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WO2022022541A1 - Rbm10基因的用途 - Google Patents

Rbm10基因的用途 Download PDF

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WO2022022541A1
WO2022022541A1 PCT/CN2021/108791 CN2021108791W WO2022022541A1 WO 2022022541 A1 WO2022022541 A1 WO 2022022541A1 CN 2021108791 W CN2021108791 W CN 2021108791W WO 2022022541 A1 WO2022022541 A1 WO 2022022541A1
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rbm10
gene
protein
mrna
ovarian cancer
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PCT/CN2021/108791
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English (en)
French (fr)
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山松
潘德思
乔伟
姚何
周游
宁志强
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深圳微芯生物科技股份有限公司
成都微芯药业有限公司
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Publication of WO2022022541A1 publication Critical patent/WO2022022541A1/zh

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    • C—CHEMISTRY; METALLURGY
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
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    • 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
    • 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
    • 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
    • G01N33/57449—Specifically defined cancers of ovaries
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • C—CHEMISTRY; METALLURGY
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    • 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
    • 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
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to the technical field of medicine, in particular to the use of RBM10 gene.
  • Ovarian cancer ranks third among gynecological malignant tumors, and its mortality ranks first, and its incidence is increasing year by year.
  • Ovarian cancer patients can achieve complete remission (CR) after ideal cytoreduction (residual tumor lesions ⁇ 1 cm) combined with platinum and paclitaxel systemic chemotherapy, but 60%-70% of patients will be Relapse occurs.
  • Relapsed patients are less effective for re-chemotherapy: platinum-sensitive relapsed populations have an effective rate of about 30-80% for platinum-containing chemotherapy.
  • platinum-sensitive patients will become platinum-resistant after 2 to 3 platinum-containing treatments; platinum-refractory
  • the effective rate of platinum-free single-agent chemotherapy is only 5-17%, the progression-free survival time is about 3 months, and the overall survival time is less than 1 year.
  • the relevant research mainly includes:
  • GOG0170D study a phase II study of bevacizumab monotherapy in patients with platinum-refractory/resistant ovarian cancer, enrolled 62 subjects, ORR was 21%, of which 2 (3.2%) CR, 11 Case (17.7%) PR. Median PFS and OS were 4.7 and 17 months, respectively.
  • the GOG0170F study a phase II study of sorafenib monotherapy in ovarian cancer patients with recurrence and disease progression less than 12 months from the last platinum-containing chemotherapy, enrolled 71 patients, including platinum-sensitive 21 (29.6%) and platinum-sensitive Drug resistance was found in 50 cases (70.4%), including 59 evaluable cases. Two patients (3.4%) achieved PR, ORR was 3.4%, and median PFS and OS were 2.1 and 16.3 months, respectively.
  • the VEG104450 study pazopanib monotherapy for patients with high recurrence risk ovarian cancer with elevated CA125 after initial treatment, enrolled 36 subjects, of whom 14 (39.0%) were platinum-resistant and 22 (61.0%) were platinum-resistant. %) platinum sensitive.
  • the response rate was 11 (31.0%), and the response rate of the evaluable cases according to the RECIST standard was 0.
  • PARP polyadenosine diphosphate ribose polymerase
  • olapa Niraparib and Niraparib have clear curative effect on ovarian cancer patients with BRCA mutation, but they have not obtained significant benefit for most platinum-refractory/resistant recurrent ovarian cancer patients without BRCA mutation.
  • Ovarian cancer requires the search for more effective treatment options.
  • Cioroni is a small molecule anti-tumor drug targeting multiple protein kinases. It has high selective inhibitory activity on Aurora B, VEGFR/PDGFR/c-Kit, and CSF-1R targets, and has the ability to inhibit tumor cells. Multi-channel synergistic mechanisms such as mitosis, anti-tumor angiogenesis, and regulation of tumor immune microenvironment play a comprehensive anti-tumor effect. Due to the unique anti-tumor mechanism of cioronib, the research on the marker genes related to the efficacy of cioroni will help to find the potential benefit patient population and better therapeutic effect for the clinical application of cioroni .
  • the purpose of the present invention is to provide the use of RBM10 gene or its mRNA or its encoded protein or protein fragment as a biomarker in evaluating the efficacy of cioronitrile or instructing the administration of cioronib or predicting the therapeutic effect of ovarian cancer .
  • Cioroni capsules are used to conduct Phase Ib clinical trials for relapsed and refractory advanced ovarian cancer.
  • ctDNA plasma cell-free tumor DNA
  • 548 tumor-related genes are used to conduct accompanying research on therapeutic efficacy-related biomarkers.
  • Blood samples were drawn from all patients before enrollment, and gene sequences were detected for tumor-related genes, including gene mutations and copy number abnormalities.
  • the detection results selected all genes with a mutation rate of more than 0.4%, and used the patient's progression-free survival (PFS) as the efficacy index to analyze the correlation between tumor-related gene abnormalities and the efficacy of cioronib.
  • PFS progression-free survival
  • the present invention accordingly relates to the preparation of a reagent for detecting the RBM10 gene or its mRNA or its encoded protein or protein fragment for evaluating the curative effect of cioronib or guiding the administration of cioronib or predicting the treatment of ovarian cancer Use in kits or microarrays for effect.
  • a reagent for detecting the RBM10 gene or its mRNA or its encoded protein or protein fragment for evaluating the curative effect of cioronib or guiding the administration of cioronib or predicting the treatment of ovarian cancer Use in kits or microarrays for effect.
  • a reagent for detecting the RBM10 gene or its mRNA or its encoded protein or protein fragment for evaluating the curative effect of cioronib or guiding the administration of cioronib or predicting the treatment of ovarian cancer Use in kits or microarrays for effect.
  • cioronib if there is variation in the RBM10 gene or its
  • the reagent for detecting the RBM10 gene or its mRNA or its encoded protein or protein fragment is a binding agent that binds to the RBM10 gene encoded protein or protein fragment, or hybridizes with the RBM10 gene or its mRNA Or a substance that amplifies the RBM10 gene or its mRNA.
  • the binding agent that binds to the protein or protein fragment encoded by the RBM10 gene is an anti-RBM10 antibody.
  • the substance that hybridizes to or amplifies the RBM10 gene or its mRNA is an oligonucleotide primer or probe.
  • the present invention relates to a kit or microarray for evaluating the curative effect of cioronib or instructing the administration of cioronib or predicting the therapeutic effect of ovarian cancer, comprising a kit or microarray for detecting the RBM10 gene or its mRNA or its Reagents for encoded proteins or protein fragments.
  • a kit or microarray for detecting the RBM10 gene or its mRNA or its Reagents for encoded proteins or protein fragments.
  • if there is variation in the RBM10 gene or its mRNA or the protein encoded by the subject compared with the wild type it indicates that for the subject, cioronib has better curative effect and can The use of cioroni therapy or ovarian cancer treatment is better.
  • the reagent for detecting the RBM10 gene or its mRNA or its encoded protein or protein fragment is a binding agent that binds to the RBM10 gene encoded protein or protein fragment, or hybridizes with the RBM10 gene or its mRNA Or a substance that amplifies the RBM10 gene or its mRNA.
  • the binding agent that binds to the protein or protein fragment encoded by the RBM10 gene is an anti-RBM10 antibody
  • the substance that hybridizes with the RBM10 gene or its mRNA or amplifies the RBM10 gene or its mRNA is an oligonucleotide Nucleotide primers or probes.
  • the present invention relates to the use of cioronib in the preparation of a medicament for the treatment of ovarian cancer, especially ovarian cancer with RBM10 gene mutation.
  • the present invention relates to a biomarker for evaluating the efficacy of cioronib or guiding the administration of cioronib or predicting the treatment effect of ovarian cancer
  • the biomarker is the RBM10 gene or its mRNA or its encoding protein or protein fragment.
