WO2016104777A1 - Procédé de traitement d'un cancer - Google Patents

Procédé de traitement d'un cancer Download PDF

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WO2016104777A1
WO2016104777A1 PCT/JP2015/086383 JP2015086383W WO2016104777A1 WO 2016104777 A1 WO2016104777 A1 WO 2016104777A1 JP 2015086383 W JP2015086383 W JP 2015086383W WO 2016104777 A1 WO2016104777 A1 WO 2016104777A1
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fbxw7
cancer
cells
mice
ccl2
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敬一 中山
功士 三森
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国立大学法人九州大学
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    • 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
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology

Definitions

  • the present invention relates to cancer treatment.
  • Metastasis is a major cause of death in cancer patients, and elucidation of the genes and mechanisms underlying this process is expected to provide the basis for the development of new cancer therapies. Because metastases are complex, including the detachment of cancer cells from the primary tumor, followed by infiltration of the cells into the surrounding tissue, entry into the circulatory system, and invasion and proliferation in distal organs, An understanding of these mechanisms remains unsatisfactory. In addition to genomic variation between malignant tumor cells, recent research has focused on the link between cancer and the host environment.
  • T cells B cells, granulocytes and monocytic bone marrow derived suppressor cells (G- and Mo-MDSC, respectively), macrophages, bone marrow derived stromal cells (BMSC), hematopoietic progenitor cells (HPC) and endothelial progenitor cells (EPC) Bone marrow derived cells (BMDC), including), play a central role in promoting metastasis, including promoting tumor cell growth and invasion and angiogenesis.
  • G- and Mo-MDSC monocytic bone marrow derived suppressor cells
  • macrophages macrophages
  • BMSC bone marrow derived stromal cells
  • HPC hematopoietic progenitor cells
  • EPC endothelial progenitor cells
  • BMDC bone marrow derived cells
  • Non-Patent Documents 1 and 2 Tumor cells and surrounding stromal cells secrete various growth factors, cytokines, and chemokines that promote cancer development.
  • Chemokines promote tumor development and progression in addition to recruitment of immune cells to the tumor site.
  • Chemokine CC motif ligand 2 (CCL2) [also known as monocyte chemotactic protein (MCP) -1], through its interaction with its receptor CCR2, monocytes, macrophages and other inflammatory cells The replenishment to the inflammatory site is controlled (Non-patent Document 3).
  • CCL2 also contributes to monocyte-macrophage recruitment to the site of lung metastases and then promotes tumor growth in breast cancer mice (4).
  • Systemic administration of neutralizing antibodies against CCL2 in mouse cancer models has resulted in marked attenuation of tumor growth, decreased tumor vessel density, and inhibition of metastasis (Non-Patent Documents 4-8).
  • Fbxw7 (also known as Fbw7, Sel-10, hCdc4, or hAgo) is the F box protein component of the SCF (Skp1-Cul1-F box protein) type ubiquitin ligase, in which ligase It functions as a receptor involved.
  • SCF Skp1-Cul1-F box protein
  • Most of the substrates of Fbxw7 are growth promoting factors, which include c-Myc (Non-Patent Documents 9 and 10), Notch (Non-Patent Documents 11 to 13), and Cyclin E (Non-patent Documents 14 to Non-Patent Documents).
  • Non-Patent Document 16 Analysis of FBXW7 in many primary human tumors revealed that ⁇ 6% of tumors have mutations in this gene (Non-Patent Document 22). Mutations were most frequently detected in cholangiocarcinoma (35%) and T cell acute lymphocytic leukemia (T-ALL, 31%). Of note, about half (43%) of the identified mutations are missense mutations that result in amino acid substitutions at key arginine residues (Arg 465 and Arg 479 ) within the WD40 domain involved in substrate recognition. It was found to be a mutation.
  • Fbxw7-null mice (Fbxw7 ⁇ / ⁇ / Apc min / + ) having a mutation in the colorectal adenomatous polyposis (APC) gene show an increase in both the number and size of intestinal tumors, compared to Apc min / + mice Resulted in decreased survival (Non-patent Document 26).
  • Chemokine (C-C motif) ligand 2 engages CCR2 + stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J Biol Chem. 2009; 284 (42): 2908796. Welcker M, et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci U S A. 2004; 101 (24): 9085-90. Yada M, et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J. 2004; 23 (10): 2116-25.
  • Fbxw7 is a potent tumor suppressor in mice and in humans.
  • the combined role of Fbxw7 in mice with conditional deletion of Fbxw7 in various tissues confirms the central role of Fbxw7 in suppressing tumor development in vivo.
  • Fbxw7 expression in the host environment is an important determinant of cancer metastasis.
  • metastasis was found to be enhanced in mice lacking Fbxw7 in the bone marrow compared to control mice.
  • deletion of Fbxw7 is the accumulation of Notch in bone marrow mesenchymal stromal cells (BMSC) and consequently the activity of CCL2 gene transcription Has occurred.
  • BMSC bone marrow mesenchymal stromal cells
  • CCL2 gene transcription Has occurred Increased production of CCL2 by these cells appeared to promote metastatic niche formation through Mo-MDSC and macrophage recruitment.
  • Inhibition of CCL2-CCR2 signaling reduced the frequency of metastasis in Fbxw7-deficient mice.
  • Our results therefore suggest that the Fbxw7-Notch-CCL2 pathway plays a central role in cancer metastasis control.
  • the present invention provides the following.
