WO2021075559A1 - Inhibiteur de croissance cellulaire ou inducteur de mort cellulaire pour fibroblastes associés au cancer - Google Patents

Inhibiteur de croissance cellulaire ou inducteur de mort cellulaire pour fibroblastes associés au cancer Download PDF

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WO2021075559A1
WO2021075559A1 PCT/JP2020/039145 JP2020039145W WO2021075559A1 WO 2021075559 A1 WO2021075559 A1 WO 2021075559A1 JP 2020039145 W JP2020039145 W JP 2020039145W WO 2021075559 A1 WO2021075559 A1 WO 2021075559A1
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foxo1
cafs
cancer
inhibitor
antibody
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Japanese (ja)
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義弘 目澤
拓洋 小山
朗 片倉
彰 折茂
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学校法人順天堂
学校法人東京歯科大学
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a cell growth inhibitor or cell death inducer of cancer-related fibroblasts (Carcinoma-Associated Fibroblasts; CAFs) or activated fibroblasts.
  • cancer-related fibroblasts Carcinoma-Associated Fibroblasts; CAFs
  • activated fibroblasts Carcinoma-Associated Fibroblasts
  • Cancer-related fibroblasts are cancer-promoting activated fibroblasts that are rich in ⁇ -smooth muscle actin ( ⁇ -SMA) -positive myofibroblasts.
  • ⁇ -SMA smooth muscle actin
  • the present inventor has previously shown that CAFs constitutively activate the autocline signals of TGF- ⁇ and SDF-1 during cancer progression and maintain their cancer-promoting activated fibroblast potential. (Non-Patent Document 1).
  • FOXO1 forkheadbox protein O1
  • PDX1 pancreatic and duodenal homeobox 1
  • neurogenin 3 the regulation of NeuroD and MafA.
  • Non-Patent Document 2 It has also been reported that FOXO1 is recruited to the TGF- ⁇ -Smad complex and contributes to transcriptional regulation.
  • AS1842856 is known to have a therapeutic effect on myelogenous leukemia, but AS1708727 is known not to have a therapeutic effect on myelogenous leukemia (Patent Document 1).
  • An object of the present invention is to elucidate how FOXO1 interacts with CAFs and to provide an inhibitor for CAFs.
  • FOXO1 inhibitors such as anti-FOX1 antibody, shRNA, and AS1842856 act on CAFs, a decrease in myofibroblast ability, a decrease in inflammatory cytokine production ability, and a decrease in tumor promoting ability in CAFs are observed, and at the same time, a decrease in tumor promoting ability is observed.
  • control human normal fibroblasts did not cause such growth inhibition or cell death.
  • the present invention provides the following [1] to [8].
  • [1] A CAFs cell growth inhibitor or a CAFs cell death inducer containing a FOXO1 inhibitor as an active ingredient.
  • FOXO1 inhibitor is selected from anti-FOXO1 antibody, FOXO1 siRNA, FOXO1 shRNA, AS1842856 and AS1708727.
  • FOXO1 inhibitor is selected from anti-FOXO1 antibody, FOXO1 siRNA, FOXO1 shRNA, AS1842856 and AS1708727.
  • the FOXO1 inhibitor according to [5] which is selected from anti-FOXO1 antibody, FOXO1 siRNA, FOXO1 shRNA, AS1842856 and AS1708727.
  • a method for inhibiting cell growth of CAFs or a method for inducing cell death of CAFs which comprises administering an effective amount of a FOXO1 inhibitor.
  • the FOXO1 inhibitor is selected from anti-FOXO1 antibody, FOXO1 siRNA, FOXO1 shRNA, AS1842856 and AS1708727.
  • the present invention it is possible to provide a new drug having a cell growth inhibitory action and a cell death inducing action on CAFs which are cancer-promoting activated fibroblasts.
  • FOXO1-positive myofibroblasts increased in patient breast cancer tissue a. Immunostaining of sections prepared from non-cancerous and cancerous parts of human breast cancer tissue using anti-FOXO1 antibody. FOXO1 is positively detected in Alpha-smooth muscle actin ( ⁇ -SMA) -positive myofibroblasts (arrow). Scale bar, 50 ⁇ m b. Comparison of the proportion of FOXO1-positive fibroblasts in non-cancerous and cancerous areas in 9 breast cancer patients. Immunohistochemistry with anti-FOXO1 antibody in the non-cancerous and cancerous areas resected from the same patient significantly increased the proportion of FOXO1-positive fibroblasts in the cancerous areas compared to the non-cancerous areas.