  • the present invention relates to the use of the RBM10 gene or its mRNA or its encoded protein or protein fragment as a biomarker in evaluating the efficacy of cioronib or guiding the administration of cioronib or predicting the therapeutic effect of ovarian cancer.
  • the present invention relates to the use of the RBM10 gene or its mRNA or its encoded protein or protein fragment in the preparation of biomarkers for evaluating the efficacy of cioronib or guiding the administration of cioronib or predicting the therapeutic effect of ovarian cancer.
  • the present invention relates to a method for evaluating the curative effect of cioronitrile or instructing the administration of cioronib or predicting the therapeutic effect of ovarian cancer, comprising the following steps:
  • the curative effect of cioronib is better, and the cioronib can be used for treatment or ovarian cancer. Cancer treatment is better.
  • the biological sample is ctDNA, tumor tissue, circulating tumor cells, or tissue from other sources of the human body.
  • the detection method is gene sequencing, PCR, FISH, immunohistochemistry, ELISA, Western or flow cytometry.
  • the ovarian cancer tumor tissue ctDNA is used as the detection sample, and the next-generation sequencing technology is used for detection.
  • the present invention relates to the use of cioronib in the treatment of ovarian cancer, especially ovarian cancer with mutations in the RBM10 gene.
  • Figure 1 shows the progression-free survival of RBM10 mutant and wild-type.
  • the present invention relates to the relationship between the mutation and/or expression of a newly discovered biomarker (ie, RBM10) and the efficacy of cioronib, the administration of cioronib, and/or the therapeutic effect of ovarian cancer.
  • the biomarkers described herein provide methods for evaluating the efficacy of cioronib, guiding the administration of cioronib, and/or predicting the effect of treatment in ovarian cancer.
  • one embodiment of the present invention represents an improvement in biomarkers suitable for evaluating the efficacy of cioronib, guiding the administration of cioronib and/or predicting the effect of ovarian cancer treatment.
  • the newly discovered biomarkers of the present invention may be combined with one or more other cancer markers known in the art (eg, CEA, NSE, CA 19-9, CA 125, CA 72-4, PSA, proGRP, SCC, NNMT, VEGFR2, HER2, MISIIR, VEGFA, CD24) in combination, for example, for evaluating the efficacy of cioronib, guiding the administration of cioronib and/or predicting the treatment effect of ovarian cancer or For the preparation of kits for this purpose.
  • cancer markers known in the art eg, CEA, NSE, CA 19-9, CA 125, CA 72-4, PSA, proGRP, SCC, NNMT, VEGFR2, HER2, MISIIR, VEGFA, CD24
  • the invention verifies the correlation between the RBM10 gene variation and the curative effect of cioroni by taking the patient's progression-free survival (PFS) as the curative effect index, and the detection of the RBM10 gene mutation information can guide the clinical medication and treatment of cioroni.
  • PFS progression-free survival
  • the curative effect of cioronib is better, the treatment effect of cioronib can be better, or the effect of ovarian cancer treatment is better
  • the kit of the present invention is used to evaluate the efficacy of cioronib in the treatment of ovarian cancer and/or to guide the administration of cioronib for the treatment of ovarian cancer.
  • sample means a material known or suspected to express or contain a biomarker (i.e. RBM10) or a binding agent, such as an antibody specific for the biomarker (i.e. RBM10).
  • Samples may be derived from biological sources ("biological samples"), such as tissues (eg, biopsy samples), extracts or cell cultures including cells (eg, tumor cells), cell lysates, and biological or physiological fluids, such as Whole blood, plasma, serum, saliva, cerebrospinal fluid, sweat, urine, milk, peritoneal fluid, etc. Samples obtained from sources or after pretreatment to improve sample characteristics (eg, preparation of plasma from blood, dilution of mucus, etc.) can be used directly.
  • biological samples such as tissues (eg, biopsy samples), extracts or cell cultures including cells (eg, tumor cells), cell lysates, and biological or physiological fluids, such as Whole blood, plasma, serum, saliva, cerebrospinal fluid, sweat, urine, milk, peritoneal fluid, etc.
  • the sample is a human physiological fluid, such as human serum.
  • the sample is a biopsy sample such as tumor tissue or cells obtained by tissue examination.
  • the sample is a malignant or normal tissue sample such as a paracancerous normal tissue sample.
  • Samples that can be analyzed in accordance with the present invention include polynucleotides of clinical origin.
  • target polynucleotides can include RNA, including but not limited to total cellular RNA, poly(A)+ messenger RNA (mRNA) or a portion thereof, cytoplasmic mRNA, or RNA transcribed from cDNA (i.e. cRNA).
  • the target polynucleotide can be detectably labeled on one or more nucleotides using methods known in the art.
  • Detectable labels can be, without limitation, luminescent, fluorescent, bioluminescent, chemiluminescent, radioactive, and colorimetric labels.
  • marker refers to a molecule to be used as a target for analyzing a patient's experimental sample.
  • molecular targets are genes, proteins or polypeptides.
  • the genes, proteins or polypeptides used as markers in the present invention are intended to include naturally occurring variants of said genes or proteins as well as fragments of said genes or proteins or said variants, particularly immunologically detectable fragments .
  • Immunologically detectable fragments preferably comprise at least 6, 7, 8, 10, 12, 15 or 20 contiguous amino acids of the marker polypeptide.
  • proteins released by cells or present in the extracellular matrix may be damaged (eg, during inflammation) and may be degraded or cleaved into such fragments.
  • markers are synthesized in an inactive form, which can then be activated by proteolysis.
  • proteins or fragments thereof can also be present as part of a complex.
  • Such complexes can also be used as markers in the sense of the present invention.
  • the amino acid sequence of the variant is 95%, 96%, 97%, 98%, 99% or more identical to the corresponding marker sequence.
  • marker polypeptides or variants thereof may carry post-translational modifications.
  • Non-limiting examples of post-translational modifications are glycosylation, acylation and/or phosphorylation.
  • Expression of the marker can also be identified by detecting translation of the marker (ie, detection of the marker protein in the sample).
  • Methods suitable for detecting marker proteins include any suitable method for detecting and/or measuring proteins from cells or cell extracts. Such methods include, but are not limited to, immunoblotting (eg, Western blotting), enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunohistochemistry, and immunofluorescence.
  • Particularly preferred methods for detecting proteins include any cell-based assay, including immunohistochemistry and immunofluorescence assays. Such methods are well known in the art.
  • subject refers to a warm-blooded animal, such as a mammal.
  • the term includes, but is not limited to, livestock, rodents (eg, rats and mice), primates, and humans. Preferably the term refers to humans.
  • RBM10 (NG_012548.1) belongs to a family of RNA motif-containing binding proteins, located on chromosome Xp11.23, encoding a 930 amino acid nuclear protein, and contains two RNA recognition domains (RRM), two zinc finger domains and A G-patch domain. This gene is also known as DXS8237E, GPATC9, GPATCH9, S1-1, TARPS and ZRANB5.
  • wild-type is to be understood according to the general understanding of those skilled in the art and refers to a nucleic acid or amino acid sequence in its naturally occurring form without any artificial mutation, nucleotide change or amino acid modification.
  • mutant should be understood according to the general understanding of those skilled in the art.
  • a nucleic acid sequence is referred to as “mutated” if it contains at least one nucleotide addition, deletion or substitution in its nucleic acid sequence compared to its native or native nucleic acid sequence, ie if it contains a nucleic acid mutation.
  • An amino acid sequence is referred to as “mutated” if it contains at least one added, deleted or substituted amino acid in its amino acid sequence compared to its native or native amino acid sequence, ie if it contains an amino acid mutation.
  • the variation of the RBM10 gene or its mRNA refers to the mutation in the wild-type RBM10 gene or its mRNA, which includes addition, deletion and substitution of one or more nucleotides and changes in copy number (including amplification and missing).
  • the nucleotides may be nucleotides of a coding region or a non-coding region.