  • [1] A method for predicting the prognosis of cancer or for early detection of cancer, comprising a step of detecting the expression level of FBXW7 in a subject.
  • [2] A method for selecting a method for treating cancer in a cancer patient, comprising a step of detecting the expression level of FBXW7 in the cancer patient.
  • [3] The method according to 1 or 2, wherein the cancer is breast cancer.
  • the CCR2 antagonist has the following general formula (I) [(O 1/2 ) 3 Ge-A-COOH] n (I) (In the formula, n represents an integer of 100 to 1000, and A represents a lower alkylene group.) 6.
  • the pharmaceutical composition according to 8, wherein the cancer is breast cancer.
  • a CCR2 antagonist is represented by the following general formula (I): [(O 1/2 ) 3 Ge-A-COOH] n (I) (In the formula, n represents an integer of 100 to 1000, and A represents a lower alkylene group.) 11.
  • a method for selecting a patient to be treated with a pharmaceutical composition comprising a CCR2 antagonist comprising a step of detecting the FBXW7 gene or an expression product thereof.
  • the CCR2 antagonist has the following general formula (I) [(O 1/2 ) 3 Ge-A-COOH] n (I) (In the formula, n represents an integer of 100 to 1000, and A represents a lower alkylene group.) 16.
  • the present invention also provides the following.
  • a method for predicting a prognosis after administering an anticancer drug to a patient or for early detection of cancer comprising a step of detecting the expression level of FBXW7 in a cancer patient.
  • a method for determining whether or not to administer an anticancer agent to a patient comprising the step of detecting the expression level of FBXW7 in a cancer patient.
  • the method according to 1 or 2 wherein the cancer patient is a patient with breast cancer.
  • a CCR2 antagonist is represented by the following general formula (I): [(O 1/2 ) 3 Ge-A-COOH] n (I) (In the formula, n represents an integer of 100 to 1000, and A represents a lower alkylene group.) 6.
  • a custom-made medicine for the treatment of cancer wherein the presence or absence and / or the amount of at least one anticancer agent is adjusted according to the expression level of FBXW7 detected in cancer patients Product.
  • the anticancer agent is a pharmaceutical composition containing a CCR2 antagonist.
  • a CCR2 antagonist is represented by the following general formula (I): [(O 1/2 ) 3 Ge-A-COOH] n (I) (In the formula, n represents an integer of 100 to 1000, and A represents a lower alkylene group.) 11.
  • the product according to 10 which is a pharmaceutical composition comprising the organic acid polymer represented by the formula: [12] The product according to 11, wherein the organic acid polymer represented by the general formula (I) is propagermanium. [13] Use of the FBXW7 gene or an expression product thereof as a marker for predicting a prognosis after administration of an anticancer drug to a patient or for early detection of cancer. [14] The use according to 13, wherein the cancer patient is a patient with breast cancer. [15] The use according to any one of 12 to 14, wherein the anticancer agent is a pharmaceutical composition comprising a CCR2 antagonist.
  • a CCR2 antagonist is represented by the following general formula (I): [(O 1/2 ) 3 Ge-A-COOH] n (I) (In the formula, n represents an integer of 100 to 1000, and A represents a lower alkylene group.) 15.
  • Fbxw7 deletion in bone marrow (BM) promotes cancer metastasis in an intravenous tumor cell transplant model.
  • Gross lung findings (A) and occupancy with tumor colonies (B) were examined. Horizontal bars in B show mean values.
  • E Total tumor area
  • F number of tumor nodules
  • G tumor mean area
  • HJ WT mice were reconstituted with the mouse BM cells shown and with tdTomato labeled E0771 cells.
  • tumor cells and cell nuclei stained with Hoechst 33238
  • lungs were subjected to fluorescence microscopy (H)
  • the box plot in J shows the minimum, lower quartile, median, upper quadrant.
  • TCR (A), B220 (B), Ly6G (C), Ly6C (D), F4 / 80 (E), and FSP (F)
  • Representative immunohistofluorescence staining (left panel) is shown, intrinsic fluorescence of EGFP, tdTomato, and Hoechst 33258 was also imaged.
  • Be. Scale bar 100 [mu] m. In both peritumoral area and the non-peripheral region, to quantify the percentage of EGFP + BMDC positive for each marker (right panel).
  • * P ⁇ 0.05, *** P ⁇ 0.001 one-way ANOVA and Bonferroni test).
  • C Luciferase assay of CCL2 gene in BMSCs infected with NICD1, c-Myc, or KLF5 retroviruses.
  • D CAG-Cre-ER T2 / Fbxw7 ( / (Relative abundance of CCL2 mRNA in BMSC.
  • E WT and mutant schematics of mouse CCL2 gene promoter fused to firefly luciferase gene) The consensus binding sequence of Notch-RBP-J ⁇ is shown in bold.In G, the proximal and distal amplicons are shown.
  • Bone marrow cells, HPC, and EPC in the microenvironment of metastatic tumors in mouse lung reconstituted with Fbxw7-deficient bone marrow cells.
  • Representative immunohistofluorescence staining (left panel) for Mac1 (A), c-Kit (B), and VE-cadherin (C) is shown for lung sections from WT mice.
