Evaluation marker reflecting the efficacy of a cancer therapeutic composition

Abstract

The present invention addresses the problem of providing: a method of detecting an evaluation marker that reflects the efficacy of a cancer treatment composition on pancreatic tumor; a cancer treatment composition; a method of using the evaluation marker; the evaluation marker; a test reagent; and an evaluation device that reflects the efficacy of a cancer treatment composition.　This problem is solved by a method of detecting an evaluation marker that reflects the efficacy of a cancer treatment composition on a pancreatic tumor patient with peritoneal dissemination, said method comprising a step for detecting CXCL12 in an area of interest including pancreatic tumor cells in a tissue that is collected from the target patient, wherein the cancer treatment composition comprises a paclitaxel compound.

Description

[Technical Field]

[0001] This specification discloses a method for detecting an evaluation marker that reflects the effectiveness of a cancer therapeutic composition, a cancer therapeutic composition, a method for using the evaluation marker, an evaluation marker, a test reagent, and an evaluation device that reflects the effectiveness of a cancer therapeutic composition. [Background technology]

[0002] Conversion surgery is generally not applicable to pancreatic cancer patients with peritoneal dissemination. However, as described in Non-Patent Documents 1 to 3, there are cases in which intraperitoneal paclitaxel administration therapy is highly effective among pancreatic cancer patients with peritoneal dissemination, making conversion surgery possible and significantly improving the prognosis. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] J Hepatobiliary Pancreat Sci. 2017 May;24(5):289-296. doi: 10.1002 / jhbp.447. Epub 2017 Apr 19. [Non-patent document 2] Ann Surg. 2017 Feb;265(2):397-401. doi: 10.1097 / SLA.0000000000001705. [Non-patent document 3] Br J Surg. 2020 Jul 7. doi: 10.1002 / bjs.11792. Online ahead of print. Summary of the Invention [Problem to be solved by the invention]

[0004] There are no known indicators for distinguishing patients who will respond to intraperitoneal paclitaxel therapy from those who will not.

[0005] An object of the present invention is to provide a method for detecting an evaluation marker that reflects the effectiveness of a cancer therapeutic composition against pancreatic tumors, a cancer therapeutic composition, a method for using the evaluation marker, an evaluation marker, a test reagent, and an evaluation device that reflects the effectiveness of a cancer therapeutic composition. [Means for solving the problem]

[0006] As a result of extensive research, the present inventors have found that paclitaxel-based compounds are effective in pancreatic tumor patients in whom the amount of CXCL12 (SDF-1) present in pancreatic tumor cells is low. The present invention was completed based on this finding and includes the following aspects. Section 1. detecting CXCL12 in a region of interest containing pancreatic tumor cells in tissue collected from the subject; A method for detecting an evaluation marker that reflects the efficacy of a cancer therapeutic composition in a pancreatic tumor patient with peritoneal dissemination, comprising: The method for detecting the evaluation marker, wherein the cancer therapeutic composition comprises a compound represented by the following general formula (I): [ka] (where, R 1 represents a phenyl group which may have at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group on the phenyl ring. R 2 represents (2-1) a phenylcarbonyl group which may have, on the phenyl ring, at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group, or (2-2) an amino group which may have an alkenylcarbonyl group having 2 to 6 carbon atoms in the alkenyl moiety. R 3 , R 4 and R 5 are the same or different and represent a hydrogen atom or a hydroxyl group. R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are the same or different and represent a C1-3 linear alkyl group. R 12 represents a phenyl group which may have, on the phenyl ring, at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group. Section 2. The method further comprises a step of displaying a label indicating that the cancer therapeutic composition is effective when the score indicating the amount of CXCL12 present in the region of interest is equal to or less than a reference value, Item 2. The method for detecting an evaluation marker according to Item 1, wherein the score is obtained based on (1) the staining intensity of CXCL12 protein in the pancreatic tumor cells and (2) the proportion of pancreatic tumor cells that are positive for CXCL12 protein staining, when the number of pancreatic tumor cells is taken as 100%. Section 3. Item 3. The method for detecting an evaluation marker according to Item 1 or 2, further comprising the step of presenting a label indicating that conversion surgery may be applicable when the score in the region of interest falls below a reference value. Section 4. The compound represented by the general formula (I) is paclitaxel. A method for detecting an evaluation marker according to any one of Items 1 to 3. Section 5. A composition for cancer treatment for use in a patient with pancreatic tumor having peritoneal dissemination, comprising a compound represented by the following general formula (I): The cancer therapeutic composition is used to be administered to a subject whose CXCL12 score in a region of interest containing pancreatic tumor cells in tissue collected from the subject is equal to or lower than a reference value; the composition for cancer treatment, wherein the score is obtained based on (1) the staining intensity of CXCL12 in the pancreatic tumor cells and (2) the ratio of the number of pancreatic tumor cells that are positive for CXCL12 staining, when the number of pancreatic tumor cells is taken as 100%: [ka] (where, R 1 represents a phenyl group which may have at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group on the phenyl ring. R 2 represents (2-1) a phenylcarbonyl group which may have, on the phenyl ring, at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group, or (2-2) an amino group which may have an alkenylcarbonyl group having 2 to 6 carbon atoms in the alkenyl moiety. R 3 , R 4 and R 5 are the same or different and represent a hydrogen atom or a hydroxyl group. R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are the same or different and represent a C1-3 linear alkyl group. R 12 represents a phenyl group which may have at least one substituent on the phenyl ring selected from the group consisting of a C1-4 linear or branched alkyl group, a C-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group. Section 6. Item 7. The composition for cancer treatment according to Item 6, wherein the compound represented by general formula (I) is paclitaxel. Section 7. Item 7. A method for using CXCL12 in pancreatic tumor cells in tissue collected from a subject as a marker for evaluating the efficacy of the cancer therapeutic composition according to Item 5 or 6, wherein the subject has peritoneal dissemination of a pancreatic tumor. Section 8. Item 7. An evaluation marker consisting of CXCL12 for evaluating the effectiveness of the cancer therapeutic composition according to Item 5 or 6 in a subject with peritoneal dissemination of a pancreatic tumor. Section 9. A detection reagent for detecting CXCL12 in pancreatic tumor cells in tissue collected from a subject as a marker for evaluating the effectiveness of the cancer therapeutic composition according to Item 5 or 6, the detection reagent comprising an antibody for detecting CXCL12; wherein the subject has peritoneal dissemination of a pancreatic tumor. The detection reagent. Section 10. An apparatus for evaluating the effectiveness of a cancer therapeutic composition, comprising: The processing unit obtaining a CXCL12 score in a region of interest containing pancreatic tumor cells in tissue collected from the subject; The obtained score is compared with the standard value, When the acquired score is below the reference value, a label indicating that the composition for cancer treatment according to Item 5 or 6 is effective is output, and / or when the acquired score is below the reference value, a label indicating that conversion surgery is applicable is output, wherein the subject has peritoneal dissemination of pancreatic tumor. The evaluation device. [Effects of the Invention]