  • the coding region may be a nucleotide sequence encoding an RNA recognition domain (RRM), a zinc finger domain and/or a G-patch domain.
  • RRM RNA recognition domain
  • the variation of the RBM10 gene or its mRNA can lead to the increase or decrease of the expression level of the RBM10 gene and/or the amplification or deletion of the copy number.
  • the level or copy number is at least about 1.1, 1.25, 1.5, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times or more or at most about 1 times the control or standard, respectively /1.1, 1/1.25, 1/1.5, 1/2, 1/3, 1/4, 1/5, 1/6, 1/7, 1/8, 1/9 or 1/10 or less.
  • Copy number amplifications or deletions can be detected by techniques well known in the art, such as whole gene sequencing.
  • the variation of the protein or protein fragment encoded by the RBM10 gene includes: 1) mutations in the protein or protein fragment encoded by the wild-type RBM10 gene, which include addition, deletion or substitution of one or more amino acids; and 2 ) Changes in the expression level of the protein encoded by the wild-type RBM10 gene.
  • the amino acid may be an amino acid of an RNA recognition domain (RRM), a zinc finger domain and/or a G-patch domain.
  • the protein fragments refer to polypeptides having amino-terminal deletions, carboxy-terminal deletions and/or intermediate deletions compared to the full-length native protein.
  • the fragments may also contain modified amino acids compared to the native protein. In certain embodiments, fragments are about 5-500 amino acids in length.
  • fragments can be at least 5, 6, 8, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids in length.
  • the fragment is an immunologically detectable fragment preferably comprising at least 6, 7, 8, 10, 12, 15 or 20 contiguous amino acids of the marker polypeptide.
  • the change in the protein expression level refers to at least about 1.1, 1.25, 1.5, 2, 3, 4, 5, 6, 7, 8, 5, 5, 6, 7, 8, 9 or 10 times or more or at most about 1/1.1, 1/1.25, 1/1.5, 1/2, 1/3, 1/4, 1/5, 1/6 of the expression level of a control or standard , 1/7, 1/8, 1/9 or 1/10 or less.
  • polypeptide and “protein” are used interchangeably herein to refer to at least one molecular chain of amino acids linked by covalent and/or non-covalent bonds.
  • the term includes post-translational modifications of peptides, oligopeptides, and proteins and polypeptides, such as glycosylation, acetylation, phosphorylation, and the like. Protein fragments, analogs, muteins or variant proteins, fusion proteins, etc. are also included within the meaning of the term.
  • determining "protein expression level", “gene expression” or “gene expression level” as used herein includes, but is not limited to, determining corresponding RNA, protein or peptide levels (or combinations thereof).
  • the present invention is not limited to specific methods and reagents for measuring protein, peptide or RNA levels, all of which are well known in the art.
  • Methods for determining the amount or concentration of protein in a sample are known to the skilled artisan. Such methods include radioimmunoassays, competitive binding assays, Western blot analysis and ELISA assays.
  • methods using antibodies both monoclonal and polyclonal antibodies are suitable.
  • the antibody may be immunologically specific for a protein, protein epitope or protein fragment.
  • oligonucleotide refers to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides.
  • the term includes double- and single-stranded DNA and RNA, modified and unmodified forms such as methylation or capping of polynucleotides.
  • polynucleotide and oligonucleotide are used interchangeably herein.
  • the oligonucleotide may, but need not, include other coding or non-coding sequences, or it may, but need not, be linked to other molecules and/or vectors or support materials.
  • oligonucleotides used in the methods or kits of the invention can be of any length suitable for the particular method.
  • the term refers to an antisense nucleic acid molecule (eg, an mRNA or DNA strand in the opposite orientation to a sense polynucleotide encoding a cancer marker of the invention (eg, RBM10)).
  • Oligonucleotides for use in the present invention include complementary nucleic acid sequences and nucleic acids substantially identical to those sequences, and also include sequences that differ from nucleic acid sequences due to the degeneracy of the genetic code. Oligonucleotides useful in the present invention also include nucleic acids that hybridize to oligonucleotide cancer marker nucleic acid sequences under stringent conditions, preferably high stringency conditions.
  • Nucleotide hybridization assays are well known in the art. Hybridization assay procedures and conditions will vary depending on the application and are chosen according to known general binding methods, see eg, J. Sambrook et al., Molecular Cloning: A Laboratory Guide (Third Edition. Science Press, 2002); and Young and Davis , PNAS, 80:1194 (1983). Methods and apparatus for performing repetitive and controlled hybridization reactions have been described in US Pat. Nos. 5,871,928, 5,874,219, 6,045,996, 6,386,749, and 6,391,623, each of which is incorporated herein by reference.
  • Genomic samples can be amplified by various mechanisms, some of which employ PCR. Samples can be amplified on the array. See, eg, US Patent No. 6,300,070 and US Patent Application Serial No. 09/513,300.
  • LCR ligase chain reaction
  • LCR ligase chain reaction
  • Genomics 4 eg Wu and Wallace, Genomics 4, 560 (1989), Landegren et al. Science 241, 1077 (1988) and Barringer et al. Gene 89:117 (1990)
  • transcription Amplification Kwoh et al., Proc. Natl. Acad. Sci. USA 86, 1173 (1989) and WO 88/10315
  • self-sustaining sequence replication (Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990) ) and WO90/06995)
  • selective amplification of target polynucleotide sequences US Pat. No.
  • CP-PCR consensus-primed polymerase chain reaction
  • AP-PCR arbitrarily primed polymerase chain reaction reaction
  • NABSA Nucleic Acid-Based Sequence Amplification
  • Reagents that can be used to detect RBM10 expression levels and/or copy number are well known in the art. Such reagents suitable for use in the present invention are commercially available or routinely prepared by methods well known to those skilled in the art.
  • binding agent refers to substances such as polypeptides, antibodies, ribosomes or aptamers that specifically bind to the biomarkers of the invention (RBM10).
  • a substance “specifically binds" to a biomarker of the invention if it reacts at a detectable level with the biomarker of the invention but not detectably reacts with a peptide containing an unrelated sequence or a sequence of a different polypeptide. Binding properties can be assessed using an ELISA that can be readily performed by those skilled in the art.
  • the binding agent may be a ribosome, RNA or DNA molecule or polypeptide with or without a peptide component.
  • the binding agent may be a polypeptide comprising a polypeptide biomarker sequence, a peptide variant thereof, or a non-peptide mimetic of such a sequence.
  • Aptamers include DNA or RNA molecules that bind nucleic acids and proteins. Aptamers that bind the markers of the present invention can be generated using conventional techniques without undue experimentation. [See, for example, the following publications describing in vitro selection of aptamers: Klug et al., Mol. Biol. Reports 20:97-107 (1994); Wallis et al., Chem. Biol. 2:543-552 (1995); Ellington, Curr. Biol. 4:427-429 (1994); Lato et al., Chem. Biol. 2:291-303 (1995); Conrad et al., Mol. Div. 1:69-78 (1995); and Uphoff et al., Curr. Opin . Struct. Biol. 6:281-287 (1996)].
  • Antibodies useful in the present invention include, but are not limited to, synthetic antibodies, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, antibody fragments (eg, Fab, Fab', F(ab')2), dAbs (domain antibodies; see Ward et al.
  • antibody heavy chain intrabody, humanized antibody, human antibody, antibody light chain, single-chain Fv (scFv) (eg, including monospecific, bispecific, etc.) , anti-idiotypic (ant-Id) antibodies, proteins comprising antibody moieties, chimeric antibodies (eg, antibodies containing the binding specificity of a murine antibody but where the remainder is of human origin), derivatives such as enzyme conjugates or labeled Derivatives, diabodies, linear antibodies, disulfide-linked Fvs (sdFv), multispecific antibodies (eg, bispecific antibodies), epitope-binding fragments of any of the foregoing, and antigen recognition comprising the desired specificity Any other modified configuration of the immunoglobulin molecule at the site.