  • Serum was mixed with a biotinylated detection antibody cocktail and then incubated with panel A (ARY006) (A) and panel B (ARY015) (B). The array was then incubated with streptavidin labeled horseradish peroxidase and subjected to chemiluminescence based detection. Image J was used to quantify the optical density of cytokines in two different exposures of a representative array. Solid circles indicate points analyzed with respect to FIG. 4A. The average relative intensity in Panel A and Panel B is shown in FIG. 4A for CCL2, CCL3, CXCL1, CXCL10, CXCL12, GM-CSF, IL-1 ⁇ , IL-10, and TIMP-1.
  • the position of the capture antibody for each analyte is shown in the table on the right. Fbxw7 deficiency in bone marrow cells, T cells, or B cells does not affect the metastasis of intravenously injected B16F10 melanoma cells.
  • treatment includes diagnosis, prevention, treatment, suppression of progression, and suppression of metastasis, unless otherwise specified.
  • treatment includes diagnosis, prevention, treatment, suppression of progression, and suppression of metastasis, unless otherwise specified.
  • the present invention relates to a method for treating cancer, comprising a step of detecting the expression level of FBXW7 in a cancer patient.
  • Cancer treatment methods include diagnostic methods (including companion diagnostic methods), early detection methods, prognosis prediction methods, cancer metastasis suppression methods, treatment methods (including individual treatment methods), and the like.
  • the present invention relates to a prognosis of cancer comprising the step of detecting the expression level of FBXW7 (F-box / WD repeat-containing protein 7, also known as Fbw7, Sel-10, hCdc4, or hAgo) in a subject.
  • a method for selecting a method for treating cancer in a cancer patient comprising: a method for predicting cancer, or for early detection of cancer, and detecting the expression level of FBXW7 in the cancer patient provide.
  • Fbxw7 is a molecule with many mutations found in cancer.
  • the present inventors examined the blood cells of breast cancer patients and found that people with low expression levels of Fbxw7 tend to relapse cancer. It was also found that when a gene is artificially disrupted in a mouse, metastasis of cancer cells is likely to occur.
  • CCL2 chemokine CC motif ligand 2. also known as monocyte chemotactic protein (MCP) -1
  • MCP monocyte chemotactic protein
  • the expression level of Fbxw7 refers to the amount of mRNA, which is a transcription product from the FBXW7 gene, or a polypeptide, which is its translation product, unless otherwise specified. The amount may be expressed as a concentration. Expression can occur in cancer cells, in a niche, or in peripheral blood. According to the study by the present inventors, in the present invention, the expression level of Fbxw7 in a niche or peripheral blood can be used as an index. In a particularly preferred embodiment, the expression level of Fbxw7 in peripheral blood is used as an index. And
  • Whether the expression level of Fbxw7 is low or high may be determined by setting a standard in advance and comparing it with the standard.
  • the standard can be, for example, a median value obtained from statistical data of FBXW7 expression levels of a plurality of cancer patients.
  • the expression level of a protein that is constitutively expressed for example, Glyceraldehyde (3-phosphate dehydrogenase, GAPDH) may be determined as a relative amount.
  • the reference may be a value based on a quantitative ratio with a constitutively expressed protein.
  • the expression level of Fbxw7 when it is referred to as low FBXW7 expression, unless otherwise specified, when the expression level of Fbxw7 is 1 or less with respect to the expression level of GAPDH, it is preferably 0.7 or less More preferably, it is when it is 0.5 or less.
  • selection of cancer treatment method for cancer patients In the method for selecting a cancer treatment method in a specific cancer patient of the present invention, for example, administration of a pharmaceutical composition containing a CCR2 antagonist is selected as the treatment method.
  • CCR2 antagonists include CCR2 antagonists, CCR2 antagonists, CCR2 antagonists, CCR2 blockers, CCR2 blockers, MCP-1 receptor antagonists, MCP-1 receptor antagonists (JP 2000-136139 A), MCP- 1 receptor antagonist, MCP-1 receptor blocker, MCP-1 receptor blocker, etc.
  • a CCR antagonist binds to CCR2 or inhibits binding of CCR to a ligand of CCR2, and thereby inhibits the biological function of CCR2.
  • Antagonists include antibodies, synthetic or native sequence peptides, and small molecule antagonists.
  • antagonists are those that bind to the receptor (eg, antibodies, natural ligand variants, small molecular weight organic molecules, other competitive inhibitors of ligand binding), and receptor function without binding to the receptor. It refers to a substance that includes an inhibitory substance (eg, an anti-idiotype antibody).
  • CCR2 antagonist examples include the following general formula (I) [(O 1/2 ) 3 Ge-A-COOH] n (I) (Wherein n represents an integer of 100 to 1000, and A represents a lower alkylene group) It is an organic acid polymer shown by.
  • the lower alkylene group of A is preferably a lower alkylene group having 1 to 3 carbon atoms.
  • Particularly preferred is a 3-oxygermylpropionic acid polymer in which A is an ethylene group.
  • n representing the degree of polymerization is preferably an integer of 200 to 900.
  • the 3-oxygermylpropionic acid polymer a 3-oxygermylpropionic acid polymer having a polymerization degree n of 200 to 900 is well known. Its three-dimensional structure is
  • R represents —CH 2 CH 2 COOH
  • m represents a weight average degree of polymerization converted from the weight average molecular weight of the 3-oxygermylpropionic acid propyl ester polymer, 137 ⁇ 84 (average ⁇ standard
  • the minimum structural unit is (O 1/2 ) 3 GeCH 2 CH 2 COOH, and the empirical formula is C 6 H 10 Ge 2 O 7 , Presumed to be a structure.
