WO2022075318A1 - Marqueur d'évaluation reflétant l'efficacité d'une composition de traitement du cancer - Google Patents

Marqueur d'évaluation reflétant l'efficacité d'une composition de traitement du cancer Download PDF

Info

Publication number
WO2022075318A1
WO2022075318A1 PCT/JP2021/036820 JP2021036820W WO2022075318A1 WO 2022075318 A1 WO2022075318 A1 WO 2022075318A1 JP 2021036820 W JP2021036820 W JP 2021036820W WO 2022075318 A1 WO2022075318 A1 WO 2022075318A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
cxcl12
pancreatic tumor
linear
tumor cells
Prior art date
Application number
PCT/JP2021/036820
Other languages
English (en)
Japanese (ja)
Inventor
壯平 里井
智久 山本
大典 良田
壮 山木
光明 石田
Original Assignee
学校法人関西医科大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 学校法人関西医科大学 filed Critical 学校法人関西医科大学
Priority to JP2022555503A priority Critical patent/JPWO2022075318A1/ja
Publication of WO2022075318A1 publication Critical patent/WO2022075318A1/fr

Links

Images

Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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

Definitions

  • the present specification describes a method for detecting an evaluation marker that reflects the effectiveness of a composition for treating cancer, a composition for treating cancer, a method for using the evaluation marker, an evaluation marker, a test reagent, and a composition for treating cancer.
  • An evaluation device that reflects the effectiveness of the above is disclosed.
  • Non-Patent Documents 1 to 3 among pancreatic cancer patients with peritoneal dissemination, intraperitoneal paclitaxel administration therapy is remarkably effective, conversion surgery is possible, and the prognosis is significantly improved. exist.
  • the present invention relates to a method for detecting an evaluation marker that reflects the effectiveness of a composition for treating cancer for pancreatic tumor, a composition for treating cancer, a method for using the evaluation marker, an evaluation marker, a test reagent, and a composition for treating cancer.
  • the subject is to provide an evaluation device that reflects the effectiveness of an object.
  • paclitaxel-based compounds are effective in pancreatic tumor patients with a low abundance of CXCL12 (SDF-1) in pancreatic tumor cells.
  • the present invention has been completed based on the findings and includes the following aspects.
  • Item 1. Including the step of detecting CXCL12 in a region of interest containing pancreatic tumor cells in a tissue collected from a subject.
  • a method for detecting the evaluation marker, wherein the composition for treating cancer contains a compound represented by the following general formula (I).
  • R 1 has a linear or branched alkyl group of C1-4, a linear or branched alkoxy group of C1-4, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group on the phenyl ring.
  • R2 has (2-1) a linear or branched alkyl group of C1-4 on the phenyl ring, a linear or branched alkoxy group of C1-4, a halogen atom, an amino group, a hydroxyl group, a nitro group, and the like.
  • a phenylcarbonyl group which may have at least one selected from the group consisting of a carboxy group and a cyano group as a substituent, or an alkenylcarbonyl group having (2-2) an alkenyl moiety having 2 to 6 carbon atoms. Indicates an amino group that may have.
  • R 3 , R 4 and R 5 represent the same or different hydrogen atom or hydroxyl group.
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 represent the same or different linear alkyl groups of C1-3.
  • R 12 has a linear or branched alkyl group of C1-4, a linear or branched alkoxy group of C1-4, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group on the phenyl ring. Indicates a phenyl group which may have at least one selected from the group consisting of as a substituent. ). Item 2. Further comprising the step of presenting a label indicating that the composition for treating cancer is effective when the score indicating the abundance of CXCL12 in the region of interest is equal to or less than the reference value.
  • the score is based on the ratio of (1) the staining intensity of CXCL12 protein in the pancreatic tumor cells and (2) the number of pancreatic tumor cells positive for CXCL12 protein staining when the number of pancreatic tumor cells is 100%.
  • the method for detecting the evaluation marker according to Item 1. Item 3.
  • Item 2. The method for detecting an evaluation marker according to Item 1 or 2, further comprising a step of presenting a label indicating that the conversation surgery is applicable when the score in the region of interest falls below a reference value.
  • the compound represented by the general formula (I) is paclitaxel.
  • a composition for treating cancer for use in patients with pancreatic tumors having peritoneal dissemination which comprises a compound represented by the following general formula (I).
  • the cancer therapeutic composition is used for administration to the subject having a CXCL12 score of less than or equal to a reference value in an area of interest containing pancreatic tumor cells in a tissue collected from the subject.
  • the score is obtained based on the ratio of (1) the staining intensity of CXCL12 in the pancreatic tumor cells and (2) the number of pancreatic tumor cells positive for CXCL12 staining when the number of pancreatic tumor cells is 100%.
  • R 1 has a linear or branched alkyl group of C1-4, a linear or branched alkoxy group of C1-4, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group on the phenyl ring.
  • R2 has (2-1) a linear or branched alkyl group of C1-4, a linear or branched alkoxy group of C1-4, a halogen atom, an amino group, a hydroxyl group, and a nitro group on the phenyl ring.
  • a phenylcarbonyl group which may have at least one selected from the group consisting of a carboxy group and a cyano group as a substituent, or an alkenylcarbonyl group having (2-2) an alkenyl moiety having 2 to 6 carbon atoms. Indicates an amino group that may have.
  • R 3 , R 4 and R 5 represent the same or different hydrogen atom or hydroxyl group.
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 represent the same or different linear alkyl groups of C1-3.
  • R 12 has a linear or branched alkyl group of C1-4, a linear or branched alkoxy group of C-4, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group on the phenyl ring. Indicates a phenyl group which may have at least one selected from the group consisting of as a substituent. ).
  • Item 6. The composition for treating cancer according to Item 6, wherein the compound represented by the general formula (I) is paclitaxel.
  • Item 9. A detection reagent for detecting CXCL12 in pancreatic tumor cells in a tissue collected from a subject as a marker for evaluating the effectiveness of the cancer therapeutic composition according to Item 5 or 6, wherein the detection reagent is used.
  • Item 10. A device for evaluating the effectiveness of a composition for treating cancer, which comprises a processing unit.