  • scFv single-chain Fv
  • anti-Id anti-idiotypic antibodies
  • proteins comprising antibody moieties
  • chimeric antibodies eg, antibodies containing the binding specificity of a murine antibody but where the remainder is of human origin
  • derivatives
  • Antibodies include antibodies of any class (e.g., IgA, IgD, IgE, IgG, IgM, and IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (e.g., IgG2a and IgG2b), and antibodies do not have to be is any particular type, class or subclass.
  • the antibody is an IgG antibody or a class or subclass thereof.
  • Antibodies can be from any animal source, including birds and mammals (eg, human, murine, donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken).
  • antibodies for use in the present invention are commercially available from, for example, Invitrogen (Cat. Nos. PA5-83253, PA5-40331, PA5-40330, etc.), Abcam (eg, antibody under Cat. No. ab224149), and the like.
  • the antibodies can be prepared by recombinant methods well known in the art.
  • the antibody is a monoclonal antibody.
  • monoclonal antibodies see, eg, Kohler et al. (1975) Nature 256:495-497; Kozbor et al. (1985) J. Immunol Methods 81:31-42; Cote et al. (1983) Proc Natl Acad Sci 80:2026-2030 and Cole et al. (1984) Mol Cell Biol 62:109-120.
  • kits can be prepared by conventional methods in the art.
  • the kits may contain materials or reagents (including reagents for detecting the RBM10 gene or its mRNA or its encoded protein or protein fragment) for use in carrying out the methods of the present invention.
  • Kits may include storage reaction reagents (eg, primers, dNTPs, enzymes, etc. in suitable containers) and/or support materials (eg, buffers, instructions for performing assays, etc.).
  • a kit may include one or more containers (eg, cassettes) containing the respective reaction reagents and/or support materials. Such contents may be delivered to the intended recipient together or separately.
  • the kit may contain reagents, buffers, and instructions for use in detecting the RBM10 gene or its mRNA or its encoded protein or protein fragment.
  • the kit may also contain polymerase and dTNP, among others.
  • the kit may also contain internal standards, positive and negative controls, etc. for quality control.
  • the kit may also contain reagents for preparing nucleic acid, eg, DNA, from the sample.
  • nucleic acid eg, DNA
  • a microarray refers to a solid support with a flat surface that has an array of nucleic acids, each member of the array comprising identical copies of oligonucleotides or polynucleotides immobilized on spatially defined regions or sites, so The regions or sites do not overlap with regions or sites of other members of the array; that is, the regions or sites are spatially discrete.
  • a spatially defined hybridization site may be "addressable" in that its location and the identity of its immobilized oligonucleotide are known or predetermined (eg, known or predetermined prior to its use). definite).
  • the oligonucleotide or polynucleotide is single stranded and is usually covalently attached to the solid support from the 5'- or 3'-end.
  • the density of nucleic acids containing non-overlapping regions in the microarray is typically greater than 100/cm 2 , more preferably greater than 1000/cm 2 .
  • Microarray technology is disclosed, for example, in the following references: Microarrays: A Practical Approach, edited by Schena (IRL Press, Oxford, 2000); Southern, Current Opin. Chem. Biol., 2:404-410, 1998, the entire contents of which are via Reference is incorporated herein.
  • the invention discloses the use of the RBM10 gene, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the uses described in the present invention have been described through the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the uses described herein without departing from the content, spirit and scope of the present invention, so as to realize and apply the technology of the present invention .
  • Example 1 Phase Ib clinical trial of cioronib monotherapy in the treatment of relapsed and refractory ovarian cancer
  • Test drug Cioroni capsules, specifications: 5mg, 25mg. Produced by Shenzhen Microchip Biotechnology Co., Ltd.
  • Cioroni capsules were administered at 50 mg/day, QD (no adjustment for body weight or body surface area). Take each morning on an empty stomach, with water, and swallow the capsule whole. Continuous administration for 28 days is one treatment cycle, and there is no interval between each treatment cycle.
  • epithelial ovarian cancer Histologically diagnosed epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer;
  • Platinum-resistant patients should have received at least 2 different chemotherapy regimens for disease progression or recurrence;
  • platinum-sensitive patients should have received at least 2 chemotherapy regimens for disease progression or recurrence, or the subject refuses to receive further chemotherapy;
  • the interval between the previous chemotherapy, radiotherapy, targeted therapy, immunotherapy or study drug treatment should be more than 4 weeks. If the chemotherapy regimen includes mitomycin, the interval should be more than 6 weeks;
  • Coagulation function prothrombin time-international normalized ratio (PT-INR) ⁇ 1.5 times ULN.
  • test subjects took cioroni capsules 50 mg orally once a day, every 28 days as a treatment cycle, and there was no discontinuation interval during the treatment cycle. Throughout the trial, all subjects continued treatment until any of the following occurred (whichever occurred first): disease progression, intolerable toxicity, death, withdrawal of informed consent, or loss to follow-up.
  • Efficacy evaluation According to RECIST1.1 criteria, the evaluation was performed at the baseline and the 4th week after treatment, and repeated every 8 weeks until disease progression. Tumor imaging examinations include CT or MRI of the neck, chest, whole abdomen, and pelvis. Examinations of other parts are performed according to clinical indications and when necessary. The same techniques and methods should be used for baseline and follow-up assessment of lesions.
  • Safety assessment including physical examination, vital signs, ECOG performance score, blood routine, urine routine, 12-lead ECG, blood biochemistry, electrolytes, coagulation function, cardiac enzymes, troponin, TSH, FT3, FT4, amylase, Echocardiography, 24-hour urine protein quantification (if necessary), adverse events.
  • Test results include genetic mutations and copy number abnormalities.
  • a concomitant study of efficacy-related biomarkers was performed on 548 tumor-related genes for the detection and analysis of cell-free tumor DNA (ctDNA) in the plasma of the evaluated patients.
  • the detection results selected all genes with a mutation rate of more than 0.4%, and used the patient's progression-free survival (PFS) as the efficacy index to analyze the correlation between tumor-related gene abnormalities and the efficacy of cioronib.
  • PFS progression-free survival
  • the median PFS was 232 days in 7 of the 23 evaluable subjects with RBM10 mutations (30.4%, these mutations included nucleotide additions, deletions and substitutions, and copy number changes) and 16 with RBM10 wild-type (69.6%).
  • the median PFS of ) was 106 days, and there was a significant difference between the two groups, suggesting that the RBM10 gene is associated with the efficacy of cioronib in the treatment of ovarian cancer and can be a potential biomarker for evaluating the efficacy. See Table 1 and Figure 1 for the results.