  • the 3-oxygermylpropionic acid polymer can be produced by the method described in JP-A-2003-81843. Further, in JP-A-2003-81843, the 3-oxygermylpropionic acid polymer is described as having physical property values shown in Tables 1 and 2 below. Table 1 shows the results of molecular weight measurement by the light scattering method, and Table 2 shows the lattice constants determined by powder X-ray analysis.
  • a 3-oxygermylpropionic acid polymer can be specified as a compound having the following physical property values from FIGS. 1 to 3 of JP-A No. 54-115324. That is, there is a large diffraction peak around 6.5 °, and relatively large diffraction peaks around 11.6 °, 13.8 °, 18.4 °, 21.2 °, and 22.4 °. A characteristic powder X-ray diffraction spectrum is shown.
  • IR infrared absorption
  • a relatively large absorption band 560cm -1, 705cm -1, 760cm -1 , 780cm -1 , 1250 cm ⁇ 1 , 1350 cm ⁇ 1 , and 1400 cm ⁇ 1 are present in the vicinity (however, the absorption band near 1400 cm ⁇ 1 is a doublet).
  • a preferred embodiment of the 3-oxygermylpropionic acid polymer has the following general formula (II) (C 3 H 5 GeO 3.5 ) n (II) (In the formula, n represents a weight average degree of polymerization of 548 ⁇ 337.) And 3-oxygermylpropionic acid polymer having a weight average molecular weight of 9.29 ⁇ 10 4 ⁇ 5.72 ⁇ 10 4 (average value ⁇ standard error).
  • the 3-oxygermylpropionic acid polymer may be referred to as propagermanium, bis (2-carboxyethylgermanium) sesquioxide, or 2-carboxyethylgermane sesquioxide.
  • the pharmaceutical composition containing a CCR2 antagonist may optionally contain formulation adjuvants such as pharmaceutically acceptable excipients, carriers and diluents.
  • the pharmaceutical composition is in accordance with conventional methods, tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops. It can be in a dosage form such as a patch, ointment or injection, and can be administered orally or parenterally. Preferably it is administered orally.
  • the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. For example, for an adult, 1 to 1000 mg / day, preferably 10 to 500 mg / day may be divided into 1 to several times by oral administration. When administration is combined with surgery, it can be performed before that, for example, 1 day to several weeks before surgery.
  • a pharmaceutical composition comprising a CCR2 antagonist can be performed in combination with other therapies for the treatment of cancer, such as surgery, chemotherapy, and / or radiation therapy.
  • anticancer agents that can be used in combination are not particularly limited as long as the desired effect is obtained.
  • alkylating agents, platinum compounds, antimetabolites, topoisomerase inhibitors, microtubule inhibitors, Any of antibiotics, hormone agents, antibodies and the like may be used. More specific examples include gemcitabine, tegafur uracil, and fluorouracil.
  • a pharmaceutical composition comprising a CCR2 antagonist can be for the treatment of cancer in a cancer patient with low FBXW7 expression.
  • it is preferably used for the treatment of cancer in cancer patients with low FBXW7 expression, and more preferably used for the treatment of triple negative breast cancer in cancer patients with low FBXW7 expression.
  • the present invention provides the use of the FBXW7 gene or its expression product as a marker for predicting the prognosis of cancer or for early detection of cancer.
  • the present invention is intended for those who are in a disease or condition associated with FBXW7 expression levels or associated with suppression of cancer niche formation, a cancer patient, or a person who may have cancer, Can be used to predict whether or not to benefit from treatment with the above-described pharmaceutical composition) and to predict the response or prognosis of the subject receiving / receiving the drug treatment.
  • the present invention can be used for selection of a patient to be treated with a specific drug (for example, the above-described pharmaceutical composition) including a step of detecting the FBXW7 gene or an expression product thereof. That is, according to the present invention, a patient can be selected for treatment of a specific drug (for example, the above-described pharmaceutical composition). As such, the present invention provides for the use of certain drugs in novel indications. For example, the present invention proposes the use of the above-described pharmaceutical composition for the treatment of cancer in cancer patients with low expression levels of FBXW7.
  • a specific drug for example, the above-described pharmaceutical composition
  • Cancers to which the present invention can be applied include various solid cancers.
  • solid cancers are pancreatic cancer, glioblastoma, esophageal cancer, stomach cancer, colon cancer, lung cancer, kidney cancer, thyroid cancer, parotid gland cancer, head and neck cancer, bone / soft tissue sarcoma Ureteral cancer, bladder cancer, uterine cancer, liver cancer, breast cancer, prostate cancer, ovarian cancer, fallopian tube cancer and the like.
  • the diseases listed here are exemplifications, and in addition to these, the effects of the present invention can be expected for various cancers related to the expression level of FBXW7 or related to suppression of cancer niche formation.
  • cancers for which the effect of the present application can be particularly expected are breast cancer, melanoma, and lung cancer, preferably breast cancer.
  • Breast cancer mainly includes three types of hormone receptor positive breast cancer, HER2 positive breast cancer, and triple negative breast cancer. Of these, hormone therapy is used for hormone receptor-positive breast cancer and Herceptin is used for HER2-positive breast cancer, which is very effective. However, a definitive treatment for triple-negative breast cancer has been established. There wasn't. The present inventors have found that patients with higher malignancy can be selected among triple negative breast cancers by measuring the expression level of Fbxw7 in blood cells. In addition, for the patient thus selected, the present invention proposes administration of a pharmaceutical composition containing, for example, a CCR2 antagonist.