  • the processing unit A score of CXCL12 in the area of interest containing pancreatic tumor cells in the tissue collected from the subject was obtained. Compare the obtained score with the standard value and When the obtained score falls below the reference value, a label indicating that the cancer therapeutic composition according to Item 5 or 6 is effective is output, and / or the obtained score sets the reference value. When it falls below, it outputs a label indicating the applicability of conversion surgery, where the subject has a peritoneal dissemination of a pancreatic tumor.
  • the evaluation device is configured to evaluate the evaluation device.
  • the present invention it is possible to identify a pancreatic tumor patient to which a paclitaxel-based compound is significantly effective.
  • An example of the overview diagram of the evaluation system 1000 is shown.
  • An example of the block diagram of the evaluation device 10 is shown.
  • An example of the processing of the evaluation program 104b is shown.
  • the score distribution of CXCL12 in the group to which the conversation surgery could not be applied and the group to which the conversation surgery could be applied is shown.
  • the score distribution of CXCR4 in the group to which the conversation surgery could not be applied and the group to which the conversation surgery could be applied is shown.
  • CXCL motif ligand 12 is a small molecule protein and is a kind of chemokine.
  • CXCL12 is also called SDF-1 (Stromal Derived Factor-1), and is typically expressed from a gene registered in the National Center for Biotechnology Information with Gene ID: 6387.
  • the evaluation marker consisting of CXCL12 includes a protein expressed from the gene or mRNA.
  • the evaluation marker includes a protein or mRNA expressed from the gene, as well as a variant thereof.
  • Pancreatic tumor is not limited as long as it is a tumor derived from cells existing in the pancreas.
  • Pancreatic tumors may include malignant tumors and benign tumors, but are preferably malignant tumors, more preferably cancers.
  • Pancreatic cancer may include pancreatic ductal adenocarcinoma, mucinous cystadenocarcinoma, serous cystadenocarcinoma and the like. It is preferably pancreatic duct adenocarcinoma.
  • the pancreatic tumor may be present in the pancreas, but may also be present in lymph nodes, portal veins, arteries, duodenum, bile duct, liver, peritoneum, lungs and the like.
  • the pancreatic tumor may be initial or relapsed. It is preferably the first time.
  • Subjects are not limited as long as they have a pancreatic tumor.
  • the person has peritoneal dissemination of a pancreatic tumor.
  • composition for cancer treatment contains a paclitaxel-based compound as an active ingredient.
  • the paclitaxel-based compound is represented by the compound represented by the following general formula (I):
  • R 1 has a linear or branched alkyl group of C1-4, a linear or branched alkoxy group of C1-4, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group on the phenyl ring.
  • R2 has (2-1) a linear or branched alkyl group of C1-4, a linear or branched alkoxy group of C1-4, a halogen atom, an amino group, a hydroxyl group, and a nitro group on the phenyl ring.
  • a phenylcarbonyl group which may have at least one selected from the group consisting of a carboxy group and a cyano group as a substituent, or an alkenylcarbonyl group having (2-2) an alkenyl moiety having 2 to 6 carbon atoms. Indicates an amino group that may have.
  • R 3 , R 4 and R 5 represent the same or different hydrogen atom or hydroxyl group.
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 represent the same or different linear alkyl groups of C1-3.
  • R 12 has a linear or branched alkyl group of C1-4, a linear or branched alkoxy group of C1-4, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group on the phenyl ring. Indicates a phenyl group which may have at least one selected from the group consisting of as a substituent. ).
  • C in the description of “C1-4", “C1-3”, “C3-4”, etc. relating to the compound represents the number of carbon atoms.
  • C1-4 indicates that the number of carbon atoms is 1 to 4
  • C1-3 indicates that the number of carbon atoms is 1 to 3
  • C3-4" indicates that the number of carbon atoms is 3 to 4. Show that.
  • the linear or branched alkyl group of C1-4 is the linear alkyl group of C1-4, and the branched chain of C3-4. Indicates an alkyl group.
  • the linear alkyl group of C1-4 is one selected from, for example, a methyl group, an ethyl group, a propyl group, and an n-butyl group.
  • the branched chain alkyl group of C3-4 is one selected from an isopropyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.
  • the linear or branched alkoxy group of C1-4 is the linear alkoxy group of C1-4, and the branched chain of C3-4. Indicates an alkoxy group.
  • the alkyl moiety of the linear alkoxy group of C1-4 is one selected from, for example, a methyl group, an ethyl group, a propyl group, and an n-butyl group.
  • the alkyl moiety of the branched chain alkoxy group of C3-4 is one selected from an isopropyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.
  • the alkenyl moiety having 2 to 5 carbon atoms is, for example, a linear or branched alkenyl group.
  • the linear alkenyl group having 2 to 5 carbon atoms include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group and a 1-pentynyl group.
  • 2-pentynyl group, 3-pentynyl group, 4-pentynyl group can be raised.
  • Examples of the alkenyl group of the branched chain having 3 to 5 carbon atoms include a methyl-propenyl group, a methyl-butenyl group, an ethyl-propenyl group and the like.
  • the halogen atom may include, for example, a chlorine atom, a fluorine atom, a bromine atom, an iodine atom and the like.
  • the substituents on the phenyl ring at R 1 , R 2 , and R 12 may be at any of the ortho, meta, and para positions with respect to the carbon atom to which the alkylene group is attached.
  • R 1 is preferably a phenyl group without a substituent.
  • R2 is preferably a phenylcarbonyl group, an alkenylcarbonyl group having 4 carbon atoms in the alkenyl group, or an unsubstituted amino group.
  • R 3 is preferably a hydrogen atom or a hydroxyl group.
  • R 4 and R 5 are preferably hydroxyl groups.
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are preferably methyl groups.
  • R 12 is preferably a phenyl group without a substituent.
  • the paclitaxel-based compound is preferably any of the compounds represented by the following formulas (II) to (V).
  • the paclitaxel-based compound is more preferably any of the compounds represented by the following formulas (II') to (V').
  • the common name of the compound represented by the above formula (II) or (II') is paclitaxel.
  • the most preferable paclitaxel-based compound is paclitaxel.
  • compositions for treating cancer are generally used as ordinary drugs depending on the dosage form of the pharmaceutical composition, such as excipients, binders, disintegrants, lubricants, etc. It may contain a colorant, a flavoring agent, a flavoring agent, a surfactant and the like.