  • Table 1 RBM10 gene mutation and median PFS correlation analysis

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Abstract

提供了一种用于评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果的生物标志物，所述生物标志物是RBM10基因或其mRNA或其编码的蛋白或蛋白片段。通过以患者的无进展生存期(PFS)作为疗效指标，验证了RBM10基因变异与西奥罗尼疗效的关联性，对RBM10基因突变信息的检测，可以指导西奥罗尼的临床用药和评价其对肿瘤治疗的疗效，特别适用于复发、晚期的卵巢癌。

Description

RBM10基因的用途 技术领域
本发明涉及药物技术领域，具体涉及RBM10基因的用途。
背景技术
卵巢癌位居妇科恶性肿瘤的第三位，其死亡率位居第一位，且发病率有呈逐年上升之趋势。卵巢癌患者经理想的肿瘤细胞减灭术(肿瘤残存病灶<1cm)并辅以铂类加紫杉醇的系统化疗，大多数患者可达到完全缓解(CR)，但60％-70％患者治疗后会出现复发。复发患者对再次化疗效果较差：铂敏感复发人群对含铂化疗有效率约30-80％，即使是铂敏感患者，经过2～3次含铂治疗也会转变为铂耐药；铂难治/耐药复发人群对无铂单药化疗有效率仅5-17％，无进展生存期为3个月左右，总生存期小于1年。
近几年，靶向治疗及免疫治疗临床研究证据越来越多，特别是抗血管生成药在铂难治复发卵巢癌患者的应用，相关研究主要包括：
GOG0170D研究，贝伐珠单抗单药用于铂类难治/耐药卵巢癌患者的II期研究，入组62例受试者，ORR为21％，其中2例(3.2％)CR、11例(17.7％)PR。中位PFS和OS分别为4.7和17个月。
GOG0170F研究，索拉非尼单药用于复发且疾病进展距离末次含铂化疗小于12个月的卵巢癌患者的II期研究，共入组71例，包括铂敏感21例(29.6％)和铂耐药50例(70.4％)，其中可评价病例59例。2例(3.4％)获得PR，ORR为3.4％，中位PFS和OS分别为2.1和16.3个月。
VEG104450研究，帕唑帕尼单药用于初始治疗CA125完全缓解后升高的高复发风险卵巢癌患者，入组36例受试者，其中14例(39.0％)铂耐药，22例(61.0％)铂敏感。参照GCIG(妇科肿瘤协会)标准缓解率为11例(31.0％)，可评估病例按照RECIST标准的缓解率为0。
除了抗血管生成药物，其他机制靶向治疗或免疫治疗在铂难治/耐药复发卵巢癌中的研究也有所进展，如多聚二磷酸腺苷核糖聚合酶(PARP)抑制剂如奥拉帕尼、尼拉帕尼，对有BRCA突变的卵巢癌患者有明确的疗效，但对大多数无BRCA突变的铂难治/耐药复发卵巢癌患者仍未得到显著获益。卵巢癌需要探寻更高疗效的治疗方案。
西奥罗尼是一个以多蛋白激酶为靶点的小分子抗肿瘤靶向药物，通过对Aurora B、VEGFR/PDGFR/c-Kit、CSF-1R靶点的高选择抑制活性，具有抑制肿瘤细胞有丝分裂、抗肿瘤血管生成、调控肿瘤免疫微环境等多通路协同作用机制，发挥综合抗肿瘤作用。由于西奥罗尼存在独特的抗肿瘤作用机制，对西奥罗尼与疗效相关的标志物基因研究将有助于为西奥罗尼临床应用找到潜在的获益患者人群和更优的治疗效果。
发明内容
有鉴于此，本发明的目的在于提供RBM10基因或其mRNA或其编码的蛋白或蛋白片段作为生物标志物在评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果中的用途。
本发明以西奥罗尼胶囊针对复发难治的晚期卵巢癌进行Ib期临床试验，通过对血浆游离肿瘤DNA(ctDNA)的检测分析，对548个肿瘤相关基因进行了疗效相关生物标志物的伴随研究。所有患者在入组前均提取血液样品，对肿瘤相关基因的基因序列检测，包括基因突变和拷贝数异常。检测结果选取了所有突变发生率0.4％以上的基因，以患者的无进展生存期(PFS)作为疗效指标，分析肿瘤相关基因异常与西奥罗尼疗效的关联性。结果显示，在评价的肿瘤相关基因中，RBM10基因与西奥罗尼疗效有显著的关联性。
具体试验结果表明，RBM10基因的变异与西奥罗尼在卵巢癌患者中的PFS存在显著相关性。在可评价23例受试者中，中位PFS在RBM10基因突变患者中为232天，在野生型患者中为106天，P值为0.02。表明该基因可以成为西奥罗尼疗效相关的生物标志物。
根据上述技术效果，本发明相应地涉及用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂在制备用于评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果的试剂盒或微阵列中的用途。在一个实施方案中，如果与野生型相比，受试者的RBM10基因或其mRNA或其编码的蛋白存在变异，则表明对于该受试者而言，西奥罗尼的疗效较佳、能够使用西奥罗尼治疗或者卵巢癌治疗效果较好。在另一个实施方案中，所述用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂为与RBM10基因编码的蛋白或蛋白片段结合的结合剂，或与RBM10基因或其mRNA杂交或扩增RBM10基因或其mRNA的物质。在另一个实施方案中，所述与RBM10基因编码的蛋白或蛋白片段结合的结合剂为抗RBM10的抗体。在另一个实施方案中，所述与RBM10基因或其mRNA杂交或扩增RBM10基因或其mRNA的物质为寡核苷酸引物或探针。
在另一方面，本发明涉及一种用于评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果的试剂盒或微阵列，其包含用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂。在一个实施方案中，如果与野生型相比，受试者的RBM10基因或其mRNA或其编码的蛋白存在变异，则表明对于该受试者而言，西奥罗尼的疗效较佳、能够使用西奥罗尼治疗或者卵巢癌治疗效果较好。在另一个实施方案中，所述用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂为与RBM10基因编码的蛋白或蛋白片段结合的结合剂，或与RBM10基因或其mRNA杂交或扩增RBM10基因或其mRNA的物质。在另一个实施方案中，所述与RBM10基因编码的蛋白或蛋白片段结合的结合剂为抗RBM10的抗体，以及所述与RBM10基因或其mRNA杂交或扩增RBM10基因或其mRNA的物质为寡核苷酸引物或探针。
在另一方面，本发明涉及西奥罗尼在制备用于治疗卵巢癌、尤其是存在RBM10基因突变的卵巢癌的药物中的用途。
在又一方面，本发明涉及一种用于评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果的生物标志物，所述生物标志物是RBM10基因或其mRNA或其编码的蛋白或蛋白片段。
在又一方面，本发明涉及RBM10基因或其mRNA或其编码的蛋白或蛋白片段作为生物标志物在评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果中的用途。
在又一方面，本发明涉及RBM10基因或其mRNA或其编码的蛋白或蛋白片段在制备评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果的生物标志物中的用途。
在又一方面，本发明涉及一种评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果的方法，其包括以下步骤：
(1)获取受试者的生物样品；和
(2)检测所述样品的RBM10基因或其mRNA或其编码的蛋白或蛋白片段是否存在突变；
其中当受试者的RBM10基因或其mRNA或其编码的蛋白或蛋白片段存在突变的话，则对于该受试者而言，西奥罗尼的疗效较佳、能够使用西奥罗尼治疗或者卵巢癌治疗效果较好。
