JAK1 ; or at least SIX1 , PLOD2; TK2 and JAK1 ; or at least PLOD2, JAK1 and H19; or at least PLOD2, SIX1 and JAK1 ; or at least PLOD2, SIX1 and PCDHA1 ; or at least PLOD2, SIX1 and S100A1 ; or at least PLOD2, JAK1 and MRPS16; or or
  • prediction is used herein to refer to the prediction of the likelihood of benefit from therapy.
  • prediction or predicting refers to the likelihood that a patient will respond either favourably or unfavourably to a particular therapy.
  • prediction or predicting relates to the extent of those responses.
  • the prediction or predicting relates to whether and/or the probability that a patient will survive or improve following treatment, for example treatment with a particular therapeutic agent, and for a certain period of time without disease recurrence.
  • the predictive methods of the invention can be used clinically to make treatment decisions by choosing the most appropriate treatment modalities for any particular patient.
  • the predictive methods of the present invention are valuable tools in predicting if a patient is likely to respond favourably to a treatment regimen, such as a given therapeutic regimen, or whether long-term survival of the patient following a therapeutic regimen is likely.
  • therapeutic regimen refers to a course of treatment intended to reduce or eliminate the affects or symptoms of a disease or to prevent progression of a disease from one state to a second, more detrimental state.
  • a therapeutic regimen can comprise a prescribed drug, surgery or radiation treatment.
  • the individual or patient is preferably a human individual.
  • the individual may thus also correspond to a non-human individual, preferably a non-human mammal such as a rodent, a feline, a canine, or a primate.
  • the invention concerns a panel of cancer therapy markers, said panel comprising or consisting of at least one marker selected from the group consisting of PLOD2; H19; SIX1 ; PCDHA1 ; S100A1 ; MRPS16; TK2; C8orf75; CDH4; LOC100131756; ZC3H12B; CHAC2; EIF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6; ST8SIA4; CCNO; PCDHB14; ITGA4; PCDHB18; PPIF; RHOU; TMEM63A; RPS6KL1 ; CSPP1 ; FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf39; TRD@ and TAP2.
  • marker in the expression “cancer therapy markers” means a distinctive biological or biologically-derived indicator of a process, event, or condition.
  • the term marker as used herein refers to a gene that is differentially expressed in individuals with cancer such as breast cancer, according to their sensitivity or resistance to therapy and notably taxanes
  • the marker according to the invention is suitable to be used in methods of diagnosis (e.g. clinical screening), prognosis assessment; in monitoring the results of therapy, identifying patients most likely to respond to a particular therapeutic treatment, drug screening and development.
  • the marker is a gene, mRNA, a protein or peptide or variant of PLOD2; H19; SIX1 ; PCDHA1 ; S100A1 ; MRPS16; TK2; C8orf75; CDH4; LOC100131756; ZC3H12B; CHAC2; EIF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6; ST8SIA4; CCNO; PCDHB14; ITGA4; PCDHB18; PPIF; RHOU; TMEM63A; RPS6KL1 ; CSPP1 ; FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf39; TRD@ and TAP2. Markers and uses thereof are valuable for identification of new drug treatments and for discovery of new targets for drug treatment.
  • said panel comprises or consists of at least PLOD2 and TK2; or at least PLOD2 and SIX1 ; or at least PLOD2 and JAK1 ; or at least TK2 and SIX1 ; or at least TK2 and JAK1 ; or at least SIX1 and JAK1 ; or at least SIX1 ; PLOD2 and TK2; or at least SIX1 , PLOD2 and JAK1 ; or at least SIX1 , TK2 and JAK1 ; or at least TK2, PLOD2 and JAK1 ; or at least SIX1 , PLOD2; TK2 and JAK1 ; or at least PLOD2, JAK1 and H19; or at least PLOD2, SIX1 and JAK1 ; or at least PLOD2, SIX1 and PCDHA1 ; or at least PLOD2, SIX1 and S100A1 ; or at least PLOD2, JAK1 and MRPS16; or at least
  • kits that are useful in the above methods. Indeed is provided a kit for predicting responsiveness of a cancer patient to a therapy comprising a treatment with a taxane, said kit comprising means for detecting the panel of markers according to the invention.
  • the kit further comprises a control sample indicative of the amount and/or expression level of said at least one gene of table 1 .