  • the composition for cancer treatment can be administered by intravenous drip infusion, intraperitoneal administration, or the like according to a conventionally reported method for administering a paclitaxel-based compound. Intraperitoneal administration or a combination of intraperitoneal administration and intravenous drip administration is preferable.
  • the composition for treating cancer can be determined according to the dose of the paclitaxel-based compound previously reported. For example, when only a paclitaxel-based compound is used as an active ingredient for cancer treatment, in the case of intravenous drip infusion, the dose of the paclitaxel-based compound is 80 mg / m 2 (body surface area) once a day for adults.
  • the dose of paclitaxel-based compounds should be about 10 mg / m 2 (body surface area) to 40 mg / m 2 (body surface area) per day for adults. Can be administered. Intraperitoneal administration can be performed, for example, once or twice a week.
  • the dose of paclitaxel-based compound to adults is 30 mg / m 2 (body surface area) to 30 mg / m 2 per day by intravenous drip infusion. It can be administered to about (body surface area) and intraperitoneally at about 10 mg / m 2 (body surface area) to 40 mg / m 2 (body surface area) per day.
  • the composition for treating cancer can be administered, for example, once or twice a week.
  • composition for treating cancer may be used in combination with other drugs.
  • S-1 which is one of the oral fluoropyrimidine derivatives can be mentioned.
  • 50 mg / m 2 (body surface area) to 100 per day is continued from the start of administration of the cancer therapeutic composition to adults. It can be orally administered at mg / m 2 (body surface area) in about 1 to 2 weeks.
  • the detection method includes a step of detecting CXCL12 in a region of interest containing pancreatic tumor cells in a tissue collected from a subject. That is, CXCL12 expressed or present in the region of interest containing pancreatic tumor cells in the tissue collected from the examiner is an evaluation that reflects the effectiveness of the cancer therapeutic composition in pancreatic tumor patients with peritoneal dissemination. It can be used as a marker.
  • pancreatic tumor cells such as pancreatic tumor cells or pancreatic tumor tissue collected from a subject.
  • Pancreatic tumor cells or pancreatic tumor tissue can be collected, for example, by surgical excision or biopsy from the primary or metastatic lesion, endoscopic excision or biopsy, separation from ascites, or the like. Whether it is a tumor tissue or a normal tissue can be determined by macroscopic findings, microscopic observation, or the like.
  • the tissue may be determined whether or not the tissue is a tumor tissue by using the cell proliferation ability and the expression of a tumor marker (for example, CA19-9) as an index.
  • a tumor marker for example, CA19-9
  • the tissue to be inspected is said to be the tissue to be inspected. It can be determined that the tissue is likely to be tumor tissue.
  • the tumor marker is used as an index, it can be determined that the tissue in which the expression of the tumor marker is positive is highly likely to be the tumor tissue.
  • Pancreatic tumor cells or pancreatic tumor tissue collected from the subject are pretreated according to the detection method of CXCL12.
  • CXCL12 in pancreatic tumors can be detected as a protein or as mRNA.
  • Examples of the method for detecting CXCL12 as a protein include known methods such as immunostaining and Western blotting. Further, as a method for detecting CXCL12 as mRNA, known methods such as in situ hybridization, RT-PCR (including quantitative RT-PCR), microarray, RNA-Seq and the like can be mentioned.
  • pancreatic tumor tissue When performing immunostaining or in situ hybridization using pancreatic tumor tissue, as a pretreatment, the pancreatic tumor tissue is fixed with a known fixing solution such as formalin and paraformaldehyde, and then the paraffin-embedded block is placed. To make. Alternatively, the pancreatic tumor tissue is fixed or not fixed, and then embedded in a resin for making a frozen block such as OCT compound (registered trademark) to prepare a frozen block. Next, the prepared paraffin-embedded block or frozen block is sliced to prepare a tissue section, which is subjected to immunostaining or in situ hybridization.
  • the pancreatic tumor tissue embedded in the block may be only the tumor portion, but may include, for example, a normal region or the like.
  • the cells are smeared or collected on a slide glass as a pretreatment, and fixed with formalin, paraformaldehyde, ethanol, or the like.
  • pancreatic tumor cells or pancreatic tumor tissue are lysed with a predetermined lysis buffer as a pretreatment.
  • the sample dissolved in the dissolution buffer is used as the inspection sample.
  • RNA or mRNA is extracted from pancreatic tumor cells or pancreatic tumor tissue as a pretreatment. Further, if necessary, the extracted total RNA or mRNA may be used as a template for reverse transcription to synthesize complementary DNA (cDNA). Total RNA or mRNA, or cDNA is used as a test sample.
  • the primary antibody for detecting CXCL12 by immunostaining or Western blotting is not limited as long as CXCL12 can be detected.
  • CXCL12 can be detected.
  • Anti-SDF-1 rabbit polyclonal antibody (ab9797, abcam) and the like can be mentioned.
  • the primary antibody bound to CXCL12 can be detected by the reaction between the enzyme-labeled secondary antibody bound to the primary antibody and the enzyme and the substrate.
  • tissue sections may be treated with a proteolytic enzyme such as trypsin after deparaffinization and water immersion treatment, and then immunostaining may be performed.
  • a method for producing a probe used for in situ hybridization is known.
  • a commercially available probe may be used.
  • a commercially available primer can be used as the primer used for RT-PCR (in the case of quantitative RT-PCR, a probe may be included).
  • a commercially available primer can be used as the primer used for RT-PCR.
  • commercially available microarrays can also be used.
  • the number of reads of CXCL12 mRNA can be obtained using a next-generation sequencer (for example, manufactured by Illumina).
  • CXCL12 When CXCL12 is detected by immunostaining or in situ hybridization, the presence or absence of CXCL12 is detected by observing a tissue specimen subjected to immunostaining or in situ hybridization by a human using a microscope or a slide scanner. be able to. When a signal of immunostaining or in situ hybridization is confirmed in the tumor cells in the tissue specimen, it can be determined (determined) that CXCL12 has been detected. When at least one tumor cell having CXCL12 in the cell is detected in the tumor portion in the tissue specimen, it may be determined that "CXCL12 is detected" or "expression of CXCL12 is positive".
  • the number of tumor cells existing in a predetermined section of a microscope or a slide scanner is 100%