[0007] According to the present invention, it is possible to identify pancreatic tumor patients who respond well to paclitaxel-based compounds, and also to identify patients who can undergo conversion surgery from among patients with peritoneal dissemination of pancreatic tumors who have conventionally been considered ineligible for conversion surgery. [Brief explanation of the drawings]

[0008] [Figure 1] 1 shows an example of an overview of an evaluation system 1000. [Figure 2] 1 shows an example of a block diagram of an evaluation device 10. [Figure 3] An example of the processing of the evaluation program 104b will be shown. [Figure 4] The distribution of CXCL12 scores in the group in which conversation surgery was not possible and the group in which it was possible is shown. [Figure 5] The distribution of CXCR4 scores in the group in which conversation surgery was not possible and the group in which it was possible is shown. DETAILED DESCRIPTION OF THE INVENTION

[0009] 1. Explanation of terms (1) Evaluation Marker CXCL motif ligand 12 (CXCL12) is a low molecular weight protein and a type of chemokine. CXCL12 is also known as SDF-1 (stromal derived factor-1), and is typically expressed from the gene registered with the National Center for Biotechnology Information under Gene ID: 6387. Evaluation markers consisting of CXCL12 include proteins or mRNA expressed from the gene. Evaluation markers also include variants thereof, in addition to proteins or mRNA expressed from the gene.

[0010] (2) Pancreatic tumor Pancreatic tumors are not limited as long as they are tumors derived from cells present in the pancreas. Pancreatic tumors may include malignant tumors and benign tumors, but are preferably malignant tumors, and more preferably cancers. Pancreatic cancers may include pancreatic ductal adenocarcinoma, mucinous cystic adenocarcinoma, serous cystic adenocarcinoma, etc. Pancreatic ductal adenocarcinoma is preferred. Pancreatic tumors may be present in the pancreas, but may also be present in lymph nodes, portal vein, artery, duodenum, bile duct, liver, peritoneum, lung, etc. Furthermore, pancreatic tumors may be primary or recurrent. Primary tumors are preferred. The subject is not limited as long as it has a pancreatic tumor, and preferably has peritoneal dissemination of a pancreatic tumor.

[0011] (3) Cancer treatment composition The composition for cancer treatment contains a paclitaxel-based compound as an active ingredient. The paclitaxel-based compound is represented by the following general formula (I):

[0012] [ka] (where, R 1 represents a phenyl group which may have at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group on the phenyl ring. R 2 represents (2-1) a phenylcarbonyl group which may have, on the phenyl ring, at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group, or (2-2) an amino group which may have an alkenylcarbonyl group having 2 to 6 carbon atoms in the alkenyl moiety. R 3 , R 4 and R 5 are the same or different and represent a hydrogen atom or a hydroxyl group. R 6, R 7 , R 8 , R 9 , R 10 and R 11 are the same or different and represent a C1-3 linear alkyl group. R 12 represents a phenyl group which may have, on the phenyl ring, at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group and a cyano group.

[0013] In this specification, "C" in the descriptions of compounds such as "C1-4," "C1-3," and "C3-4" 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, and "C3-4" indicates that the number of carbon atoms is 3 to 4.

[0014] R 1 , R 2 , and R 12 In the substituents on the phenyl ring, the C1-4 linear or branched alkyl group refers to a C1-4 linear alkyl group or a C3-4 branched alkyl group. The C1-4 linear alkyl group is, for example, one selected from a methyl group, an ethyl group, a propyl group, and an n-butyl group. The C3-4 branched alkyl group is one selected from an isopropyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.

[0015] R 1 , R 2 , and R 12In the substituent on the phenyl ring in the formula (I), the C1-4 linear or branched alkoxy group refers to a C1-4 linear alkoxy group or a C3-4 branched alkoxy group. The alkyl portion of the C1-4 linear alkoxy group is, for example, a member selected from a methyl group, an ethyl group, a propyl group, and an n-butyl group. The alkyl portion of the C3-4 branched alkoxy group is, for example, a member selected from an isopropyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.

[0016] R 2 In the amino group described above, which may have an alkenylcarbonyl group in which the alkenyl moiety has 2 to 5 carbon atoms, examples of the alkenyl moiety having 2 to 5 carbon atoms include linear and branched alkenyl groups. Examples of linear alkenyl groups having 2 to 5 carbon atoms include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. Examples of branched alkenyl groups having 3 to 5 carbon atoms include methylpropenyl, methylbutenyl, and ethylpropenyl.

[0017] R 1 , R 2 , and R 12 In the substituent on the phenyl ring in the formula (I), examples of the halogen atom include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.

[0018] R 1 , R 2 , and R 12 The substituent on the phenyl ring in the formula (I) may be located in the ortho, meta, or para position relative to the carbon atom to which the alkylene group is bonded.

[0019] R 1 is preferably an unsubstituted phenyl group.

[0020] R 2is preferably a phenylcarbonyl group, an alkenylcarbonyl group in which the alkenyl group has 4 carbon atoms, or an unsubstituted amino group.

[0021] R 3 is preferably a hydrogen atom or a hydroxyl group.

[0022] R 4 and R 5 and are preferably both hydroxyl groups.

[0023] R 6 , R 7 , R 8 , R 9 , R 10 and R 11 and are preferably both methyl groups. R 12 is preferably an unsubstituted phenyl group.

[0024] The paclitaxel compound is preferably any of the compounds represented by the following formulas (II) to (V).