  • the present invention also provides a companion diagnostic method and a diagnostic product, and a companion for a person having a disease or condition associated with the expression level of FBXW7, a cancer patient, or a person who may have cancer
  • a companion diagnostic method and a diagnostic product for a person having a disease or condition associated with the expression level of FBXW7, a cancer patient, or a person who may have cancer
  • products for use in personalized therapy custom-made therapy
  • Products for diagnosis are, for example, probes, probe and primer sets, kits, and the like.
  • Products for use in personalized therapy (custom-made therapy) include a specific drug (for example, the above-described pharmaceutical composition) as a result of companion diagnosis, and the drug is effective. If not, the drug is not included.
  • a product can be a combination of multiple drugs.
  • Fbxw7 F / F mice are also RbpJ ⁇ F / F (44) or c-Myc F / F (45) mice, or Lck-Cre (46), LysM-Cre (47), CD19-Cre (48), CAG -Cre-ER T2 (49) or CAG-EGFP (50) transgenic mice were also crossed.
  • C57BL / 6 or other recipient mice (8 weeks old) are irradiated with a lethal dose (11 Gy) of gamma radiation and through the tail vein, 8 weeks old CAG-EGFP, CAG-EGFP / Fbxw7 F / F , or BM cells (2.0 ⁇ 10 6 in 100 ⁇ l phosphate buffered saline) isolated from CAg-EGFP / Mx1-Cre / Fbxw7 F / F mice were injected.
  • BM cells 2.0 ⁇ 10 6 in 100 ⁇ l phosphate buffered saline
  • recipients Two months after transplantation, recipients were injected with poly (I: C) as described above to delete the loxP-introduced Fbxw7 allele, and 3 days after the last poly (I: C) injection, they were B16F10, LLC, or E0771 cells were injected as described below.
  • the peripheral blood cells of the recipients were examined for chimerism by flow cytometry.
  • Tumor volume (mm 3 ) is measured using calipers and calculated as (W 2 ⁇ L) / 2, where W is the width and L is the length.
  • B16F10 (provided by Tohoku University Cell Resource Center), LLC (provided by Tohoku University Cell Resource Center), B16F1 (donated by Kyushu University, S. Okano), and E0771 cells (purchased from CH3 BioSystems) 10% fetal bovine serum (Invitrogen) in RPMI 1640 medium (Sigma) supplemented with 1 mM sodium pyruvate, penicillin (100 U / ml), streptomycin (100 ⁇ g / ml), 2 mM L-glutamine, and non-essential amino acids (10 ml / l, Gibco). Maintained.
  • BMSCs were isolated from BM collected from the tibia and femur of 8-10 week old mice and these were isolated from 10% fetal calf serum, 10% horse serum, 2 mM L-glutamine, penicillin (100 U / ml), And cultured in RPMI 1640 medium supplemented with streptomycin (100 ⁇ g / ml). After 24 hours, non-adherent cells were removed and adherent cells were maintained with medium replenishment every 3 days. In order to delete the loxP-introduced Fbxw7 allele, BMSCs were treated with 10 ⁇ M tamoxifen (Sigma) for 2 days. They were also treated with DAPT (Calbiochem) for 2 days to inhibit Notch signaling.
  • MEFs were prepared and maintained from embryos at embryonic stage 13.5 (51) and these were treated with 2 ⁇ M tamoxifen (Sigma) to delete the loxP-introduced Fbxw7 allele. Treated for 2 days.
  • erythrocytes were lysed with hemolysis buffer (0.14M NH 4 Cl and 0.01M Tris-HCl, pH 7.5) and an antibody against F4 / 80 (BM8, eBioscience), The remaining cells were stained with an antibody against CD115 (AFS98, eBioscience), an antibody against Mac1 (M1 / 70, eBioscience), an antibody against Ly6G (1A8, BD Biosciences), and an antibody against Ly6C (AL-21, BD Biosciences). Stained cells were analyzed on a FACSCalibur flow cytometer (Becton Dickinson).
  • the tissue was fixed with 4% paraformaldehyde in 0.1M phosphate buffer, embedded in 30% sucrose overnight, and cryostated as described above. Sectioned at 15 ⁇ m thickness and stained (52).
  • Antibodies against TCR ⁇ H57-597
  • antibodies against B220 RA3-6B2
  • antibodies against Mac1 M1 / 70
  • antibodies against c-Kit (2B8) were obtained from eBioscience; against Ly6C (AL-21) For Ly6G (1A8) and for VE-cadherin (11D4.1) from BD Biosciences; for F4 / 80 (A3-1) from Sertec; and for FSP (D9F9D) Obtained from Cell Signaling Technology.
  • Immune complexes were detected with secondary antibodies labeled with 1: 2000 dilutions of Alexa 633 or Alexa 405 (Molecular Probes), respectively. Sections were mounted in Fluoromount (Diagnostic BioSystems) and examined with a laser scanning confocal microscope (LSM700, Carl Zeiss).
  • Lysis buffer [50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.5% Triton X-100, 10 mM NaF, 10 mM Na 4 P 2 O 7 , 0.4 mM Na 3 VO 4 , 0.4 mM EDTA, Total protein extract was prepared from BMSC using leupeptin (20 ⁇ g / ml), aprotinin (10 ⁇ g / ml), 1 mM phenylmethylsulfonyl fluoride]. The extract (20 ⁇ g protein) was subjected to immunoblot analysis as previously described (53).