  • the number of tumor cells having CXCL12 in the cells is 10% or more, preferably 5% or more, more preferably. May be determined that "CXCL12 was detected” or "CXCL12 expression is positive” when 1% or more is present.
  • CXCL12 When CXCL12 is detected by Western blotting, RT-PCT, RNA-Seq, "CXCL12 is detected” or “Expression of CXCL12” when CXCL12 is detected in a sample extracted from tumor cells or tumor tissue. Is positive. " Alternatively, the amount of protein of CXCL12 in the test sample derived from tumor cells or tissue is compared with the amount of protein of CXCL12 derived from normal cells or normal tissue or the amount of mRNA of CXCL12 from the test sample derived from tumor cells or tissue.
  • “showing a high value” can be exemplified as a case where a value showing a value 1.2 times or more, preferably 1.5 times or more, more preferably 2 times or more, still more preferably 5 times or more is shown.
  • “Same degree” can be exemplified by about 0.8 to 1.1 times.
  • the amount of protein or RNA in each test sample is adjusted to the amount of protein derived from housekeeping genes such as GAPDH, ⁇ 2-microglobulin, and ⁇ -actin. Alternatively, it may be normalized by the amount of mRNA.
  • the amount of protein may be expressed by mass or concentration, but may also be expressed by the emission intensity of the substrate or the like.
  • the amount of mRNA may be the number of copies or reads of mRNA, but may be expressed by fluorescence intensity or the like.
  • the reference value of the CXCL12 protein amount or the RNA amount is determined in advance and the CXCL12 protein amount or the RNA amount in the test sample derived from the tumor cell or the tumor tissue is higher than the reference value, " It may be determined that "CXCL12 has been detected” or "the expression of CXCL12 is positive”. Further, when the amount of CXCL12 protein or RNA in the test sample derived from the tumor cell or tumor tissue is lower than the reference value, it is determined that "CXCL12 is not detected” or "the expression of CXCL12 is negative”. May be good.
  • the reference value is not limited as long as it is a value that can determine whether the amount of protein of CXCL12 or the amount of mRNA of CXCL12 is detected or the expression is positive, and can be determined by a known method.
  • the value that can determine whether the amount of protein of CXCL12 or the amount of mRNA of CXCL12 is detected or the expression is positive is the ROC (receiver operating characteristic curve) curve, discriminant analysis method, mode method, Kittler method, 3 ⁇ method. , P-tile method or the like.
  • sensitivity, specificity, negative predictive value, positive predictive value, first quartile, and the like can be exemplified.
  • the evaluation marker detection method may further include a step of determining that the cancer therapeutic composition is effective when CXCL12 is not detected. Alternatively, it may include a step of determining that the cancer therapeutic composition is not effective when CXCL12 is detected.
  • the method for detecting the evaluation marker may include a step of acquiring a score indicating the abundance of CXCL12 in the region of interest.
  • the score is based on the ratio of (1) the staining intensity of CXCL12 protein in the pancreatic tumor cells and (2) the number of pancreatic tumor cells positive for CXCL12 protein staining when the number of pancreatic tumor cells is 100%. Is obtained.
  • the CXCL12 protein in pancreatic tumor cells is stained by, for example, immunostaining, and the staining intensity is determined. No expression: level 0, Weak: Level 1, Medium: Level 2 or Strong: Level 3 It is classified into 4 stages.
  • the ratio of the number of pancreatic tumor cells positive for CXCL12 protein staining when the number of pancreatic tumor cells is 100% is determined. 0%: Level 0, 1 to 5%: Level 1, From 5% to 25%: Level 2, Higher than 25 and up to 50%: Level 3, Higher than 50 up to 75%: Level 4 or Higher than 75 up to 100%: Level 5 It is classified into 5 stages. Then, the value obtained by multiplying the values of each level obtained in (1) and (2) is used as the score.
  • the evaluation marker detection method compares the score of the region of interest obtained by the above method with the reference value of the predetermined score, and when the score of the region of interest falls below the reference value, the composition for cancer treatment is described. It can be determined that the thing is valid. Further, when the score of the region of interest is equal to or higher than the reference value, it can be determined that the composition for treating cancer is not effective.
  • the evaluation marker detection method compares the score of the region of interest obtained by the above method with the reference value of the predetermined score, and when the score of the region of interest falls below the reference value, the cancer treatment is described. Suggests that the composition for use is effective. Further, when the score of the region of interest is equal to or higher than the reference value, it is suggested that the composition for treating cancer is not effective.
  • the reference value is not limited as long as it is possible to distinguish between a group in which the composition for treating cancer is effective and a group in which the composition for cancer treatment is not effective.
  • a score of 6 can be used as a reference value.
  • the cancer therapeutic composition is effective when CXCL12 is not detected in the area of interest, or when the score indicating the abundance of CXCL12 in the area of interest falls below the reference value. It may include a step of presenting a label indicating that. Further, as a method for detecting the evaluation marker, the cancer therapeutic composition is effective when CXCL12 is detected in the area of interest, or when the score indicating the abundance of CXCL12 in the area of interest is equal to or higher than the reference value. It may include a step of presenting a label indicating that it is not.
  • the evaluation marker detection method may be applicable to conversion surgery when CXCL12 is not detected in the area of interest, or when the score indicating the abundance of CXCL12 in the area of interest falls below the reference value. It may include a step of presenting a label indicating. In addition, the evaluation marker detection method is not applicable to conversion surgery when CXCL12 is detected in the area of interest, or when the score indicating the abundance of CXCL12 in the area of interest is equal to or higher than the reference value. It may include a step of presenting a label indicating.
  • the presentation of whether or not the composition for cancer treatment is effective and the presentation of whether or not the combination surgery is applicable may be either one or both.
  • Test Reagent Another aspect of the present disclosure relates to a test reagent for detecting CXCL12 present in pancreatic tumor cells collected from a subject as a marker for evaluating the effectiveness of the above-mentioned cancer therapeutic composition.