[0025] [ka]

[0026] [ka]

[0027] [ka]

[0028] [ka] The paclitaxel compound is more preferably any of the compounds represented by the following formulae (II') to (V').

[0029] [ka]

[0030] [ka]

[0031] [ka]

[0032] [ka] The compound represented by the above formula (II) or (II') has the common name paclitaxel.

[0033] The compound represented by the above formula (III) or (III') has the common name cephalomannine.

[0034] The compound represented by the above formula (IV) or (IV') has the common name 3'-N-debenzoyltaxol.

[0035] The compound represented by the above formula (V) or (V') has the general name 3'-N-debenzoyl-2'-deoxytaxol.

[0036] The most preferred paclitaxel compound is paclitaxel.

[0037] The cancer therapeutic composition may contain, in addition to the paclitaxel compound, various substances commonly used in conventional drugs, such as excipients, binders, disintegrants, lubricants, colorants, flavoring agents, odorants, surfactants, etc., depending on the dosage form of the pharmaceutical composition.

[0038] The cancer therapeutic composition can be administered by intravenous drip infusion, intraperitoneal drip infusion, or the like, according to the previously reported administration methods of paclitaxel compounds. Preferably, it is administered intraperitoneally, or a combination of intraperitoneal drip infusion and intravenous drip infusion. The cancer therapeutic composition can be determined according to the previously reported dose of paclitaxel compounds. For example, when a paclitaxel compound is used alone as an active ingredient in cancer treatment, in the case of intravenous drip infusion, the dose of the paclitaxel compound for an adult is 80 mg / m once daily. 2 (body surface area) to 210 mg / m 2 (body surface area) over 1 to 24 hours, and if necessary, administer continuously for 3 to 6 weeks. After administration, it is preferable to rest for at least 2 to 3 weeks as needed. The period from the start of administration to the end of administration, or if there is a rest period, from the start of administration to the end of the rest period, is considered one course, and the degree of tumor shrinkage can be observed while repeating the course as needed.

[0039] When administered intraperitoneally, the dose of paclitaxel compounds for adults is 10 mg / m per day. 2 (body surface area) to 40 mg / m 2 (body surface area). Intraperitoneal administration can be carried out, for example, about once or twice a week.

[0040] When administered intraperitoneally and intravenously, the dose of paclitaxel compounds in adults is 30 mg / m per day by intravenous infusion. 2 (body surface area) to 30 mg / m 2 (body surface area) and intraperitoneally at 10 mg / m per day 2 (body surface area) to 40 mg / m 2 The composition for treating cancer can be administered, for example, once or twice a week.

[0041] The cancer therapeutic composition may also be used in combination with other drugs. Examples of such drugs include S-1, an oral fluoropyrimidine derivative. When the cancer therapeutic composition and S-1 are used in combination, the dose for an adult is 50 mg / m per day, continuing from the start of administration of the cancer therapeutic composition. 2 (body surface area) to 100 mg / m 2 (body surface area) and can be administered orally in about one to two weeks.

[0042] 2. Methods for detecting evaluation markers One aspect of the present disclosure relates to an evaluation marker that reflects the efficacy of a cancer therapeutic composition in pancreatic tumor patients with peritoneal dissemination and a detection method thereof. The detection method includes a step of detecting CXCL12 in a region of interest containing pancreatic tumor cells in tissue collected from a subject. That is, CXCL12 expressed or present in a region of interest containing pancreatic tumor cells in tissue collected from a subject can be used as an evaluation marker that reflects the efficacy of a cancer therapeutic composition in pancreatic tumor patients with peritoneal dissemination.

[0043] Detection of CXCL12 in pancreatic tumors is performed in a region of interest, which is the region to be detected for CXCL12. The region of interest is not limited as long as it contains 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 resection or biopsy from a primary or metastatic lesion, endoscopic resection or biopsy, or isolation from ascites. Whether a tissue is tumorous or normal can be determined by macroscopic observation, microscopic observation, or the like. Alternatively, cell proliferation activity or the expression of a tumor marker (e.g., CA19-9) may be used as an indicator to determine whether the tissue is tumorous. When cell proliferation activity is used as an indicator to determine whether the tissue is tumorous, for example, if the labeling index of BrdU or Ki-67 protein in the tissue to be examined is higher than that in normal tissue, the tissue to be examined can be determined to be tumorous. When a tumor marker is used as an indicator, tissue that is positive for tumor marker expression can be determined to be tumorous.

[0044] Pancreatic tumor cells or pancreatic tumor tissue collected from a subject is pretreated according to the method for detecting CXCL12.

[0045] CXCL12 in pancreatic tumors can be detected as protein or as mRNA.

[0046] Methods for detecting CXCL12 as a protein include known methods such as immunostaining and Western blotting, and methods for detecting CXCL12 as mRNA include known methods such as in situ hybridization, RT-PCR (including quantitative RT-PCR), microarray, and RNA-Seq.

[0047] When immunostaining or in situ hybridization is performed using pancreatic tumor tissue, the pancreatic tumor tissue is pretreated by fixing it with a known fixative such as formalin or paraformaldehyde, followed by preparation of a paraffin-embedded block. Alternatively, the pancreatic tumor tissue is embedded in a resin for preparing frozen blocks, such as OCT Compound (registered trademark), either with or without fixation, to prepare a frozen block. The prepared paraffin-embedded block or frozen block is then thinly sliced ​​to prepare tissue sections, which are then subjected to immunostaining or in situ hybridization. Here, the pancreatic tumor tissue embedded in the block may consist of only the tumor tissue, but may also include, for example, normal tissue.

[0048] When immunostaining or in situ hybridization is performed using pancreatic tumor cells, the cells are smeared or collected on a slide glass and fixed with formalin, paraformaldehyde, ethanol, or the like as a pretreatment.

[0049] Here, when CXCL12 is immunostained, a positive signal appears on the cell surface, i.e., on the cell membrane.

[0050] When detecting CXCL12 as a protein by Western blotting or the like, pancreatic tumor cells or pancreatic tumor tissues are lysed in a predetermined lysis buffer as a pretreatment. The sample lysed in the lysis buffer is used as a test sample.