  • Antibodies against Notch3 M-20 and antibodies against KLF5 (BTEB2, H-300) were obtained from Santa Cruz Biotechnology; one against cleaved Notch1 (D1E11), one against Notch2 (D76A6), one against c-Jun (60A8) , For p100-p52 (catalog number 4882), and for mTOR (7C10) are from Cell Signaling Technology; for c-Myc are from Abcam; and glyceraldehyde-3-phosphate dehydrogenase ( For GAPDH, loading control) was from BD Biosciences.
  • Retrovirus expression system Complementary DNA encoding hemagglutinin epitope-tagged mouse NICD1, mouse c-Myc, mouse KLF5, or FLAG epitope-tagged Fbxw7 ⁇ (or its ⁇ F mutant) was donated by pMX-puro (University of Tokyo, T. Kitamura) ) And the resulting vector was used to transfect Plat E cells (54), thereby producing recombinant retroviruses.
  • BMSCs were infected with recombinant retrovirus and subjected to selection in medium containing puromycin (10 ⁇ g / ml). Cells stably expressing each recombinant protein were pooled for experiments.
  • RNAi 1.10 RNAi.
  • shRNA vector construction and RNAi were performed as previously described (55).
  • the sequence targeting mouse CCL2 was 5'-GGTTATTCCCTTTCATGAATAC-3 '(SEQ ID NO: 1).
  • An EGFP RNAi vector was used as a control.
  • RT and real-time PCR analysis Total RNA (1 ⁇ g) isolated from mouse cells using Isogen (Nippon Gene) was subjected to reverse transcription (RT) using QuantTect reverse transcription kit (Qiagen), and the resulting cDNA was transferred to the StepOnePlus real-time PCR system (Applied). Biosystems) was subjected to real-time PCR analysis using SYBR green PCR master mix and specific primers.
  • sequences of the PCR primers are 5′-CAGCAGCAGGTGTCCCCAAAG-3 ′ (SEQ ID NO: 2) and 5′-TGTCTGGACCCATTCCTTCTG-3 ′ (SEQ ID NO: 3), and Rps18 for CCL2.
  • 5′-GAGGACCTGGAGAGGCTGAAG-3 ′ SEQ ID NO: 4
  • 5′-CTGCGGCAGTGGTCTTG-3 ′ SEQ ID NO: 5
  • the amount of CCL2 mRNA was normalized by the amount of Rps18 mRNA.
  • RNA 2.7 ⁇ g isolated from cells using Isogen-LS (Nippon Gene) was subjected to RT using Moloney leukemia virus reverse transcriptase (BRL) and the resulting cDNA was , Subjected to real-time PCR using SYBR-green I dye and specific primers in the LightCycler system (Roche Applied Science).
  • sequences of the PCR primers are 5′-CCTCCAGGAATGGCTAAAA-3 ′ (SEQ ID NO: 6) and 5′-AAGAGTTCATCATAAGCAAGCAA-3 ′ (SEQ ID NO: 7) for Fbxw7, and GAPDH
  • 5′-AGCCACATCGCTCAGACAC-3 ′ SEQ ID NO: 8
  • 5′-GCCCAATACGACCAAATCC-3 ′ SEQ ID NO: 9
  • the amount of Fbxw7 mRNA was normalized by the amount of GAPDH mRNA.
  • Luciferase reporter assay 1.12 Luciferase reporter assay.
  • the promoter region of the mouse CCL2 gene and deletion mutants thereof were subcloned into pGL2-Basic (Promega) encoding firefly luciferase.
  • FuGENE HD reagent Promega
  • BMSCs were transfected 24 hours before transfection with the promoter construct for Renilla luciferase (0.25 ⁇ g) and the internal control vector pRL-TK (0.25 ⁇ g, Promega). Planted at a density of 2 ⁇ 10 4 per well in a 24-well plate.
  • luciferase activity was measured using a dual luciferase reporter assay system (Promega) and a Lumat LB9507 luminometer (EG & G Berthold). Firefly luciferase activity was normalized by that of Renilla luciferase.
  • Nucleosomes were incubated with 2 ⁇ g of antibody against Notch1 (C-20, Santa Cruz Biotechnology) conjugated to 20 ⁇ l of Dynabeads-Protein G (Veritas, Japan) at 4 ° C. for 6 hours. The immunoprecipitated material was washed, the chromatin was eluted and the cross-linking was reversed. DNA fragments were purified by phenol-chloroform extraction followed by precipitation with isopropanol, and these were then used as templates for real-time PCR analysis using the SYBR select PCR system (Applied Biosystems).
  • sequences of the PCR primers are 5′-GCTCACATCCAGCTAAATACTCT-3 ′ (SEQ ID NO: 10) and 5′-GAGTATTGTTCGTTTCCCTCTCA-3 ′ (SEQ ID NO: 11) for CCL2 (distal) And for CCL2 (proximal), 5'-TTACTGGGGGTCCTTTCCCA-3 '(SEQ ID NO: 12) and 5'-GGAGTGGCTCTGCTTTCACT-3' (SEQ ID NO: 13).
  • the degree of chromatin concentration was normalized by the input.