  • the test reagent may include a reagent for detecting CXCL12 protein and / or a reagent for detecting CXCL12 mRNA.
  • the reagent for detecting CXCL12 protein contains at least one or more antibodies (eg, primary antibody) capable of binding to a part of CXCL12 protein.
  • antibodies eg, primary antibody
  • any of a polyclonal antibody, a monoclonal antibody, and a fragment thereof for example, Fab, F (ab'), F (ab) 2, etc.
  • the immunoglobulin class and subclass are not particularly limited.
  • the antibody may be one screened from an antibody library, a chimeric antibody, scFv, or the like. Further, the antibody does not necessarily have to be purified, and may be an antiserum containing the antibody, ascites, an immunoglobulin fraction fractionated from these, or the like.
  • the antibody contained in the test reagent may be in a dry state or may be dissolved in a buffer such as phosphate buffered saline.
  • the test reagent is a stabilizer such as ⁇ -mercaptoethanol and DTT; a protective agent such as albumin; a surfactant such as polyoxyethylene (20) sorbitan monolaurate and polyoxyethylene (10) octylphenyl ether. It may contain at least one preservative such as sodium azide.
  • the antibody that binds to CXCL12 may be labeled with an enzyme or a fluorescent dye.
  • the antibody that binds to CXCL12 may be immobilized on a microplate, magnetic beads, or the like.
  • the CXCL12 protein detection reagent may be provided as a test kit that includes a package insert that describes the test reagent and how to use the reagent or the URL of a web page that describes how to use the reagent.
  • the test kit may contain a secondary antibody labeled with an enzyme or a fluorescent dye.
  • the test kit may include a substrate that reacts with the enzyme.
  • the CXCL12 mRNA detection reagent contains a nucleic acid that hybridizes with all or part of CXCL12 mRNA or CXCL12 cDNA.
  • the nucleic acid is preferably a detection nucleic acid (DNA or RNA) having a function as a primer and / or a probe.
  • the length of the detection nucleic acid is not particularly limited.
  • the sequence that hybridizes with CXCL12 mRNA or CXCL12 cDNA is preferably 50 mer or less, more preferably 30 mer or less, and further preferably 15 It is about ⁇ 25 mer.
  • the primer may contain a sequence that does not hybridize with CXCL12 mRNA or CXCL12 cDNA. Further, the primer may be labeled with a fluorescent dye or the like.
  • RT-PCR can also use a quantification probe that is degraded during the PCR reaction and is used for real-time quantification of PCR products.
  • the quantification probe is also not limited as long as it hybridizes with CXCL12 mRNA or CXCL12 cDNA.
  • the quantification probe is preferably a nucleic acid of about 5 to 20 mer, which contains a sequence that hybridizes with CXCL12 mRNA or CXCL12 cDNA. Further, it is preferable that one end of the quantification probe is labeled with a fluorescent dye, and the other end of the quantification probe is labeled with a quencher of the fluorescent dye.
  • the sequence that hybridizes with CXCL12 mRNA or CXCL12 cDNA is preferably about 100 mer, more preferably about 60 mer, and further preferably. Is about 20 to 30 mer.
  • the capture probe may contain a sequence that does not hybridize to CXCL12 mRNA or CXCL12 cDNA. Further, the capture probe is preferably immobilized on the chip.
  • the detection nucleic acid when the detection nucleic acid is a probe for in situ hybridization, the detection nucleic acid may be an oligonucleotide having a sequence hybridizing with CXCL12 mRNA of about 15 to 100 mer, and a polynucleotide exceeding 100 mer. May be.
  • the polynucleotide may be DNA or RNA. Labeling substances such as digoxigenin and fluorescent dyes can be bound to the probe for in situ hybridization.
  • the probe may contain a sequence that does not hybridize to CXCL12 mRNA.
  • the CXCL12 mRNA detection reagent may be provided as a test kit containing a test reagent and an attachment containing the URL of a web page that describes how to use the reagent or how to use the reagent.
  • the test kit contains a nucleic acid amplification reagent (including polymerase, buffer, dNTP, etc. even if it is heat-resistant DNA), reverse transcriptase, etc. May be good.
  • the nucleic acid amplification reagent may contain a dye such as SYBER GREEN (registered trademark), if necessary.
  • the test kit may include a hybridization buffer, a washing buffer, and the like.
  • the test kit may include a proteolytic enzyme such as proteinase K, a hybridization buffer, a washing buffer, and the like.
  • Evaluation device for the effectiveness of the composition for cancer treatment 4-1.
  • Configuration of Evaluation Device for Efficacy of Cancer Treatment Composition One embodiment of the present disclosure is an evaluation system 1000 for the effectiveness of a cancer treatment composition in a patient with pancreatic tumor having peritoneal dissemination (hereinafter referred to as “evaluation system 1000”). (Abbreviation)) and the evaluation device 10 for evaluating the effectiveness of the composition for treating cancer (hereinafter, abbreviated as “evaluation device 10”).
  • FIG. 1 is an overview diagram of the evaluation system 1000, and the evaluation system 1000 may include an analysis device 5a or an analysis device 5b in addition to the evaluation device 10 as one aspect.
  • FIG. 2 shows a block diagram of the evaluation device 10.
  • the evaluation device 10 may be connected to the input unit 111, the output unit 112, and the storage medium 113.
  • the output interface (I / F) 107 and the media interface (I / F) 108 are connected to each other by a bus 109 so as to be capable of data communication.
  • the main storage unit 102 and the auxiliary storage unit 104 may be collectively referred to as a storage unit.
  • the storage unit volatilely or non-volatilely stores the measurement result, the score in the area of interest, the reference value, and the like.
  • the processing unit 101 is the CPU of the evaluation device 10.
  • the processing unit 101 may cooperate with the GPU.
  • the evaluation device 10 functions by the processing unit 101 executing the operation system 104a and the evaluation program 104b stored in the auxiliary storage unit 104 and processing the acquired data.
  • the ROM 103 is composed of a mask ROM, a PROM, an EPROM, an EEPROM, and the like, and records a computer program executed by the processing unit 101 and data used for the computer program.
  • the processing unit 101 may be the MPU 101.
  • the ROM 103 stores the boot program executed by the processing unit 101 when the evaluation device 10 is started, and the programs and settings related to the operation of the hardware of the evaluation device 10.
  • the main storage unit 102 is composed of a RAM (Random access memory) such as a SRAM or a DRAM.
  • the main storage unit 102 is used to read out the computer program recorded in the ROM 103 and the auxiliary storage unit 104. Further, the main storage unit 102 is used as a work area when the processing unit 101 executes these computer programs.