在一个实施方案中，所述生物样品为ctDNA、肿瘤组织、肿瘤循环细胞或人体其它来源的组织。在一个实施方案中，所述检测以基因测序、PCR、FISH、免疫组化、ELISA、Western或流式细胞技术为检测方法。在一些实施方案中，以卵巢癌肿瘤组织ctDNA为检测样品，采用二代测序技术检测。
在又一方面，本发明涉及西奥罗尼在治疗卵巢癌、尤其是存在RBM10基因突变的卵巢癌中的用途。
附图说明
图1所示为RBM10基因突变型和野生型的无进展生存期。
具体实施方式
参考用于说明的示例应用在下文中描述本发明的数个方面。应当理解的是，陈述许多具体细节、关系和方法来提供对本发明的充分理解。然而，在相关领域的普通技术人员将容易地认识到，可在不含一个或多个具体细节的情况下实施本发明或者可用其他方法来实施本发明。
本发明涉及新发现的生物标志物(即RBM10)的突变和/或表达与西奥罗尼的疗效、西奥罗尼的用药和/或卵巢癌的治疗效果之间的关系。本文所述生物标志物提供用于评价西奥罗尼疗效、指导西奥罗尼用药和/或预测卵巢癌治疗效果的方法。因此，本发明的一个实施方案代表生物标志物的改进，所述肿瘤标志物适用于评价西奥罗尼疗效、指导西奥罗尼用药和/或预测卵巢癌治疗效果。在又一个实施方案中，本发明新发现的生物标志物(即RBM10)可与本领域已知的一种或多种其它癌症标志物(例如CEA、NSE、CA 19-9、CA 125、CA 72-4、PSA、proGRP、SCC、NNMT、VEGFR2、HER2、MISIIR、VEGFA、CD24)联用，例如用于评价西奥罗尼疗效、指导西奥罗尼用药和/或预测卵巢癌治疗效果或用于制备用于此目的的试剂盒。
本发明通过以患者的无进展生存期(PFS)作为疗效指标，验证了RBM10基因变异与西奥罗尼疗效的关联性，对RBM10基因突变信息的检测，可以指导西奥罗尼的临床用药和评价其对肿瘤治疗的疗效，尤其适用于卵巢癌，特别适用于复发、晚期的卵巢癌。
在本发明中，“西奥罗尼的疗效较佳、能够使用西奥罗尼治疗或者卵巢癌治疗效果较好”尤其是指西奥罗尼能够显著延长患者例如卵巢癌患者的无进展生存期(PFS)。在某些实施方案中，本发明的试剂盒用于评价西奥罗尼对治疗卵巢癌的疗效和/或指导西奥罗尼用于治疗卵巢癌的用药。
术语“样品”意指已知或疑似表达或含有生物标志物(即RBM10)或结合剂的材料，结合剂为例如对生物标志物(即RBM10)有特异性的 抗体。样品可来源于生物来源(“生物样品”)，例如组织(例如活组织检查样品)、提取物或包括细胞(例如肿瘤细胞)、细胞裂解物在内的细胞培养物和生物或生理流体，例如全血、血浆、血清、唾液、脑髓液、汗、尿液、乳汁、腹膜液等。获自来源的样品或在预处理以改进样品特征(例如从血液制备血浆、稀释黏液等)后的样品可直接使用。在本发明的某些方面，样品是人生理流体，例如人血清。在本发明的某些方面，样品是活组织检查样品例如经组织检查获得的肿瘤组织或细胞。在本发明的某些方面，样品是恶性或正常组织样品例如癌旁正常组织样品。
可按照本发明进行分析的样品包括临床来源的多核苷酸。正如本领域技术人员应理解的是，靶多核苷酸可包括RNA，包括而不限于细胞总RNA、聚(A)+信使RNA(mRNA)或其部分、胞质mRNA或由cDNA转录的RNA(即cRNA)。
可采用本领域已知方法，在一个或多个核苷酸上对靶多核苷酸进行可检测标记。可检测标记可以是而不限于发光标记、荧光标记、生物发光标记、化学发光标记、放射性标记和比色标记。
本文使用的术语“标志物”指要用作分析患者实验样品的靶标的分子。这样的分子靶标的实例是基因、蛋白或多肽。在本发明中用作标志物的基因、蛋白或多肽预期包括所述基因或蛋白的天然存在的变体以及所述基因或蛋白或所述变体的片段，特别是免疫学上可检测的片段。免疫学上可检测的片段优选地包含所述标志物多肽的至少6、7、8、10、12、15或20个连续氨基酸。本领域的技术人员可认识到，由细胞释放的蛋白或存在于胞外基质中的蛋白可能受到损害(例如在炎症过程中)，且可被降解或切割成这样的片段。某些标志物以无活性形式合成，其可以随后通过蛋白酶解来激活。如熟练的技术人员将明白的，蛋白或其片段也可以作为复合物的部分而存在。这样的复合物也可以用作本发明意义上的标志物。标志物多肽的变体由相同的基因编码，但可能在其等电点(＝PI)或分子量(＝MW)或以上二者上有差异，例如作为可选的mRNA或mRNA前体加工的结果。变体的 氨基酸序列与对应的标志物序列具有95％、96％、97％、98％、99％或更高的同一性。另外，或在替代方案中，标志物多肽或其变体可以携带翻译后修饰。翻译后修饰的非限制性实例是糖基化、酰化和/或磷酸化。
标志物的表达也可通过检测标志物的翻译(即，样品中标志物蛋白的检测)来鉴定。适合于检测标志物蛋白的方法包括用于检测和/或测量得自细胞或细胞提取物的蛋白的任何合适方法。这样的方法包括，但不限于免疫印迹(如蛋白质印迹)、酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)、免疫沉淀、免疫组织化学和免疫荧光。用于检测蛋白的特别优选的方法包括任何基于细胞的测定，包括免疫组织化学和免疫荧光测定。这样的方法是本领域熟知的。
术语“受试者”、“患者”和“个体”在本文可互换使用，是指温血动物，例如哺乳动物。该术语包括但不限于家畜、啮齿动物(例如大鼠和小鼠)、灵长类动物和人。优选该术语是指人。
RBM10(NG_012548.1)属于含RNA基序结合蛋白家族，位于染色体Xp11.23，编码一个含有930个氨基酸的核蛋白，并含有两个RNA识别结构域(RRM)、两个锌指结构域和一个G-patch结构域。该基因也称为DXS8237E、GPATC9、GPATCH9、S1-1、TARPS和ZRANB5。
术语“野生型”应根据本领域技术人员的一般理解来理解，并且表示呈天然存在的形式而没有进行任何人工突变、核苷酸变换或氨基酸修改的核酸或氨基酸序列。
术语“突变型”应根据本领域技术人员的一般理解来理解。如果核酸序列与其自然或天然核酸序列相比，在其核酸序列中含有至少一个核苷酸的添加、缺失或取代，即如果它含有核酸突变，则将其称为“突变的”。如果氨基酸序列与其自然或天然氨基酸序列相比，在其氨基酸序列中含有至少一个增加的、缺失的或取代的氨基酸，即如果它含有氨基酸突变，则将其称为“突变的”。
在本发明中，RBM10基因或其mRNA的变异是指野生型RBM10基因或其mRNA中的突变，其包括一个或多个核苷酸的添加、缺失 和取代以及拷贝数的变化(包括扩增和缺失)。所述核苷酸可以是编码区或非编码区的核苷酸。所述编码区可以是编码RNA识别结构域(RRM)、锌指结构域和/或G-patch结构域的核苷酸序列。所述RBM10基因或其mRNA的变异可以导致RBM10基因表达水平的上升或下降和/或拷贝数的扩增或缺失。例如水平或拷贝数分别为对照或标准的至少约1.1、1.25、1.5、2、3、4、5、6、7、8、9或10倍或更多倍或者为对照或标准的至多约1/1.1、1/1.25、1/1.5、1/2、1/3、1/4、1/5、1/6、1/7、1/8、1/9或1/10或更少。拷贝数扩增或缺失可通过本领域周知的技术检测，例如全基因测序。
在本发明中，RBM10基因编码的蛋白或蛋白片段的变异包括：1)野生型RBM10基因所编码的蛋白或蛋白片段中的突变，其包括一个或多个氨基酸的增加、缺失或取代；以及2)野生型RBM10基因所编码的蛋白的表达水平的变化。所述氨基酸可以是RNA识别结构域(RRM)、锌指结构域和/或G-patch结构域的氨基酸。所述蛋白片段是指与全长天然蛋白相比具有氨基末端缺失、羧基末端缺失和/或中间缺失的多肽。所述片段还可含有与天然蛋白相比经修饰的氨基酸。在某些实施方案中，片段长度为约5-500个氨基酸。例如，片段长度可为至少5、6、8、10、14、20、50、70、100、110、150、200、250、300、350、400或450个氨基酸。在一个实施方案中，所述片段是免疫学上可检测的片段，其优选地包含标志物多肽的至少6、7、8、10、12、15或20个连续氨基酸。所述蛋白表达水平的变化是指与对照或标准的表达水平相比，至少为对照或标准的表达水平的至少约1.1、1.25、1.5、2、3、4、5、6、7、8、9或10倍或更多倍或者为对照或标准的表达水平的至多约1/1.1、1/1.25、1/1.5、1/2、1/3、1/4、1/5、1/6、1/7、1/8、1/9或1/10或更少。