  • T cell receptor ⁇ for T cells (FIG. 3A), B220 for B cells (FIG. 3B), Ly6G for G-MDSC (FIG. 3C), Ly6C for Mo-MDSC (FIG. 3D), for monocyte-macrophages F4 / 80 (FIG. 3E), fibroblast specific protein (FSP) for stromal cells (FIG. 3F), Mac1 for bone marrow cells (FIG. 11A), c-Kit for HPC (FIG.
  • CCL2 and CCL12 induce monocyte-macrophage migration by binding to the common receptor CCR2.
  • CCL12 is secreted mainly from macrophages, but disappearance of Fbxw7 in these cells of LysM-Cre / Fbxw7 F / F mice has no effect on metastasis frequency (FIGS. 13, A and B). It was suggested that it is not greatly involved in the promotion of metastasis. We have therefore concentrated on CCL2 and found that the serum concentration of CCL2 is greater in Mx1-Cre / Fbxw7 ⁇ / ⁇ mice than in control mice, both before and after transplantation of E0771 cells. (FIG. 4B).
  • the CCL2 gene is activated in Fbxw7-deficient BMSCs.
  • Fbxw7-deficient BMSCs We next examined which cells of BM are responsible for promoting metastasis and increasing CCL2 serum levels in Fbxw7-deficient mice.
  • the abundance of CCL2 mRNA was increased in CAG-Cre-ER T2 / Fbxw7 ⁇ / ⁇ BMSC compared to control cells (FIG. 5C).
  • the amount of CCL2 released from the CAG-Cre-ER T2 / Fbxw7 ⁇ / ⁇ BMSC into the medium was also substantially higher than that released from the control cells (FIG. 5D).
  • WT Fbxw7 ⁇ cDNA is introduced into CAG-Cre-ER T2 / Fbxw7 ⁇ / ⁇ BMSC
  • the abundance of CCL2 mRNA is significantly reduced, while a mutant ( ⁇ F) cDNA of Fbxw7 ⁇ lacking the F box domain is generated. There was no such effect when introduced (FIG. 5E), suggesting that Fbxw7 negatively regulates CCL2 production in BMSC.
  • BMSCs small hairpin RNA (shRNA) -mediated RNA interference (RNAi).
  • shRNA small hairpin RNA
  • RNAi RNA interference
  • -ER T2 / Fbxw7 ⁇ / ⁇ BCL was depleted of CCL2 (FIG. 5F) and these cells were then transferred into the recipient mice through the tail vein along with B16F10 melanoma cells.
  • BMSC has been shown to be detected in many tissues such as bone marrow and lung even after 4 months of transplantation (33).
  • the degree of lung metastasis in recipient mice was increased by co-infusion of melanoma cells and Fbxw7 ⁇ / ⁇ BMSC compared to that seen after co-infusion of control BMSC (FIGS. 5, G and H).
  • Fbxw7 deletion was abolished by CCL2 depletion in BMSC, suggesting that increased CCL2 production by Fbxw7-deficient BMSC contributed to the promotion of metastasis.
  • Notch accumulation in Fbxw7-deficient BMSCs promotes metastasis by increasing CCL2 production.
  • Immunoblot analysis revealed that, among the Fbxw7 substrates examined, Notch1 intracellular domain (NICD1), c-Myc, and KLF5 accumulate at high levels in Fbxw7-deficient BMSCs (FIG. 6A).
  • Notch1 intracellular domain NICD1
  • c-Myc c-Myc
  • FIG. 7F Immunohistochemical analysis of Fbxw7 in primary tumor lesions
  • FIG. 7G shows that the abundance of Fbxw7 mRNA in peripheral blood is not significantly correlated with Fbxw7 expression in tumor cells (FIG. 7G), but surrounding stromal cells was found to be highly correlated with (Fig. 7H).
  • FIG. 7I shows that the abundance of Fbxw7 mRNA in peripheral blood is a marker of Fbxw7 expression in stromal cells surrounding tumor cells.
  • the inventors have also found that a negative correlation is apparent between the abundance of Fbxw7 mRNA in peripheral blood (FIG. 7I).
  • High serum levels of CCL2 correlate with poor prognosis in breast cancer patients (SA and KM, unpublished data).
  • the Fbxw7 gene is due to a number of corresponding mutations associated with human cancer (noted 22), as well as tumor formation observed in conditional knockout mice (noted 23, 24, 26). ) As demonstrated, it is a powerful tumor suppressor.
  • the anti-cancer function of Fbxw7 is a growth-promoting oncoprotein such as c-Myc (Non-Patent Documents 9 and 10), Notch (Non-Patent Documents 11, 12, and 35), Cyclin E (Non-Patent Documents).
  • CCL2 is thought to be secreted from both cancer cells and non-cancer cells in the tumor environment.
  • administration of an antibody specific for human CCL2 or an antibody specific for mouse CCL2 inhibits tumor growth and metastasis and is secreted from both the tumor and host environment.
  • CCL2 plays an important role in tumor development (Non-Patent Documents 4 and 6).
  • the Fbxw7-Notch1-CCL2 axis in cancer cells also appears to play an important role in metastasis.
  • FBXW7 expression levels in peripheral blood are associated with prognosis in breast cancer patients.
  • CXCL13 also known as trigger receptor 1, expressed on bone marrow cells, TREM-1
  • CXCL2 epidermal growth factor
  • platelet derived growth factor-AA Suggests an effect on tumor growth. Serum levels of these proteins increased or decreased more than 2-fold in Mx1-Cre / Fbxw7 ⁇ / ⁇ mice after E0771 cell transplantation compared to controls. Further studies are needed to elucidate the molecular mechanisms responsible for increased tumor cell engraftment in Fbxw7-deficient mice.