  • Scale bar 50 ⁇ m Decreased FOXO1 expression due to shRNA introduction in CAFs reduces myofibroblast ability.
  • B Western blot using myofibroblast markers in CAFs into which two different FOXO1-SHRNAs were introduced and antibodies specific for Smad2 / 3 activation. Suppression of FOXO1 expression by shRNA introduction in CAFs reduces the ability to produce inflammatory cytokines.
  • Suppression of FOXO1 activity in CAFs treated with AS1842856 reduces myofibroblast capacity.
  • An asterisk indicates that there is a significant difference in the student's t-test as compared with CAFs after DMSO treatment.
  • Suppression of FOXO1 activity in CAFs treated with AS1842856 reduces myofibroblast capacity and TGF-b-Smad2 / 3 signal activation over time.
  • Western blot analysis using antibodies against various genes in CAFs treated with AS1842856 Suppression of FOXO1 activity in CAFs treated with AS1842856 reduces the ability to produce inflammatory cytokines.
  • CAFs treated with DMSO and AS1842856 (1.0 ⁇ m) by Incute TM over time Asterisks indicate that there is a significant difference compared to DMSO-treated CAFs. Significant suppression of cell proliferation and increased apoptosis in CAFs treated with AS1842856.
  • Expression of FOXO1 is essential for the ability of CAFs to promote cancer cell growth in vivo.
  • Control fibroblasts and CAFs into which GFP-SHRNA or FOXO1-SHRNA was introduced were co-transplanted subcutaneously with DCIS cancer cells and immunodeficient mice. Then, the volume (a) and weight (b) of the formed cancer were measured over time. Compared with the control GFP-SHRNA, CAFs into which FOXO1-SHRNA was introduced significantly suppressed the volume and weight of DICS cancer formed in mice.
  • the CAFs cell growth inhibitor or CAFs cell death inducer of the present invention contains a FOXO1 inhibitor as an active ingredient.
  • FOXO1 is present in various organs, and in the liver, it controls systemic glucose metabolism through the regulation of gluconeogenic enzymes. In the pancreas, it regulates the new generation of ⁇ cells. Then, the FOXO1 inhibitor is known to suppress gluconeogenesis and lower the blood glucose level in a diabetic state. However, the association between FOXO1 inhibitors and CAFs has not been clearly shown.
  • FOXO1 inhibitor examples include anti-FOXO1 antibody, FOXO1 siRNA, FOXO1 shRNA, and the following AS1842856 and AS1708727.
  • AS1842856 and AS1708727 are already known compounds, can be produced by a known method, and commercially available products can also be used.
  • Anti-FOXO1 antibodies include monoclonal and polyclonal antibodies, as well as antibody variants and derivatives such as antibodies and T-cell receptor fragments that retain the ability to specifically bind antigenic determinants.
  • the type of anti-FOXO1 antibody is not particularly limited, and is artificial for the purpose of reducing heterologous antigenicity to humans, mouse antibody, human antibody, rat antibody, rabbit antibody, sheep antibody, camel antibody, triantibody, etc.
  • a recombinant antibody for example, a chimeric antibody, a humanized antibody, or the like, which is specifically modified, can be appropriately used. Recombinant antibodies can be produced using known methods.
  • a chimeric antibody is an antibody consisting of a heavy chain and a variable region of a light chain of a non-human mammal, for example, a mouse antibody and a constant region of a heavy chain and a light chain of a human antibody, and is a DNA encoding the variable region of a mouse antibody.
  • a humanized antibody also referred to as a restored human antibody, is obtained by transplanting a complementarity determining region (CDR) of a non-human mammal, for example, a mouse antibody, into a complementarity determining region of a human antibody.
  • CDR complementarity determining region
  • oligos prepared so as to have an overlapping portion at the end of a DNA sequence designed to link the CDR of a mouse antibody and the framework region (FR) of a human antibody. It is synthesized from nucleotides by the PCR method. It is obtained by ligating the obtained DNA with the DNA encoding the human antibody constant region, then incorporating it into an expression vector, introducing it into a host and producing it (European Patent Application Publication No. EP 239400, International Patent Application Publication No. See WO 96/02576).
  • the FR of the human antibody linked via the CDR is selected so that the complementarity determining region forms a good antigen-binding site.
  • amino acids in the framework regions of the variable region of the antibody may be substituted such that the complementarity determining regions of the reconstituted human antibody form the appropriate antigen binding site (Sato, K. et al., Cancer). Res, 1993, 53, 851-856.).