术语“多肽”和“蛋白质”在本文可互换使用，表示通过共价和/或非共价键连接的氨基酸的至少一个分子链。该术语包括肽、寡肽和蛋白质及多肽的翻译后修饰，例如糖基化、乙酰化、磷酸化等。蛋白质片段、类似物、突变蛋白质或变体蛋白质、融合蛋白等也包括在该术 语的含义中。
在某些实施方案中，如本文所用的测定“蛋白表达水平”、“基因表达”或“基因表达水平”包括但不限于测定相应的RNA、蛋白或者肽水平(或其组合)。本发明不限于测定蛋白、肽或RNA水平的具体方法和试剂，所有这些方法和试剂是本领域熟知的。
用于测定样品中蛋白质的量或浓度的方法为技术人员所知。所述方法包括放射性免疫测定、竞争性结合测定、蛋白质印迹分析和ELISA测定。对于使用抗体的方法，单克隆和多克隆抗体都适用。所述抗体对于蛋白质、蛋白表位或蛋白片段可为免疫学上特异的。
术语“寡核苷酸”是指任何长度的核苷酸的多聚体形式，为核糖核苷酸或脱氧核糖核苷酸。该术语包括双链和单链DNA和RNA，例如多核苷酸的甲基化或帽化等修饰形式和未修饰形式。术语“多核苷酸”和“寡核苷酸”在本文可互换使用。寡核苷酸可但非必需包括其它编码或非编码序列，或者它可以但不一定与其它分子和/或载体或支持材料连接。用于本发明方法或试剂盒的寡核苷酸可具有适于具体方法的任何长度。在某些应用中，该术语是指反义核酸分子(例如处于与编码本发明癌症标志物(例如RBM10)的有义多核苷酸相反方向的mRNA或DNA链)。
用于本发明的寡核苷酸包括互补核酸序列和与这些序列基本相同的核酸，并且还包括因遗传密码简并而不同于核酸序列的序列。可用于本发明的寡核苷酸还包括在严格条件下、优选高严格性条件下与寡核苷酸癌症标志物核酸序列杂交的核酸。
核苷酸杂交测定是本领域熟知的。杂交测定程序和条件将根据应用而变化并依据已知的通用结合方法选择，参见例如J.萨姆布鲁克等，分子克隆：实验指南(第三版.科学出版社，2002)；以及Young和Davis，P.N.A.S，80:1194(1983)。进行重复和受控杂交反应的方法和设备已经描述于美国专利号5,871,928、5,874,219、6,045,996、6,386,749和6,391,623中，其各自通过引用结合到本文中。
在某些情况下，可能需要扩增样品。基因组样品可通过各种机制 扩增，其中一些机制可采用PCR。样品可在阵列上扩增。参见，例如美国专利号6,300,070和美国专利申请系列号09/513,300。
其它合适的扩增方法包括连接酶链反应(LCR)(如Wu和Wallace，Genomics 4，560(1989)、Landegren等Science 241、1077(1988)和Barringer等Gene 89:117(1990))、转录扩增(Kwoh等，Proc.Natl.Acad.Sci.USA 86，1173(1989)和WO88/10315)、自维持序列复制(Guatelli等，Proc.Nat.Acad.Sci.USA，87，1874(1990)和WO90/06995)、目标多核苷酸序列的选择性扩增(美国专利号6,410,276)、共有序列引发的聚合酶链反应(CP-PCR)(美国专利号4,437,975)、任意引发的聚合酶链反应(AP-PCR)(美国专利号5,413,909、5,861,245)和基于核酸的序列扩增(NABSA)(参见美国专利号5,409,818、5,554,517和6,063,603，其各自通过引用结合到本文中)。
可用于检测RBM10表达水平和/或拷贝数的试剂是本领域众所周知的。适用于本发明的这种试剂可市购获得或通过本领域技术人员熟知的方法常规地制得。
术语“结合剂”是指例如与本发明生物标志物(RBM10)特异性结合的多肽、抗体、核糖体或适体等物质。如果物质以可检测的水平与本发明生物标志物起反应，而不与含有无关序列或不同多肽的序列的肽可检测地起反应，则它与本发明生物标志物“特异性结合”。可采用本领域技术人员可容易进行的ELISA来评价结合性质。
结合剂可以是含或不含肽组分的核糖体、RNA或DNA分子或多肽。结合剂可以是包含多肽生物标志物序列、其肽变体或这类序列的非肽模拟物的多肽。
适体包括与核酸和蛋白质结合的DNA或RNA分子。与本发明标志物结合的适体可在无需过多实验的情况下利用常规技术产生。[例如参见下列描述适体体外选择的出版物：Klug等,Mol.Biol.Reports 20:97-107(1994)；Wallis等,Chem.Biol.2:543-552(1995)；Ellington,Curr.Biol.4:427-429(1994)；Lato等,Chem.Biol.2:291-303(1995)；Conrad等,Mol.Div.1:69-78(1995)；以及Uphoff等,Curr.Opin. Struct.Biol.6:281-287(1996)]。
用于本发明的抗体包括但不限于合成抗体、单克隆抗体、多克隆抗体、重组抗体、抗体片段(例如Fab、Fab'、F(ab')2)、dAb(结构域抗体；参见Ward等，1989，Nature，341:544-546)、抗体重链、胞内抗体、人源化抗体、人抗体、抗体轻链、单链Fv(scFv)(例如包括单特异性、双特异性等)、抗独特型(ant-Id)抗体、包含抗体部分的蛋白质、嵌合抗体(例如含有鼠抗体的结合特异性但其中其余部分是人来源的抗体)、衍生物例如酶缀合物或标记的衍生物、双链抗体、线性抗体、二硫键连接的Fv(sdFv)、多特异性抗体(例如双特异性抗体)、上述任一种的表位结合片段和包含所需特异性的抗原识别部位的免疫球蛋白分子的任何其它修饰构型。抗体包括任何类型(例如IgA、IgD、IgE、IgG、IgM和IgY)、任何类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或任何亚类(例如IgG2a和IgG2b)的抗体，抗体不必是任何特定的类型、类别或亚类。在本发明的某些实施方案中，抗体是IgG抗体或其类别或亚类。抗体可来自任何动物来源，包括鸟类和哺乳动物(例如人、鼠、驴、绵羊、兔、山羊、豚鼠、骆驼、马或鸡)。
例如，用于本发明的抗体可市购自例如Invitrogen(货号PA5-83253、PA5-40331、PA5-40330等)、Abcam(例如货号为ab224149的抗体)等。或者，所述抗体可通过本领域周知的重组方法制备。在一些实施方案中，所述抗体是单克隆抗体。对于单克隆抗体的制备参见例如Kohler等(1975)Nature 256:495-497；Kozbor等(1985)J.Immunol Methods 81:31-42；Cote等(1983)Proc Natl Acad Sci 80:2026-2030和Cole等(1984)Mol Cell Biol 62:109-120。
本发明的试剂盒可以通过本领域常规方法制备。试剂盒可包含实施本发明方法所用的材料或试剂(包括用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂)。试剂盒可以包括储存反应试剂(例如在合适容器中的引物、dNTP、酶等)和/或支持材料(例如缓冲液、实施检测的说明书等)。例如，试剂盒可以包括一个或多个含有相应反应试剂和/或支持材料的容器(例如盒子)。这样的内容物可 一起或分开递送给既定的接受者。作为一个实例，试剂盒可含有用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂、缓冲液以及使用说明书。试剂盒还可含有聚合酶和dTNP等。试剂盒还可含有用于质控的内标、阳性和阴性对照等。试剂盒还可包含用于从样品制备核酸例如DNA的试剂。以上实例不能理解为限制适用于本发明的试剂盒及其内容物。