[0051] When detecting CXCL12 mRNA using RT-PCR, microarray, RNA-Seq, etc., total RNA or mRNA is extracted from pancreatic tumor cells or pancreatic tumor tissue as a pretreatment. If necessary, the extracted total RNA or mRNA may be used as a template for reverse transcription to synthesize complementary DNA (cDNA). The total RNA, mRNA, or cDNA is used as the test sample.

[0052] The primary antibody used to detect CXCL12 by immunostaining or Western blotting is not limited as long as it can detect CXCL12. For example, an anti-SDF-1 rabbit polyclonal antibody (ab9797, Abcam) can be used. The primary antibody bound to CXCL12 can be detected by a reaction between an enzyme-labeled secondary antibody that binds to the primary antibody and the enzyme and its substrate. When immunostaining is performed, tissue sections may be deparaffinized and immersed in water, and then treated with a protease such as trypsin before immunostaining.

[0053] Methods for preparing probes used in in situ hybridization are known, and commercially available probes may also be used.

[0054] Commercially available primers (which may include a probe in the case of quantitative RT-PCR) can be used for RT-PCR, and commercially available microarrays can also be used.

[0055] RNA-Seq can obtain the number of CXCL12 mRNA reads using a next-generation sequencer (for example, manufactured by Illumina).

[0056] When detecting CXCL12 by immunostaining or in situ hybridization, the presence or absence of CXCL12 can be detected by observing the immunostained or in situ hybridized tissue specimen using a microscope, slide scanner, or the like. CXCL12 can be determined (confirmed) as detected when an immunostaining or in situ hybridization signal is confirmed in tumor cells within the tissue specimen. When even one tumor cell containing CXCL12 is detected in a tumor area within the tissue specimen, it may be determined that "CXCL12 has been detected" or "CXCL12 expression is positive." Alternatively, for example, when the number of tumor cells present in a predetermined section of a microscope or slide scanner is taken as 100%, it may be determined that "CXCL12 has been detected" or "CXCL12 expression is positive" when 10% or more, preferably 5% or more, more preferably 1% or more of tumor cells contain CXCL12.

[0057] When CXCL12 is detected by Western blotting, RT-PCR, or RNA-Seq, if CXCL12 is detected in a sample extracted from tumor cells or tumor tissue, it may be determined that "CXCL12 is detected" or "CXCL12 expression is positive." Alternatively, by comparing the amount of CXCL12 protein or CXCL12 mRNA in a test sample derived from tumor cells or tumor tissue with that derived from normal cells or normal tissue, it may be determined that "CXCL12 is detected" or "CXCL12 expression is positive" if the amount of CXCL12 protein or CXCL12 mRNA in the test sample derived from tumor cells or tumor tissue is higher than the amount of CXCL12 protein or CXCL12 mRNA in the test sample derived from normal cells or normal tissue. Furthermore, when the amount of CXCL12 protein or mRNA in a test sample derived from tumor cells or tumor tissue is comparable to the amount of CXCL12 protein or mRNA in a test sample derived from normal cells or normal tissue, it may be determined that "CXCL12 is not detected" or that "CXCL12 expression is negative." Here, "high value" refers to a value that is 1.2 times or more, preferably 1.5 times or more, more preferably 2 times or more, and even more preferably 5 times or more higher. "Similar" refers to a value of approximately 0.8 to 1.1 times. Furthermore, before comparing the amounts of CXCL12 protein or CXCL12 mRNA, the amount of protein or RNA in each test sample may be normalized to the amount of protein or mRNA derived from a housekeeping gene such as GAPDH, β2-microglobulin, or β-actin. Protein amount may be expressed in terms of mass or concentration, or may be expressed in terms of the luminescence intensity of a substrate. The amount of mRNA may be expressed as the copy number or read number of mRNA, or may be expressed as fluorescence intensity or the like.

[0058] In another embodiment, a reference value for the amount of CXCL12 protein or RNA may be determined in advance, and if the amount of CXCL12 protein or RNA in a test sample derived from tumor cells or tumor tissue is higher than the reference value, it may be determined that "CXCL12 is detected" or "CXCL12 expression is positive." Alternatively, if the amount of CXCL12 protein or RNA in a test sample derived from tumor cells or tumor tissue is lower than the reference value, it may be determined that "CXCL12 is not detected" or "CXCL12 expression is negative." The reference value is not limited as long as it is a value that can determine whether the amount of CXCL12 protein or CXCL12 mRNA is detected or whether expression is positive, and can be determined by known methods. The value that can determine whether the amount of CXCL12 protein or CXCL12 mRNA is detected or whether expression is positive can also be determined by ROC (receiver operating characteristic curve) curve, discriminant analysis, mode method, Kittler method, 3σ method, p-tile method, etc. Furthermore, examples of reference values ​​include sensitivity, specificity, negative predictive value, positive predictive value, and first quartile.

[0059] The method for detecting an evaluation marker may further comprise the step of determining that the cancer therapeutic composition is effective when CXCL12 is not detected, or may comprise the step of determining that the cancer therapeutic composition is ineffective when CXCL12 is detected.

[0060] In another embodiment, the method for detecting an evaluation marker may include a step of obtaining a score indicating the amount of CXCL12 present in the region of interest.

[0061] The score is obtained based on (1) the staining intensity of CXCL12 protein in the pancreatic tumor cells and (2) the percentage of pancreatic tumor cells that are positive for CXCL12 protein staining, when the number of pancreatic tumor cells is taken as 100%.

[0062] In (1), CXCL12 protein in pancreatic tumor cells is stained by, for example, immunostaining, and the staining intensity is measured. No expression: level 0; Weak: Level 1, Moderate: Level 2, or Strong: Level 3 It is classified into four stages: In (2), the percentage of pancreatic tumor cells that were positive for CXCL12 protein staining was calculated based on the number of pancreatic tumor cells taken as 100%. 0%: Level 0, 1 to 5%: Level 1; Higher than 5% up to 25%: Level 2, 25 and above up to 50%: Level 3, 50 to 75%: Level 4, or 75+ up to 100%: Level 5 It is classified into five levels: Then, the values ​​of each level obtained in (1) and (2) are multiplied and the resulting value is used as the score.