  • the auxiliary storage unit 104 is composed of a hard disk, a semiconductor memory element such as a flash memory, an optical disk, or the like.
  • the auxiliary storage unit 104 stores an operation system 104a, an evaluation program 104b described later, and a reference value database (DB) 104c for storing reference values.
  • the evaluation program 104b cooperates with the operation system 104a to perform evaluation processing.
  • the communication I / F 105 includes a serial interface such as USB, IEEE1394, RS-232C, a parallel interface such as SCSI, IDE, IEEE1284, an analog interface including a D / A converter, an A / D converter, and a network interface controller ( It is composed of Network interface controller (NIC) and the like.
  • the communication I / F 105 receives data from the analyzers 5a and 5b or other external devices, and stores or generates information as needed by the evaluation device 10 in the analyzer 5a, 5b or send or display to the outside.
  • the communication I / F 105 may communicate with the analyzers 5a, 5b or other external devices via the network.
  • the input I / F 106 is composed of, for example, a serial interface such as USB, IEEE1394, RS-232C, a parallel interface such as SCSI, IDE, and IEEE1284, and an analog interface including a D / A converter and an A / D converter.
  • a serial interface such as USB, IEEE1394, RS-232C
  • a parallel interface such as SCSI, IDE, and IEEE1284
  • an analog interface including a D / A converter and an A / D converter.
  • the input I / F 106 accepts character input, click, voice input, and the like from the input unit 111.
  • the received input contents are stored in the main storage unit 102 or the auxiliary storage unit 104.
  • the input unit 111 is composed of a touch panel, a keyboard, a mouse, a pen tablet, a microphone, etc., and inputs characters or voices to the evaluation device 10.
  • the input unit 111 may be connected from the outside of the evaluation device 10 or may be integrated with the evaluation device 10.
  • the output I / F 107 is composed of an interface similar to that of the input I / F 106, for example.
  • the output I / F 107 outputs the information generated by the processing unit 101 to the output unit 112.
  • the output I / F 107 outputs the information generated by the processing unit 101 and stored in the auxiliary storage unit 104 to the output unit 112.
  • the output unit 112 is composed of, for example, a display, a printer, or the like, and displays measurement results transmitted from the analyzers 5a and 5b, various operation windows in the evaluation device 10, analysis results, and the like.
  • the media I / F 108 reads, for example, application software stored in the storage medium 113.
  • the read application software and the like are stored in the main storage unit 102 or the auxiliary storage unit 104. Further, the media I / F 108 writes the information generated by the processing unit 101 into the storage medium 113.
  • the media I / F 108 writes the information generated by the processing unit 101 and stored in the auxiliary storage unit 104 to the storage medium 113.
  • the storage medium 113 is composed of a flexible disk, a CD-ROM, a DVD-ROM, or the like.
  • the storage medium 113 is connected to the media I / F 108 by a flexible disk drive, a CD-ROM drive, a DVD-ROM drive, or the like.
  • the storage medium 113 may store an application program or the like for the computer to execute an operation.
  • the processing unit 101 may acquire the evaluation program 104b and various settings necessary for controlling the evaluation device 10 via the network instead of reading from the ROM 103 or the auxiliary storage unit 104.
  • the application program is stored in the auxiliary storage unit of the server computer on the network, and the evaluation device 10 may access the server computer to download the computer program and store it in the ROM 103 or the auxiliary storage unit 104. It is possible.
  • an operation system that provides a graphical user interface environment such as Windows (registered trademark) manufactured and sold by Microsoft Corporation in the United States is installed in the ROM 103 or the auxiliary storage unit 104.
  • the application program according to the second embodiment shall operate on the operating system. That is, the evaluation device 10 may be a personal computer or the like.
  • the evaluation system 1000 does not have to be installed in one place, and the evaluation device 10 and the analysis devices 5a and 5b may be arranged in different places and connected by a network. Further, the evaluation device 10 may be a device that does not require an operator who omits the input unit 111 and the output unit 112.
  • the analyzer 5a is a device for measuring the amount or concentration of protein, and includes a sample storage area 51, a reaction unit 52, and a detection unit 53.
  • the cytolytic solution set in the sample storage area 51 is dispensed and incubated into a microplate on which the antigen-capturing antibody placed in the reaction unit 52 is immobilized. After removing the unreacted antigen as needed, the detected antibody is dispensed into microplates and incubated. After removing the unreacted antigen as needed, the substrate for detecting the detection antibody is dispensed to the microplate, the microplate is moved to the detection unit 53, and the signal generated by the reaction of the substrate is measured. Will be done. It was
  • Another aspect of the analyzer 5a is an apparatus for measuring the expression level of mRNA by microarray analysis, in which the reverse transcriptase set in the sample storage area 51 is divided onto the microarray chip set in the reaction unit 52. After pouring, hybridization, and washing, the sample is moved to the detection unit 53 to detect the signal.
  • another aspect of the analyzer 5a is an apparatus for measuring the expression level of mRNA by RT-PCR, in which the reverse transcription reagent set in the sample storage 51 is placed in a microtube set in the reaction unit 52. Dispense, then dispense the quantitative PCR reagent into a microtube. While performing the PCR reaction in the reaction unit 52, the detection unit 53 detects the signal in the tube.
  • the analyzer 5b is an apparatus for measuring the expression level of mRNA by the RNA-Seq method, and includes a sequence analysis unit 54.
  • the sample subjected to the reaction for RNA-Seq is set in the sequence analysis unit 54, and the base sequence is analyzed in the sequence analysis unit 54.
  • the analyzer 5b is a fully automated Western blotting device for measuring the amount of protein by Western blotting, and includes a chemiluminescence signal detection unit 54.
  • a sample of pancreatic tumor cells or pancreatic tumor tissue lysed with a lysis buffer is set in a predetermined position on an automatic Western blotting device, and SDS-PAGE, blotting to a membrane, antibody reaction, chemiluminescence is performed, and a chemiluminescence signal detector is performed. Analysis is performed at 54 to quantify the signal intensity.