  • the siRNA of FOXO1 may be a low molecular weight double-stranded RNA consisting of 21-23 base pairs, which is involved in PNA interference (RNAi) and can suppress gene expression in a sequence-specific manner by disrupting the mRNA. ..
  • RNAi PNA interference
  • the shRNA of FOXO1 may be one that is transcribed from a plasmid, forms a hairpin structure, and is processed to become siRNA.
  • FOXO1 is highly expressed in myofibroblasts and cultured CAFs in patient breast cancer tissues, as shown in Examples below.
  • FOXO1 inhibitors such as anti-FOX1 antibody, shRNA, and AS1842856 act on CAFs
  • the myofibroblast characteristics of CAFs are attenuated, the ability of CAFs to produce inflammatory cytokines is attenuated, and the cell proliferation of CAFs is remarkable.
  • inhibition and cell death induction occur, and that the tumor-promoting ability of CAFs is attenuated, and that such growth inhibition and cell death do not occur in control human normal fibroblasts. Therefore, since the FOXO1 inhibitor is useful as a cell growth inhibitor and a cell death inducer for CAFs, it is suggested that it may be useful as a cancer progression inhibitor in which CAFs coexist.
  • the cancer to be treated by the medicament of the present invention is a cancer in which CAFs coexist, and specifically, epithelial cancer (respiratory cancer, digestive organ cancer, urogenital cancer, secretory system cancer, skin cancer, etc.). , Middle dermatoma, breast cancer, sarcoma, central nervous system tumor, peripheral nervous system tumor and the like.
  • respiratory cancer include lung cancer (non-small cell lung cancer, small cell lung cancer, etc.).
  • Examples of gastrointestinal cancer include esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (cholangiocarcinoma / cholangiocarcinoma, etc.), pancreatic cancer, colon cancer, colorectal cancer (colon cancer, rectal cancer, etc.) and the like. ..
  • Examples of urogenital cancer include ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), renal cancer, bladder cancer, prostate cancer, testicular tumor and the like.
  • Examples of secretory cancers include neuroendocrine tumors.
  • mesothelioma examples include pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and testicular mesothelioma.
  • sarcoma examples include gastrointestinal stromal tumors, bone / soft tissue tumors, and the like.
  • central nervous system tumors examples include brain tumors and the like.
  • Peripheral nervous system tumors include, for example, malignant schwannoma. Of these, gastrointestinal stromal tumor, breast cancer, lung cancer, gastric cancer, prostate cancer, ovarian cancer and colon cancer are preferable, and among lung cancers, non-small cell lung cancer is preferable.
  • the route of administration of the medicament of the present invention is not particularly limited, and the drug can be administered orally or parenterally.
  • Parenteral administration includes intravenous, intramuscular, subcutaneous or intradermal injection, inhalation, rectal, intranasal administration, external administration and the like.
  • the FOXO1 inhibitor which is an active ingredient may be administered to a patient as it is, but it is preferably administered in the form of a pharmaceutical composition containing the active ingredient and a pharmaceutically acceptable additive. Should be.
  • Pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegrants, binders, lubricants, coatings, dyes, diluents, bases, solubilizers or solubilizers, etc. Tensioning agents, pH regulators, stabilizers, propellants, adhesives and the like can be used.
  • preparations suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, syrups and the like
  • preparations suitable for parenteral administration include, for example, injection.
  • Agents, drops, suppositories, inhalants or external preparations including patches, ointments, creams, gels, lotions, sprays, etc.
  • preparations suitable for parenteral administration include, for example, injection.
  • Agents, drops, suppositories, inhalants or external preparations including patches, ointments, creams, gels, lotions, sprays, etc.
  • Formulations suitable for oral administration include, as additives, excipients such as, for example, glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants or disintegrant aids such as carboxymethyl cellulose, starch, or carboxymethyl cellulose calcium.
  • Binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, or gelatin; Lubricants such as magnesium stearate or talc; Coating agents such as hydroxypropylmethyl cellulose, sucrose, polyethylene glycol or titanium oxide; Vaseline, liquid paraffin , Polyethylene glycol, gelatin, kaolin, glycerin, purified water, or a base such as hard fat can be used.
  • Formulations suitable for injection and infusion include solubilizers or solubilizers that may constitute aqueous or time-dissolving injectables such as distilled water for injection, saline, propylene glycol; glucose, sodium chloride, D- Isotonic agents such as mannitol and glycerin; pharmaceutical additives such as pH adjusters such as inorganic acids, organic acids, inorganic bases or organic bases can be used.