[0063] The method for detecting an evaluation marker compares the score of a region of interest obtained by the above method with a predetermined reference score, and if the score of the region of interest is below the reference value, it can be determined that the cancer therapeutic composition is effective. Alternatively, if the score of a region of interest is equal to or greater than the reference value, it can be determined that the cancer therapeutic composition is ineffective. Alternatively, the method for detecting an evaluation marker compares the score of a region of interest obtained by the above method with a predetermined reference score, and if the score of a region of interest is below the reference value, it suggests that the cancer therapeutic composition is effective. Alternatively, if the score of a region of interest is equal to or greater than the reference value, it suggests that the cancer therapeutic composition is ineffective.

[0064] The reference value is not limited as long as it can distinguish between a group for which the cancer therapeutic composition is effective and a group for which it is not effective. For example, a score of 6 can be used as the reference value.

[0065] The method for detecting an evaluation marker may comprise the step of presenting a label indicating that the cancer therapeutic composition is effective when CXCL12 is not detected in the region of interest or when the score indicating the amount of CXCL12 present in the region of interest is below a reference value. Alternatively, the method for detecting an evaluation marker may comprise the step of presenting a label indicating that the cancer therapeutic composition is ineffective when CXCL12 is detected in the region of interest or when the score indicating the amount of CXCL12 present in the region of interest is equal to or greater than a reference value.

[0066] Furthermore, the method for detecting an evaluation marker may include a step of presenting a label indicating the applicability of conversion surgery when CXCL12 is not detected in the region of interest or when the score indicating the amount of CXCL12 present in the region of interest is below a reference value.Furthermore, the method for detecting an evaluation marker may include a step of presenting a label indicating the applicability of conversion surgery when CXCL12 is detected in the region of interest or when the score indicating the amount of CXCL12 present in the region of interest is equal to or greater than a reference value.

[0067] The indication of whether or not a composition for treating cancer is effective and the indication of whether or not conversion surgery is applicable may be either one or both.

[0068] 3. Testing reagents 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.

[0069] The test reagent may include a reagent for detecting CXCL12 protein and / or a reagent for detecting CXCL12 mRNA.

[0070] The reagent for detecting CXCL12 protein contains one or more antibodies (e.g., primary antibodies) capable of binding to at least a portion of CXCL12 protein. The "antibody" may be a polyclonal antibody, a monoclonal antibody, or a fragment thereof (e.g., Fab, F(ab'), F(ab)2, etc.). The immunoglobulin class and subclass are not particularly limited. Furthermore, the antibody may be one screened from an antibody library, or may be a chimeric antibody, scFv, etc. Furthermore, the antibody does not necessarily have to be purified, and may be an antiserum containing the antibody, ascites fluid, or an immunoglobulin fraction fractionated therefrom.

[0071] The antibody contained in the test reagent may be in a dry state or dissolved in a buffer such as phosphate-buffered saline. Furthermore, the test reagent may contain at least one of a stabilizer such as β-mercaptoethanol or DTT, a protectant such as albumin, a surfactant such as polyoxyethylene (20) sorbitan monolaurate or polyoxyethylene (10) octylphenyl ether, or a preservative such as sodium azide.

[0072] The antibody that binds to CXCL12 may be labeled with an enzyme or a fluorescent dye, or may be immobilized on a microplate, magnetic beads, or the like. The CXCL12 protein detection reagent may be provided as a test kit containing the test reagent and a package insert describing how to use the reagent or a URL for a web page describing how to use the reagent. Furthermore, when the antibody that binds to CXCL12 is an unlabeled primary antibody, the test kit may contain a secondary antibody labeled with an enzyme or a fluorescent dye. Furthermore, the test kit may contain a substrate that reacts with the enzyme.

[0073] The reagent for detecting CXCL12 mRNA 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) that functions as a primer and / or a probe. The length of the detection nucleic acid is not particularly limited.

[0074] If the detection nucleic acid is a primer used in a PCR reaction, the sequence that hybridizes with CXCL12 mRNA or CXCL12 cDNA is preferably 50 mer or less, more preferably 30 mer or less, and even more preferably about 15 to 25 mer. The primer may contain a sequence that does not hybridize with CXCL12 mRNA or CXCL12 cDNA. Furthermore, the primer may be labeled with a fluorescent dye or the like.

[0075] In addition to primers, 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 approximately 5 to 20 mer that contains a sequence that hybridizes with CXCL12 mRNA or CXCL12 cDNA. Furthermore, it is preferable that one end of the quantification probe is labeled with a fluorescent dye and the other end is labeled with a quencher for the fluorescent dye.

[0076] When the detection nucleic acid is used as a capture probe in a microarray or the like, the sequence that hybridizes with CXCL12 mRNA or CXCL12 cDNA is preferably about 100-mer, more preferably about 60-mer, and even more preferably about 20-30-mer. The capture probe may contain a sequence that does not hybridize with CXCL12 mRNA or CXCL12 cDNA. Furthermore, the capture probe is preferably immobilized on a chip.

[0077] When the detecting nucleic acid is a probe for in situ hybridization, the sequence of the detecting nucleic acid that hybridizes with CXCL12 mRNA may be an oligonucleotide of about 15 to 100 mer, or a polynucleotide of more than 100 mer. The polynucleotide may be DNA or RNA. A labeling substance such as digoxigenin or a fluorescent dye may be bound to the probe for in situ hybridization. The probe may contain a sequence that does not hybridize with CXCL12 mRNA.

[0078] The CXCL12 mRNA detection reagent may be provided as a test kit containing the test reagent and a package insert describing how to use the reagent or providing a URL for a web page describing how to use the reagent. When detecting CXCL12 mRNA or CXCL12 cDNA by RT-PCR, the test kit may contain a nucleic acid amplification reagent (including polymerase, buffer, dNTPs, etc., even if it is heat-stable DNA), reverse transcriptase, etc. The nucleic acid amplification reagent may contain a dye such as SYBER GREEN (registered trademark), as needed. When detecting CXCL12 mRNA or CXCL12 cDNA by microarray, the test kit may contain a hybridization buffer, a washing buffer, etc. When detecting CXCL12 mRNA by in situ hybridization, the test kit may contain a protease such as proteinase K, a hybridization buffer, a washing buffer, etc.