微阵列是指具有平坦表面的固相支持体，其具有核酸阵列，阵列中的各个成员包含固定在空间上确定的区域或位点上的寡核苷酸或多核苷酸的相同的拷贝，所述区域或位点不与阵列中的其它成员的区域或位点重叠；也就是说，所述区域或位点在空间上是离散的。此外，空间上确定的杂交位点可为“可寻址的”，因为其位置及其固定化的寡核苷酸的身份是已知或预先确定的(例如在其使用前是已知或预先确定的)。通常寡核苷酸或多核苷酸为单链，并通常由5'-端或3'-端与固相支持体共价连接。微阵列中含有非重叠区的核酸的密度通常大于100/cm 2，更优选大于1000/cm 2。微阵列技术公开于例如以下参考文献中：Schena编辑的Microarrays:A Practical Approach(IRL Press,Oxford,2000)；Southern,Current Opin.Chem.Biol.,2:404-410，1998，其全部内容通过引用结合到本文中。
本发明公开了RBM10基因的用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述用途已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述用途进行改动或适当变更与组合，来实现和应用本发明技术。
以下就本发明所提供的RBM10基因的用途做进一步说明。
实施例1：西奥罗尼单药治疗复发难治的卵巢癌Ib期临床试验
试验药物：西奥罗尼胶囊，规格：5mg、25mg。由深圳微芯生物科技股份有限公司生产。
给药方案：西奥罗尼胶囊按50mg/天、QD给药(对体重或体表面积不做调整)。每天上午空腹服用，用水送服，完整吞服整粒胶囊。连续给药28天为1个治疗周期，每个治疗周期间无间隔。
病例数：入组25例，其中有疗效评价的患者23例。
入选标准：
1.年龄≥18岁，≤70岁，女性；
2.经组织学确诊的上皮性卵巢癌、输卵管癌或原发性腹膜癌；
3.受试者需接受过含铂类化疗方案，即
a)铂类耐药者(含铂类化疗方案结束后≤6个月疾病进展或复发)，应接受过至少2个不同化疗方案后疾病进展或复发；
b)若铂类敏感者(含铂类化疗方案结束后>6个月疾病进展或复发)，应接受过至少2个化疗方案后疾病进展或复发，或者受试者拒绝接受再次化疗；
4.根据RECIST1.1标准，至少有一个可测量的靶病灶；
5.ECOG体力评分0-1分；
6.距离前次的化疗、放疗、靶向治疗、免疫治疗或研究药物治疗结束需间隔4周以上，如化疗方案包含丝裂霉素，间隔应在6周以上；
7.主要器官功能符合以下标准：
血常规：中性粒细胞绝对值≥1.5×10 9/L，血小板≥90×10 9/L，血红蛋白≥90g/L；
血生化：总胆红素≤1.5倍正常值参考范围上限(ULN)，AST、ALT≤2倍ULN(肝转移病例：≤5倍ULN)；血清肌酐≤1.5倍ULN；
凝血功能：凝血酶原时间-国际标准化比率(PT-INR)≤1.5倍ULN。
8.预期生存时间≥3个月；
9.自愿签署书面知情同意书。
治疗计划：
试验受试者每天口服西奥罗尼胶囊50mg一次，每28天为一个治疗周期，治疗周期间无停药间隔期。整个试验期间，所有受试者均持续治疗直至出现以下任一情况(以先发生者为准)：疾病进展、不能耐受的毒性反应、死亡、撤回知情同意或失访。
疗效评估：根据RECIST1.1标准，分别在基线期以及治疗后第4周末评估一次，后续每8周重复进行，直到疾病进展。肿瘤影像学检查包括颈部、胸部、全腹、盆腔CT或MRI，其他部位检查根据临床指征，有需要时进行，病灶基线和后续评估测量应采用同样的技术和方法。
安全性评估：包括体格检查、生命体征、ECOG体能评分、血常规、尿常规、12导联ECG、血生化、电解质、凝血功能、心肌酶、肌钙蛋白、TSH、FT3、FT4、淀粉酶、超声心动图、24小时尿蛋白定量(必要时)、不良事件。
生物标志物研究：
在受试者首次服用西奥罗尼前和疾病进展时取外周血10毫升，对血浆游离肿瘤DNA(ctDNA)和白细胞提取DNA(对照)进行基因序列的检测，共包括548个肿瘤相关基因，检测结果包括基因突变和拷贝数异常。
临床试验结果：
25例受试者中，有2例无基线后疗效评估结果，因此可评价病例为23例。23例可评价受试者中，试验期间最佳疗效为：2例(8.7％)PR(其中1例在后续评估中得到确认)，14例(60.9％)SD，7例(30.4％)PD，确认的ORR为4.3％，未确认ORR为8.7％。23例可评价受试者中，有3例铂敏感，20例铂耐药。2例PR受试者均为铂耐药受试者，确认的缓解为1例(5.0％)。结果显示西奥罗尼单药治疗卵巢癌有效。
对已评价患者血浆游离肿瘤DNA(ctDNA)检测分析，对548个肿瘤相关基因进行了疗效相关生物标志物的伴随研究。检测结果选取了所有突变发生率0.4％以上的基因，以患者的无进展生存期(PFS)作为疗效指标，分析肿瘤相关基因异常与西奥罗尼疗效的关联性。结果显示，在548个肿瘤相关基因中，发现了一个与西奥罗尼疗效有显著相关性的基因突变，为RBM10基因。可评价23例受试者中RBM10突变7例(30.4％，这些突变包括核苷酸的添加、缺失和取代以及拷贝数的变化)的中位PFS为232天，RBM10野生型16例(69.6％)的中位PFS为106天，两组具有显著差异，提示RBM10基因与西奥 罗尼治疗卵巢癌疗效相关，可以成为评价疗效的潜在生物标志物。结果参见表1和图1。
表1:RBM10基因突变与中位PFS相关分析
Figure PCTCN2021108791-appb-000001
注：P值＝0.0242，HR＝0.133
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂在制备用于评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果的试剂盒或微阵列中的用途。
  2. 根据权利要求1所述的用途，其特征在于如果与野生型相比，受试者的RBM10基因或其mRNA或其编码的蛋白存在变异，则表明对于该受试者而言，西奥罗尼的疗效较佳、能够使用西奥罗尼治疗或者卵巢癌治疗效果较好。
  3. 根据权利要求1所述的用途，其特征在于所述用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂为与RBM10基因编码的蛋白或蛋白片段结合的结合剂，或与RBM10基因或其mRNA杂交或扩增RBM10基因或其mRNA的物质。
  4. 根据权利要求3所述的用途，其特征在于所述与RBM10基因编码的蛋白或蛋白片段结合的结合剂为抗RBM10的抗体。
  5. 根据权利要求3所述的用途，其特征在于所述与RBM10基因或其mRNA杂交或扩增RBM10基因或其mRNA的物质为寡核苷酸引物或探针。
  6. 一种用于评价西奥罗尼疗效或指导西奥罗尼用药或预测卵巢癌治疗效果的试剂盒或微阵列，其特征在于，包含用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂。
  7. 根据权利要求6所述的试剂盒或微阵列，其特征在于如果与野生型相比，受试者的RBM10基因或其mRNA或其编码的蛋白存在变异，则表明对于该受试者而言，西奥罗尼的疗效较佳、能够使用西奥罗尼治疗或者卵巢癌治疗效果较好。
  8. 根据权利要求6所述的试剂盒或微阵列，其特征在于所述用于检测RBM10基因或其mRNA或其编码的蛋白或蛋白片段的试剂为与RBM10基因编码的蛋白或蛋白片段结合的结合剂，或与RBM10基因或其mRNA杂交或扩增RBM10基因或其mRNA的物质。
  9. 根据权利要求8所述的试剂盒或微阵列，其特征在于所述与RBM10基因编码的蛋白或蛋白片段结合的结合剂为抗RBM10的抗体，以及所述与RBM10基因或其mRNA杂交或扩增RBM10基因或其mRNA的物质为寡核苷酸引物或探针。
  10. 西奥罗尼在制备用于治疗卵巢癌、尤其是存在RBM10基因突变的卵巢癌的药物中的用途。
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