  • chemokines such as CCL2 in Fbxw7-deficient mice.
  • BMSC may be a major source of CCL2 production, the possible contribution of other BMDCs cannot be excluded.
  • CCL2 produced from other cell types such as fibroblasts, endothelial cells, and smooth muscle cells is also thought to promote cancer metastasis (39-42).
  • Fbxw7 and Notch as upstream regulators of CCL2 expression, thereby providing both important insights into the mechanisms by which this chemokine production is controlled, as well as the development of new strategies for cancer treatment. Provided.
  • SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction.Nature. 2011; 471 (7336): 104-9. 37. Wertz IE, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011; 471 (7336): 110-4. 38. Balamurugan K, et al. The tumour suppressor C / EBP ⁇ inhibits FBXW7 expr ession and promotes mammary tumour metastasis.EMBO J. 2010; 29 (24): 4106-17. 39. Cushing SD, et al.
  • Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells.Proc Natl Acad Sci U S A. 1990; 87 (13): 5134-8. 40. Standiford TJ, Kunkel SL, Phan SH, Rollins BJ, Strieter RM.Alveolar macrophage-derived cytokines induce monocyte chemoattractant protein-1 expression from human pulmonary type II-like epithelial cells.J Biol Chem. 1991; 266 (15): 9912-8. 41. Lu Y, et al.
  • Kamura T et al. Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. Proc Natl Acad Sci U S A. 2003; 100 (18): 10231-6. 54. Morita S, Kojima T, Kitamura T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 2000; 7 (12): 1063-6. 55. Kamura T, et al. Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27Kip1 at G1 phase. Nat Cell Biol. 2004; 6 (12): 1229-35.

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Abstract

L'invention concerne un procédé permettant de prédire le pronostic d'un cancer ou de détecter précocement un cancer, le procédé comprenant une étape de détection du niveau d'expression de FBXW7 chez un sujet, et une méthode de sélection d'un procédé de traitement du cancer pour un patient atteint d'un cancer, le procédé comprenant une étape de détection du niveau d'expression de FBXW7 chez ledit patient atteint de cancer. Des sujets adaptés au procédé de traitement du cancer reçoivent une composition pharmaceutique contenant du propagermanium. L'invention concerne également une composition pharmaceutique contenant un antagoniste de CCR2 pour traiter le cancer chez un patient ayant une faible expression de FBXW7 et un procédé pour sélectionner des patients destinés à servir de sujets à des fins de traitement par une composition pharmaceutique contenant un antagoniste de CCR2, le procédé comprenant une étape de détection du gène FBXW7 ou d'un produit d'expression de celui-ci.
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WO2018174053A1 (fr) * 2017-03-22 2018-09-27 学校法人兵庫医科大学 Médicament destiné au traitement de patients victimes d'une rechute de cancer ou d'un cancer évolué n'autorisant pas de résection thérapeutique, et ne réagissant pas ou intolérants à une chimiothérapie normale
WO2020213665A1 (fr) * 2019-04-17 2020-10-22 国立大学法人広島大学 Agent thérapeutique pour cancer urologique caractérisé en ce qu'il est administré avec un inhibiteur de il-6 et un inhibiteur de ccr2 en combinaison
US11692037B2 (en) 2017-10-20 2023-07-04 Hyogo College Of Medicine Anti-IL-6 receptor antibody-containing medicinal composition for preventing post-surgical adhesion
US11851486B2 (en) 2017-05-02 2023-12-26 National Center Of Neurology And Psychiatry Method for predicting and evaluating therapeutic effect in diseases related to IL-6 and neutrophils
JP7479404B2 (ja) 2019-06-19 2024-05-08 インターナショナル・ビジネス・マシーンズ・コーポレーション 低温デバイスの熱化のための極低温包装

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WO2018174053A1 (fr) * 2017-03-22 2018-09-27 学校法人兵庫医科大学 Médicament destiné au traitement de patients victimes d'une rechute de cancer ou d'un cancer évolué n'autorisant pas de résection thérapeutique, et ne réagissant pas ou intolérants à une chimiothérapie normale
US11851486B2 (en) 2017-05-02 2023-12-26 National Center Of Neurology And Psychiatry Method for predicting and evaluating therapeutic effect in diseases related to IL-6 and neutrophils
US11692037B2 (en) 2017-10-20 2023-07-04 Hyogo College Of Medicine Anti-IL-6 receptor antibody-containing medicinal composition for preventing post-surgical adhesion
WO2020213665A1 (fr) * 2019-04-17 2020-10-22 国立大学法人広島大学 Agent thérapeutique pour cancer urologique caractérisé en ce qu'il est administré avec un inhibiteur de il-6 et un inhibiteur de ccr2 en combinaison
CN114072173A (zh) * 2019-04-17 2022-02-18 国立大学法人广岛大学 以联合施用il-6抑制剂和ccr2抑制剂为特征的泌尿系统癌症治疗剂
JP7501876B2 (ja) 2019-04-17 2024-06-18 国立大学法人広島大学 Ｉｌ－６阻害剤及びｃｃｒ２阻害剤を組み合わせて投与することを特徴とする泌尿器がんの治療剤
JP7479404B2 (ja) 2019-06-19 2024-05-08 インターナショナル・ビジネス・マシーンズ・コーポレーション 低温デバイスの熱化のための極低温包装

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