[0079] 4. Device for evaluating the effectiveness of cancer treatment compositions 4-1. Configuration of the device for evaluating the effectiveness of a cancer treatment composition One embodiment of the present disclosure relates to a system 1000 for evaluating the effectiveness of a cancer therapeutic composition in pancreatic tumor patients with peritoneal dissemination (hereinafter abbreviated as "evaluation system 1000") and an apparatus 10 for evaluating the effectiveness of a cancer therapeutic composition (hereinafter abbreviated as "evaluation apparatus 10").

[0080] FIG. 1 is a schematic diagram of an evaluation system 1000, which in one embodiment may include an analysis device 5a or an analysis device 5b in addition to an evaluation device 10. 2 shows a block diagram of the evaluation device 10. The evaluation device 10 may be connected to an input unit 111, an output unit 112, and a storage medium 113.

[0081] In the evaluation device 10, a processing unit 101, a main memory unit 102, a ROM (read only memory) 103, an auxiliary memory unit 104, a communication interface (I / F) 105, an input interface (I / F) 106, an output interface (I / F) 107, and a media interface (I / F) 108 are connected to each other via a bus 109 so as to be able to communicate data with each other. The main memory unit 102 and the auxiliary memory unit 104 may be collectively referred to simply as a memory unit. The memory unit stores measurement results, scores in the regions of interest, reference values, etc. in a volatile or non-volatile manner.

[0082] The processing unit 101 is the CPU of the evaluation device 10. The processing unit 101 may work in cooperation with a GPU. The processing unit 101 executes an operation system 104a and an evaluation program 104b stored in the auxiliary storage unit 104, and processes acquired data, thereby causing the evaluation device 10 to function.

[0083] The ROM 103 is configured by a mask ROM, PROM, EPROM, EEPROM, or the like, and stores computer programs executed by the processing unit 101 and data used therein. The processing unit 101 may be an MPU 101. The ROM 103 stores a boot program executed by the processing unit 101 when the evaluation device 10 is started up, as well as programs and settings related to the operation of the hardware of the evaluation device 10.

[0084] The main memory unit 102 is configured by a RAM (Random Access Memory) such as an SRAM or a DRAM. The main memory unit 102 is used to read out computer programs recorded in the ROM 103 and the auxiliary memory unit 104. The main memory unit 102 is also used as a working area when the processing unit 101 executes these computer programs.

[0085] The auxiliary storage unit 104 is configured by a hard disk, a semiconductor memory element such as a flash memory, an optical disk, etc. The auxiliary storage unit 104 stores an operation system 104a, an evaluation program 104b (described later), and a reference value database (DB) 104c that stores reference values. The evaluation program 104b works in cooperation with the operation system 104a to perform evaluation processing.

[0086] The communication I / F 105 is composed of a serial interface such as USB, IEEE1394, or RS-232C, a parallel interface such as SCSI, IDE, or IEEE1284, an analog interface including a D / A converter or an A / D converter, a network interface controller (NIC), etc. Under the control of the processing unit 101, the communication I / F 105 receives data from the analytical devices 5a, 5b or other external devices, and transmits or displays information stored or generated by the evaluation device 10 to the analytical devices 5a, 5b or externally as necessary. The communication I / F 105 may communicate with the analytical devices 5a, 5b or other external devices via a network.

[0087] The input I / F 106 is configured from, for example, a serial interface such as USB, IEEE1394, or RS-232C, a parallel interface such as SCSI, IDE, or IEEE1284, and an analog interface including a D / A converter or an A / D converter. The input I / F 106 accepts character input, clicks, voice input, etc. from the input unit 111. The accepted input content is stored in the main memory unit 102 or the auxiliary memory unit 104.

[0088] The input unit 111 is composed of a touch panel, a keyboard, a mouse, a pen tablet, a microphone, etc., and is used to input characters or voices to the evaluation device 10. The input unit 111 may be connected to the evaluation device 10 from outside, or may be integrated with the evaluation device 10.

[0089] The output I / F 107 is configured, for example, from an interface similar to the input I / F 106. The output I / F 107 outputs information generated by the processing unit 101 to the output unit 112. The output I / F 107 outputs information generated by the processing unit 101 and stored in the auxiliary storage unit 104 to the output unit 112.

[0090] The output unit 112 is composed of, for example, a display, a printer, etc., and displays the measurement results sent from the analysis devices 5a and 5b, various operation windows in the evaluation device 10, analysis results, etc.

[0091] The media I / F 108 reads, for example, application software stored in the storage medium 113. The read application software is stored in the main memory unit 102 or the auxiliary memory unit 104. The media I / F 108 also writes information generated by the processing unit 101 to the storage medium 113. The media I / F 108 writes information generated by the processing unit 101 and stored in the auxiliary memory unit 104 to the storage medium 113.

[0092] The storage medium 113 is configured with a flexible disk, a CD-ROM, a DVD-ROM, etc. 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, etc. The storage medium 113 may store application programs and the like for the computer to execute operations.

[0093] The processing unit 101 may acquire the evaluation program 104b and various settings necessary for controlling the evaluation device 10 via a network instead of reading them from the ROM 103 or the auxiliary storage unit 104. The application program may be stored in the auxiliary storage unit of a server computer on the network, and the evaluation device 10 may access this server computer to download the computer program and store it in the ROM 103 or the auxiliary storage unit 104.

[0094] An operating system that provides a graphical user interface environment, such as Windows (registered trademark) manufactured and sold by Microsoft Corporation, is installed in the ROM 103 or the auxiliary storage unit 104. The application program according to the second embodiment runs on the operating system. In other words, the evaluation device 10 may be a personal computer or the like.

[0095] The evaluation system 1000 does not need to be installed in one place, and the evaluation device 10 and the analysis devices 5a and 5b may be located in different places and connected via a network. Furthermore, the evaluation device 10 may be a device that does not require an operator by omitting the input unit 111 and the output unit 112.

[0096] The analytical device 5a is a device for measuring the amount or concentration of protein, and includes a sample storage area 51, a reaction section 52, and a detection section 53. The cell lysate placed in the sample storage area 51 is dispensed into a microplate on which an antigen capture antibody is immobilized and placed in the reaction section 52, and incubated. After removing unreacted antigens as needed, a detection antibody is dispensed into the microplate and incubated. After removing unreacted antigens as needed, a substrate for detecting the detection antibody is dispensed into the microplate, the microplate is moved to the detection section 53, and a signal generated by the reaction of the substrate is measured.