  • kits according to the invention may for example comprise, in addition to the means for detecting the amount and/or expression level of said at least one gene, one of (i) to (iii) below:
  • a negative control sample indicative of the amount and/or expression level of said at least one gene in a healthy individual
  • kits for the use of said kit in monitoring efficiency of cancer therapy, prognosing or classifying the outcome of cancer in a patient and/or determining a therapeutic regimen suitable for treating a subject suffering from a cancer.
  • kit may for example comprise (i) and (ii), (i) and (iii), (ii) and (iii), or (i), (ii) and (iii).
  • Means for detecting the amount and/or expression level of said at least one gene of table 1 are well-known in the art. They include, e.g. reagents allowing the detection of said at least one gene mRNA by real-time quantitative-PCR, such as primers specific for said at least one gene of table 1 .
  • the kit may further comprise a second reagent, labeled with a detectable compound, which binds to said at least one gene mRNA synthesized during the PCR, such as e.g. SYBER GREEN reagents.
  • Means for detecting the amount and/or expression level of said at least one gene of table 1 may also include antibodies specifically binding to said at least one gene. Such means can be labeled with detectable compound such as fluorophores or radioactive compounds.
  • the probe or the antibody specifically binding to said at least one gene may be labeled with a detectable compound.
  • the kit may further comprise a secondary antibody, labeled with a detectable compound, which binds to an unlabelled antibody specifically binding to said at least one gene of table 1 or proteins coded by said at least one gene.
  • the means for detecting the amount and/or expression level of said at least one gene may also include reagents such as e.g. reaction, hybridization and/or washing buffers.
  • reagents such as e.g. reaction, hybridization and/or washing buffers.
  • the means may be present, e.g., in vials or microtiter plates, or be attached to a solid support such as a microarray as can be the case for primers and probes.
  • said kit comprises a microfluidic plate, such as a TaqMan®
  • TLDA Low Density Array
  • a microarray such as an Affimetrix® microarray or an Agilent® microarray, comprising means for detecting the expression of at least one gene as described above, preferably for simultaneously detecting the expression of the 35 genes PLOD2; H19; SIX1 ; PCDHA1 ; S100A1 ; MRPS16; TK2; C8orf75; CDH4; LOC100131756; ZC3H12B; CHAC2; EIF2AK2; PCDHB15; VGLL4; JAK1 ; APOL6; CCNO; PCDHB14; ITGA4; PCDHB18; PPIF; RHOU; ST8SIA4; TMEM63A; RPS6KL1 ; CSPP1 ; FUT6; SIDT2; HAVCR2; C5orf4; CES3; C14orf39; TRD@ and TAP2.
  • TLDA Low Density Array
  • means for detecting the expression of said genes using a TLDA or microarray are oligonucleotides.
  • each well of the TLDA according to the invention comprises a forward primer, a reverse primer and a probe, such as a fluorescent probe (e.g. a Taqman probe).
  • a probe such as a fluorescent probe (e.g. a Taqman probe).
  • each spot of the microarray comprises a probe, such as a fluorescent probe, specific for each of the said gene.
  • said specific probes are Affimetrix probes with the Set Identification Number (Set ID) as described in the Table 1 below.
  • Fig 3 Average and standard deviation of apoptosis (cleaved caspase 3) tumor slices taken from different regions within 6 different tumors and treated with a pro apoptotic reagent. The six columns correspond to the 6 different tumors: #47; #55; #64; #70; #72 and #76. Variability in the level of apoptosis seen in different slices taken from the same tumor is very low.
  • Fig 4 Paclitaxel sensitivity of tumor slices.
  • Fresh human mammary samples were obtained from patients with invasive carcinoma after surgical resection at the Institut de Cancerologie de I'gen - Rene Gauducheau, France. Informed consent was obtained from patients to use their surgical specimen and clinicopathological data for research purpose according to the French Committee for the protection of Human Subjects.
  • a fragment of tumor sample was snapped frozen and stored at -80 °C until transcriptomic analysis.
  • a second fragment of the same tumor was cut into thin slices (250 ⁇ ) using a vibratome (Microme, France) and incubated for 48h in a definite medium with or without 700nM Paclitaxel.
  • Sections (3 ⁇ ) from formalin-fixed, paraffin-embedded tumors were cut for standard histological analysis assessed by hematoxylin-eosin-saffron (HES) coloration. Immunohistochemistry was performed to assess tumoral cell apoptosis with cleaved caspase 3 antibody.
  • the active caspase 3 immunostained cells were assessed according the percentage of labeled cells out 200 carcinomatous cells counted. Non neoplastic cells (endothelial cells and lymphocytes) were excluded from counting.
  • FIG. 1 shows a comparison of the index of proliferation (FigI A) and death (FigI B).