  • the analyzers 5a and 5b are connected to the evaluation device 10 by wire or wirelessly.
  • the evaluation device 10 can acquire the measured value of the protein or the measured value of mRNA as digital data that can be calculated.
  • FIG. 3 shows an example of a flowchart of the processing executed by the evaluation program 104b.
  • the processing unit 101 of the evaluation device 10 starts processing for evaluating the effectiveness of the cancer therapeutic composition by inputting a processing start request from the input unit 111 by the operator.
  • step S11 the processing unit 101 acquires the score of CXCL12 in the region of interest including the pancreatic tumor cells in the tissue input by the operator from the input unit 111.
  • the amount of protein of CXCL12 in pancreatic tumor cells collected from the subject from the analyzer 5a or the analyzer 5b, or the amount of mRNA of CXCL12 or a value reflecting these is obtained as a measured value of CXCL12.
  • the operator inputs from the input unit 111 whether the expression of CXCL12 by immunostaining or in situ hybridization is positive or negative (or whether CXCL12 is detected), and the processing unit 101 inputs this input. It may be acquired as a measured value of CXCL12.
  • step S12 the processing unit 101 compares the reference value of the score of CXCL12 or the reference value of CXCL12 stored in the storage unit with the value acquired in step S11.
  • step S14 determines that the cancer therapeutic composition is effective, and determines the determination result.
  • the indicated label is output to the output unit 112 (step S16).
  • step S16 it is determined that the conversation surgery is applicable, and a label indicating that the conversion surgery is applicable is output.
  • step S15 when the acquired score or value is equal to or higher than the reference value, the process proceeds to step S15 (NO), it is determined that the cancer therapeutic composition is not effective, and a label indicating the determination result is shown. Is output to the output unit 112 (step S16).
  • step S16 it is determined that the conversation surgery is not applicable, and a label indicating that the conversion surgery is not applicable is output.
  • the label indicating the effectiveness of the cancer therapeutic composition contains information indicating that "the cancer therapeutic composition is effective” or "the cancer therapeutic composition may be effective”. ..
  • the label indicating that the cancer therapeutic composition is not effective contains information indicating that "the cancer therapeutic composition is ineffective” or "the cancer therapeutic composition may be ineffective”. Is done.
  • the label indicating the applicability of the conversion surgery includes information indicating that "conversion surgery is valid” or “conversion surgery may be valid".
  • the label indicating that the conversion surgery is not applicable includes information indicating that "conversion surgery is invalid” or “conversion surgery may be invalid”.
  • the information may be a mark such as x, ⁇ , exclamation mark or the like.
  • a storage medium in which a program is stored relates to a program product such as a storage medium in which the evaluation program 104b is stored. That is, the computer program can be stored in a hard disk, a semiconductor memory element such as a flash memory, or a storage medium such as an optical disk.
  • the recording format of the program on the storage medium is not limited as long as the evaluation device 10 can read the program. Recording on the storage medium is preferably non-volatile.
  • tissue sample was fixed with formalin to prepare a tissue specimen.
  • tissue specimens all fixed tissue samples were embedded in paraffin to prepare sliced sections.
  • tissue Microarray For each patient's tissue, select the most morphologically characteristic part of the hematoxylin-eosin-stained tissue specimen and select two tissue masses (2 mm in diameter) from the paraffin-embedded block. was collected with a punch. The punched tissue mass was further arranged and embedded in a paraffin block, and sliced to prepare a tissue section.
  • Immunostaining was performed using an automatic staining device (Discovery, Roche Diagnostics, Basel, Switzerland) according to the protocol attached to the device.
  • Anti-SDF-1 rabbit polyclonal antibody (ab9797, abcam) was diluted 1,000-fold and used as the primary antibody for staining CXCL12.
  • a peroxidase-labeled anti-rabbit immunoglobulin antibody was used, and diaminobenzidine (DAB) was used for color development.
  • DAB diaminobenzidine
  • Expression of CXCL12 was positive when there was a signal on the surface (on the cell membrane) of pancreatic tumor cells. Above 2. The score of each section was obtained according to the scoring method described in 1.
  • Anti-cancer drug therapy Paclitaxel is administered to 50 mg / m 2 by intravenous drip infusion and 20 mg / m 2 intraperitoneally on day 1 and day 8 with the start date of anti-cancer drug treatment as day 1. bottom.
  • S-1 was orally administered at 80 mg / m 2 / d from day 1 for 14 consecutive days.
  • the paclitaxel-based compound is effective for pancreatic tumor cells of patients with a CXCL12 score of less than 6. It was also shown that conversion surgery can be applied to these patients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Cell Biology (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Veterinary Medicine (AREA)
  • Biotechnology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Microbiology (AREA)
  • General Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Food Science & Technology (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le problème à résoudre par la présente invention est de fournir : un procédé de détection d'un marqueur d'évaluation qui reflète l'efficacité d'une composition de traitement du cancer sur une tumeur du pancréas ; une composition de traitement du cancer ; un procédé d'utilisation du marqueur d'évaluation ; le marqueur d'évaluation ; un réactif de test ; et un dispositif d'évaluation qui reflète l'efficacité d'une composition de traitement du cancer.　La solution selon l'invention porte sur un procédé de détection d'un marqueur d'évaluation qui reflète l'efficacité d'une composition de traitement du cancer sur un patient atteint d'une tumeur du pancréas avec dissémination péritonéale, ledit procédé comprenant une étape de détection de CXCL12 dans une région d'intérêt comprenant des cellules tumorales pancréatiques dans un tissu qui est collecté à partir du patient cible, la composition de traitement du cancer comprenant un composé de paclitaxel.
PCT/JP2021/036820 2020-10-08 2021-10-05 Marqueur d'évaluation reflétant l'efficacité d'une composition de traitement du cancer WO2022075318A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2022555503A JPWO2022075318A1 (fr) 2020-10-08 2021-10-05