[0097] Another embodiment of the analytical device 5a is a device for measuring the expression level of mRNA by microarray analysis, in which the reverse transcription reaction product set in the sample storage area 51 is dispensed onto a microarray chip set in the reaction section 52, hybridization is performed, and after washing, it is moved to the detection section 53 and the signal is detected.

[0098] Another embodiment of the analytical device 5a is a device for measuring the expression level of mRNA by RT-PCR, in which a reverse transcription reaction product set in a sample storage area 51 is dispensed into a microtube set in a reaction section 52, and then quantitative PCR reagents are dispensed into the microtube. While the PCR reaction is carried out in the reaction section 52, a signal in the tube is detected in a detection section 53.

[0099] The analysis device 5b is a device for measuring the expression level of mRNA by the RNA-Seq method, and includes a sequence analysis unit 54. A sample that has undergone a reaction for RNA-Seq is set in the sequence analysis unit 54, and the base sequence is analyzed within the sequence analysis unit 54.

[0100] The analytical device 5b is a fully automated Western blotting device for measuring the amount of protein by Western blotting, and is equipped with a chemiluminescent signal detection unit 54. A sample of pancreatic tumor cells or pancreatic tumor tissue dissolved in a lysis buffer is placed in a predetermined position in the automated Western blotting device, and SDS-PAGE, blotting onto a membrane, antibody reaction, and chemiluminescence are performed, followed by analysis in the chemiluminescent signal detection unit 54 to quantify the signal intensity.

[0101] The analysis devices 5a and 5b are connected to the evaluation device 10 by wire or wirelessly. The analysis device 5a A / D converts the measurement value of the protein or the measurement value of the mRNA and transmits it as digital data to the evaluation device 10. Similarly, the analysis device 5b A / D converts the measurement value of the mRNA and transmits it as digital data to the evaluation device 10. This allows the evaluation device 10 to acquire the measurement value of the protein or the measurement value of the mRNA as digital data that can be processed by calculation.

[0102] 4-2. Evaluation program processing FIG. 3 shows an example of a flowchart of the processing executed by the evaluation program 104b.

[0103] When the operator inputs a processing start request from the input unit 111, the processing unit 101 of the evaluation device 10 starts processing for evaluating the effectiveness of a composition for treating cancer.

[0104] In step S11, the processing unit 101 acquires a CXCL12 score in a region of interest containing pancreatic tumor cells in tissue, which is input by the operator via the input unit 111. Alternatively, the analysis device 5a or 5b acquires the amount of CXCL12 protein or the amount of CXCL12 mRNA in pancreatic tumor cells collected from the subject, or a value reflecting these, as a CXCL12 measurement value. Alternatively, the operator may input via the input unit 111 whether CXCL12 expression is positive or negative (or whether CXCL12 is detected) by immunostaining or in situ hybridization, and the processing unit 101 acquires this input as a CXCL12 measurement value.

[0105] Next, in step S12, the processing unit 101 compares the reference value of the score of CXCL12 stored in the storage unit or the reference value of CXCL12 with the value acquired in step S11.

[0106] If the acquired score or value in step S13 is below the reference value, the processing unit 101 proceeds to step S14 (YES), determines that the composition for cancer treatment is effective, and outputs a label indicating the determination result to the output unit 112 (step S16). Alternatively, in step S16, it determines that conversion surgery is applicable, and outputs a label indicating that conversion surgery is applicable. Also, if the acquired score or value in step S13 is equal to or greater than the reference value, it proceeds to step S15 (NO), determines that the composition for cancer treatment is ineffective, and outputs a label indicating the determination result to the output unit 112 (step S16). Alternatively, in step S16, it determines that conversion surgery is not applicable, and outputs a label indicating that conversion surgery is not applicable.

[0107] A label indicating the effectiveness of a cancer therapeutic composition includes information indicating that "the cancer therapeutic composition is effective" or "the cancer therapeutic composition may be effective." A label indicating that a cancer therapeutic composition is ineffective includes information indicating that "the cancer therapeutic composition is ineffective" or "the cancer therapeutic composition may be ineffective."

[0108] A label indicating that conversion surgery is applicable includes information indicating "conversion surgery is effective" or "conversion surgery may be effective." A label indicating that conversion surgery is not applicable includes information indicating "conversion surgery is ineffective" or "conversion surgery may be ineffective." The information may be a mark such as an x, a circle, or an exclamation mark. For details of the reference values, comparison methods, and determination methods, the explanation in 2. above is incorporated herein by reference.

[0109] 5. Storage medium storing the program Furthermore, one embodiment of this embodiment relates to a program product, such as a storage medium, that stores the evaluation program 104b. That is, the computer program can be stored in a storage medium, such as a hard disk, a semiconductor memory device such as a flash memory, or an optical disk. The format of the program recorded on the storage medium is not limited as long as the evaluation device 10 can read the program. It is preferable that the recording on the storage medium be non-volatile. [Example]

[0110] The present disclosure will be described in more detail below by showing examples, but the present disclosure should not be construed as being limited to the examples. This study was conducted with the approval of the Ethics Committee of Kansai Medical University in accordance with the Declaration of Helsinki.

[0111] 1. Patient Selection Patients with pancreatic ductal adenocarcinoma with peritoneal dissemination who visited Kansai Medical University Hospital between January 2006 and December 2018 were included.

[0112] 2. Histological Examination Surgically excised tissue samples were fixed in formalin and prepared as histological specimens, which were then embedded in paraffin and thinly sectioned.

[0113] 3. Tissue Microarray For each patient, the tissue specimens were stained with hematoxylin and eosin and the area most morphologically characteristic of cancer was selected. Two tissue blocks (2 mm in diameter) were punched from the paraffin-embedded block. The punched tissue blocks were then embedded side-by-side in paraffin blocks and thinly sliced ​​to prepare tissue sections.

[0114] 4. Immunostaining Immunostaining was performed using an automated staining system (Discovery, Roche Diagnostics, Basel, Switzerland) according to the protocol provided with the system. Anti-SDF-1 rabbit polyclonal antibody (ab9797, Abcam) was used at a 1:1,000 dilution as the primary antibody for CXCL12 staining. Peroxidase-conjugated anti-rabbit immunoglobulin antibody was used as the secondary antibody, and diaminobenzidine (DAB) was used for color development. CXCL12 expression was determined as positive if a signal was present on the surface (cell membrane) of pancreatic tumor cells. Each section was scored according to the scoring method described in 2 above.