  • Proliferation status assessed by KI67 staining, was analyzed at day 0 (immediately after surgery) and at day 2 (after 2 days of culture). At day 0, the mean of proliferating tumoral cells is 39,61 % ( ⁇ 4,85 SEM) whereas it is 28,63% ( ⁇ 4,09 SEM) at day 2 (FigI A). There is therefore a slight decrease in the overall proliferation of cells during ex vivo culture. The decrease in proliferation is, moreover, much less important than that observed between an untreated slice of tumor and a slice of the same tumor treated with paclitaxel (Fig 2).
  • Apoptosis was also assayed in duplicate and triplicate tumor slices taken from 6 different tumors. The six columns correspond to the 6 different tumors. Slices were taken from different locations (from 1 ,5mm to 2mm of the previous slice) within the tumor and treated with the same reagent. As can be seen from Figure 3, the level of apoptosis seen in different slices taken from the same tumor is very slight: the standard error is comprised between 0,5 and 9 (mean 4,54 ⁇ 1 ,71 SEM). This indicates that tumor response, in the ex vivo assay to a given treatment is independent of the localization of the tissue slice within the tumor sample, demonstrating the reproducibility of the method.
  • Tumor slices were either treated with paclitaxel for 48h or left untreated (control). After culture, slices were fixed and assessed for apoptosis as previously described. Tumors were then classified as "sensitive” or “resistant” according to their response to treatment (Fig 4). The apoptotic rates of non treated slices were 5,22% ( ⁇ 0,97 SEM). For calculation facility we considered it at 5,5%. Slices were classified as sensitive if their measured apoptotic rates were 4 times greater than that found in the non treatedgroup, ie above 22% of apotosis.
  • Tumor fragments from tumor bank were then used for affymetrix analysis.
  • Results obtained are presented in table 2.
  • Data were analyzed according to the BRB-Array tools (http://linus.nci.nih.gov/BRB-ArrayTools.html) as described in the prior art (Korde LA. et al, Breast Cancer Res Treat. 2010 Feb;1 19(3):685-99; Rabinovich El et al., PLoS One. 2012;7(4):e33770. Epub 2012 Apr 10). Briefly, the data shown is generated by the comparison of gene expression values between responders (R) and nonresponders (S).
  • the columns “Geometric mean of R or S Intensities in patients” quantify the expression in responders and non-responders respectively, which were used to calculate "fold-change” (calculated as Intensity R / Intensity S).
  • the column “Parametric p-value” quantifies the likelihood of a parametric difference between R and S (Wilcoxon test standard).
  • the columns “FDR” and “Permutation p-value” quantify the same probability taking into account the risk of false positives inherent to the large number of comparisons made, confirming the interest of a gene if the FDR and permutation p-value are small (close to 0001 or smaller than 0001 ).
  • the letter “X” refers to unidentified genes.

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Abstract

L'invention concerne des procédés servant à prédire si un patient cancéreux répondra à une thérapie, à contrôler l'efficacité d'un traitement anticancéreux, à déterminer un schéma thérapeutique adéquat pour traiter un sujet atteint d'un cancer, lesdits procédés comprenant la détermination du niveau d'expression d'au moins un gène choisi dans un panel de marqueurs dans un échantillon biologique prélevé chez le patient. La présente invention concerne en outre un kit comprenant des moyens de détection dudit panel de marqueurs.
PCT/EP2013/066662 2012-08-08 2013-08-08 Procédé d'évaluation de l'aptitude d'un patient cancéreux à répondre à une thérapie WO2014023808A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017132420A1 (fr) * 2016-01-26 2017-08-03 The Methodist Hospital Compositions et méthodes pour la suppression et le diagnostic de métastases cancéreuses
US11319354B2 (en) * 2019-07-10 2022-05-03 Masonic Medical Research Laboratory VGLL4 with UCP-1 cis-regulatory element and method of use thereof
WO2021102104A1 (fr) * 2019-11-20 2021-05-27 University Of Massachusetts Administration à base d'aav de thymine kinase 2
JP2022530595A (ja) * 2019-12-30 2022-06-30 上海海洋大学 Ｚｃ３ｈ１２ｂの遺伝子又はタンパク質の用途及び肝疾患動物モデルの確立方法
JP7263523B2 (ja) 2019-12-30 2023-04-24 上海海洋大学 Ｚｃ３ｈ１２ｂの遺伝子又はタンパク質の用途及び肝疾患動物モデルの確立方法

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