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020-170772 2020-10-08
JP2020170772 2020-10-08

Publications (1)

Publication Number Publication Date
WO2022075318A1 true WO2022075318A1 (fr) 2022-04-14

Family

ID=81126942

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/036820 WO2022075318A1 (fr) 2020-10-08 2021-10-05 Marqueur d'évaluation reflétant l'efficacité d'une composition de traitement du cancer

Country Status (2)

Country Link
JP (1) JPWO2022075318A1 (fr)
WO (1) WO2022075318A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006522148A (ja) * 2003-04-03 2006-09-28 ジェシー エル エス オウ 腫瘍を標的指向化する薬物を封入した粒子
CN105137078A (zh) * 2015-06-01 2015-12-09 中国医学科学院北京协和医院 一种预测胰腺癌病人预后不良风险的试剂盒及其应用
WO2016068160A1 (fr) * 2014-10-30 2016-05-06 Ｄｅｌｔａ－Ｆｌｙ Ｐｈａｒｍａ株式会社 Nouveau procédé de fabrication de lipoplexe pour une administration par voie locale, et médicament antitumoral utilisant le lipoplexe

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006522148A (ja) * 2003-04-03 2006-09-28 ジェシー エル エス オウ 腫瘍を標的指向化する薬物を封入した粒子
WO2016068160A1 (fr) * 2014-10-30 2016-05-06 Ｄｅｌｔａ－Ｆｌｙ Ｐｈａｒｍａ株式会社 Nouveau procédé de fabrication de lipoplexe pour une administration par voie locale, et médicament antitumoral utilisant le lipoplexe
CN105137078A (zh) * 2015-06-01 2015-12-09 中国医学科学院北京协和医院 一种预测胰腺癌病人预后不良风险的试剂盒及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ISOHEI SATO: "Diagnosis and Treatment of Peritoneal Metastasis of Pancreatic Cancer", JAPAN JOURNAL OF CANCER CLINICS, vol. 64, no. 2, 1 January 2018 (2018-01-01), JP , pages 97 - 102, XP009535675, ISSN: 0021-4949 *
YAMADA S, FUJII T, YAMAMOTO T, TAKAMI H, YOSHIOKA I, YAMAKI S, SONOHARA F, SHIBUYA K, MOTOI F, HIRANO S, MURAKAMI Y, INOUE H, HAYA: "Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis", BRITISH JOURNAL OF SURGERY, vol. 107, no. 13, 12 November 2020 (2020-11-12), GB , pages 1811 - 1817, XP055920164, ISSN: 0007-1323, DOI: 10.1002/bjs.11792 *

Also Published As

Publication number Publication date
JPWO2022075318A1 (fr) 2022-04-14

Similar Documents

Publication Publication Date Title
Crowley et al. Liquid biopsy: monitoring cancer-genetics in the blood
Thuerigen et al. Gene expression signature predicting pathologic complete response with gemcitabine, epirubicin, and docetaxel in primary breast cancer
Stoy et al. Feasibility of endobronchial ultrasound-guided transbronchial needle aspiration cytology specimens for next generation sequencing in non–small-cell lung cancer
Kloos et al. Phase II trial of sorafenib in metastatic thyroid cancer
CN106715723B (zh) 测定样品中pik3ca突变状态的方法
JP6144695B2 (ja) タキサン療法を用いて乳癌を処置する方法
AU2009262894B2 (en) Gene expression profiles to predict breast cancer outcomes
JP5971769B2 (ja) アントラサイクリン療法を用いて乳癌を処置する方法
KR101596539B1 (ko) 암 환자에서의 진단 목적용 방법 및 조성물
US20240043939A1 (en) Nucleic acid biomarker and use thereof
WO2022053065A1 (fr) Biomarqueur utilisé pour prédire ou évaluer des patients atteints d'un cancer du poumon, procédé de détection et application
Potti et al. Predictive role of HER-2/neu overexpression and clinical features at initial presentation in patients with extensive stage small cell lung carcinoma
Mehta et al. Biomarker testing for advanced lung cancer by next-generation sequencing; a valid method to achieve a comprehensive glimpse at mutational landscape
Ohyama et al. Detection of actionable mutations in archived cytological bile specimens
Gong et al. Cyclin-dependent kinase 6 (CDK6) is a candidate diagnostic biomarker for early non-small cell lung cancer
JP2020511137A (ja) ｃｆＲＮＡに関する液体生検
WO2022075318A1 (fr) Marqueur d'évaluation reflétant l'efficacité d'une composition de traitement du cancer
Ohyama et al. Development of a molecular barcode detection system for pancreaticobiliary malignancies and comparison with next-generation sequencing
WO2021046502A2 (fr) Kits et procédés pour tester des risques de cancer du poumon
WO2020105626A1 (fr) Marqueur prédictif pour le pronostic des tumeurs pancréatiques
CN111041099B (zh) 检测g蛋白偶联受体137b表达水平的试剂的应用和试剂盒
Artinyan et al. Molecular predictors of lymph node metastasis in colon cancer: increased risk with decreased thymidylate synthase expression
US20220228204A1 (en) Personalized therapeutic approaches to prostate cancer
JP2021107767A (ja) 乳腺腫瘍の予後予測マーカー
JP2022012466A (ja) 尿路系上皮腫瘍関連病変を検出するためのバイオマーカー

Legal Events

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

Ref document number: 21877617

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022555503

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21877617

Country of ref document: EP

Kind code of ref document: A1