[0115] 5. Anticancer drug therapy The day of initiation of anticancer drug treatment was counted as day 1, and on days 1 and 8, 50 mg / m 2 , and 20 mg / m i.p. 2 At the same time, S-1 was administered at 80 mg / m from day 1. 2 The drug was administered orally at 100 mg / day for 14 consecutive days.

[0116] 6.Statistical analysis Statistical analyses were performed using JMP Start Statistics version 14 (Statistical Discovery Software; SAS Institute, Cary, NC, USA).

[0117] 7.Results This shows a box plot of CXCL12 scores for the group in which paclitaxel therapy was highly effective and conversion surgery was possible (CS group) and the group in which paclitaxel therapy was ineffective and conversion surgery was not possible (- group). All patients in the CS group had CXCL12 scores below 6. On the other hand, the CXCL12 scores in the - group tended to be higher than those in the CS group (P = 0.048).

[0118] These results indicated that paclitaxel-based compounds are effective against pancreatic tumor cells in patients with a CXCL12 score below 6. They also indicated that conversion surgery is applicable to these patients.

[0119] We also scored CXCR4 expression instead of CXCL12, and compared the scores between the group in which paclitaxel therapy was highly effective and conversion surgery was possible (CS group) and the group in which paclitaxel therapy was ineffective and conversion surgery was not possible (- group). The results are shown in Figure 5. Patients in the CS group had a CXCR4 score of 10 or higher. However, a significant difference between the two groups was P = 0.423, indicating no significant difference. [Explanation of symbols]

[0120] 101 Processing section 10 Evaluation equipment

Claims

1. detecting CXCL12 in a region of interest containing pancreatic tumor cells in tissue taken from the subject; A method for detecting an evaluation marker that reflects the efficacy of a cancer therapeutic composition in a pancreatic tumor patient with peritoneal dissemination, comprising: The method for detecting an evaluation marker, wherein the composition for cancer treatment contains a compound represented by the following general formula (I): 【Chemical 1】 (where, R １ represents a phenyl group which may have at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group on the phenyl ring. R ２ teeth, (2-1) a phenylcarbonyl group which may have, on the phenyl ring, at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group, or (2-2) Alkenylcarbonyl group having 2 to 6 carbon atoms in the alkenyl moiety represents an amino group which may have the following formula: R ３ , R ４ and R ５ are the same or different and represent a hydrogen atom or a hydroxyl group. R ６ , R ７ , R ８ , R ９ , R １０ and R １１ are the same or different and represent C1-3 linear alkyl groups.

2. The method further comprises a step of displaying a label indicating that the cancer therapeutic composition is effective when the score indicating the amount of CXCL12 present in the region of interest is equal to or less than a reference value, 2. The method for detecting an evaluation marker according to claim 1, wherein the score is obtained based on (1) the staining intensity of CXCL12 protein in the pancreatic tumor cells, and (2) the proportion of the number of pancreatic tumor cells that are positive for CXCL12 protein staining, when the number of pancreatic tumor cells is taken as 100%.

3. The method for detecting an evaluation marker according to claim 2 , further comprising the step of presenting a label indicating that conversion surgery is applicable when the score in the region of interest falls below a reference value.

4. The compound represented by the general formula (I) is paclitaxel. A method for detecting the evaluation marker according to any one of claims 1 to 3.

5. A composition for cancer treatment for use in a patient with pancreatic tumor having peritoneal dissemination, comprising a compound represented by the following general formula (I): The cancer therapeutic composition is used to be administered to a subject having a CXCL12 score equal to or lower than a reference value in a region of interest containing pancreatic tumor cells in tissue collected from the subject, the composition for cancer treatment, wherein the score is obtained based on (1) the staining intensity of CXCL12 in the pancreatic tumor cells, and (2) the proportion of the number of pancreatic tumor cells that are positive for CXCL12 staining, when the number of pancreatic tumor cells is taken as 100%: 【Chemistry 2】 (where, R １ represents a phenyl group which may have at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group on the phenyl ring. R ２ teeth, (2-1) a phenylcarbonyl group which may have, on the phenyl ring, at least one substituent selected from the group consisting of a C1-4 linear or branched alkyl group, a C1-4 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group, and a cyano group, or (2-2) Alkenylcarbonyl group having 2 to 6 carbon atoms in the alkenyl moiety represents an amino group which may have the following formula: R ３ , R ４ and R ５ are the same or different and represent a hydrogen atom or a hydroxyl group. R ６ , R ７ , R ８ , R ９ , R １０ and R １１ are the same or different and represent C1-3 linear alkyl groups.

6. The composition for cancer treatment according to claim 5, wherein the compound represented by general formula (I) is paclitaxel.

7. A method for using CXCL12 in pancreatic tumor cells in tissue collected from a subject as a marker for evaluating the effectiveness of a cancer therapeutic composition described in claim 5 or 6, wherein the subject has peritoneal dissemination of a pancreatic tumor.

8. An evaluation marker consisting of CXCL12 for evaluating the effectiveness of the cancer therapeutic composition according to claim 5 or 6 in a subject with peritoneal dissemination of a pancreatic tumor.

9. A detection reagent for detecting CXCL12 in pancreatic tumor cells in tissue collected from a subject as a marker for evaluating the effectiveness of the cancer therapeutic composition according to claim 5 or 6, wherein the detection reagent comprises an antibody for detecting CXCL12; wherein the subject has peritoneal dissemination of a pancreatic tumor. The detection reagent.

10. An apparatus for evaluating the effectiveness of a cancer therapeutic composition, comprising: The processing unit obtaining a CXCL12 score in a region of interest containing pancreatic tumor cells in tissue collected from the subject; The obtained score is compared with the standard value, outputting a label indicating that the composition for cancer treatment according to claim 5 or 6 is effective when the obtained score is below the reference value, and / or outputting a label indicating that conversion surgery is applicable when the obtained score is below the reference value; wherein the subject has peritoneal dissemination of a pancreatic tumor. The evaluation device.

Images