  • Suitable preparations for suppositories include, for example, bases such as polyethylene glycol, lanolin, cacao butter, fatty acid triglycerides, and optionally additives such as surfactants such as nonionic surfactants. ..
  • bases As a preparation suitable for an ointment, commonly used bases, stabilizers, wetting agents, preservatives and the like are used as necessary.
  • the base include liquid paraffin, white petrolatum, beeswax, octyldodecyl alcohol, paraffin and the like.
  • the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.
  • preparations suitable for patches include those obtained by applying the ointment, cream, gel, paste, or the like to a normal support by a conventional method.
  • a woven fabric made of cotton, rayon, or chemical fiber, a non-woven fabric, a film such as soft vinyl chloride, polyethylene, or polyurethane, or a foam sheet is suitable.
  • the other anticancer agent that can be used in combination is not particularly limited as long as it is an anticancer agent having an anticancer effect, but an anticancer agent having tumor cytotoxicity is particularly preferable in terms of obtaining a synergistic effect.
  • Examples of the other anticancer agent include alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum preparations, molecular targeting agents, hormonal agents, biological preparations and the like.
  • Examples of the alkylating agent include cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, procarbazine, and ranimustine.
  • Antimetabolites include, for example, enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphat, neralabine, fluorouracil, fludalabine, pemetrexed
  • examples thereof include cladribine, doxiflulysin, hydroxycarbamide, mercaptopurine and the like.
  • the microtubule inhibitor include alkaloid anticancer agents such as vincristine and taxane anticancer agents such as docetaxel and paclitaxel.
  • Antibiotics Anticancer agents include, for example, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, acralubicin, idarubicin, pyrarubicin, pepromycin, mitoxantrone, amurubicin, dinostatin stimalamar and the like.
  • the topoisomerase inhibitor include CPT-11 having a topoisomerase I inhibitory action, irinotecan, nogitecan, and etoposide and sobzoxane having a topoisomerase II inhibitory action.
  • platinum preparation examples include cisplatin, nedaplatin, oxaliplatin, carboplatin and the like.
  • Hormonal agents include, for example, dexamethasone, finasteride, tamoxifen, astrosol, exemestane, ethinyl estradiol, chlormaginone, goserelin, bicalutamide, flutamide, bredonizolone, leuprorelin, letrozole, estramustine, toremifene, phosfestol, mitotan, Examples thereof include methyltestosterone, medroxyprogesterone, and mepitiostane.
  • biologics include interferon ⁇ , ⁇ and ⁇ , interleukin 2, ubenimex, dried BCG and the like.
  • Molecular-targeted drugs include, for example, rituximab, alemtuzumab, trastuzumab, cetuximab, panitummab, imatinib, dasatinib, nilotinib, gefitinib, elrotinib, temsirolimus, bebashizumab, temshirolimus, bebashizumab, vEGF trap, , Ibritumomab tiuxetan, Tamibarotene, Tretinoin and the like.
  • human epithelial growth factor receptor 2 inhibitor epithelial growth factor receptor inhibitor, Bcr-Abl tyrosine kinase inhibitor, epithelial growth factor tyrosine kinase inhibitor, mTOR inhibitor, vascular endothelial growth factor receptor 2 Inhibitors targeting angiogenesis such as inhibitors ( ⁇ -VEGFR-2 antibody), various tyrosine kinase inhibitors such as MAP kinase inhibitors, cytokine targeting inhibitors, proteasome inhibitors, antibodies-anticancer Molecular-targeted drugs such as drug formulations can also be used.
  • alkylating agents characterized by cytotoxic activity, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum preparations, molecular targeting agents and the like are particularly preferable.
  • gemcitabine 5-FU, CPT-11, etoposide, cisplatin, oxaliplatin, paclitaxel, docetaxel, dacarbazine, doxorubicin, bevacizumab, cetuximab, antivascular endothelial growth factor receptor 2 inhibitor antibody, epithelial growth factor tyrosine.
  • Kinase inhibitors and the like are particularly preferred.
  • the dose of the medicament of the present invention can be appropriately selected according to various conditions such as the progress of the disease or the degree of symptoms, the age and body weight of the patient, and for example, in the case of oral administration, 1 mg to 300 mg per day is 1 mg. It can be administered in divided doses of about 3 times.
  • Example 1 It was unclear whether FOXO1 was expressed in CAFs of human breast cancer. Therefore, we prepared sections from human breast cancer and performed immunohistochemical staining using anti-FOXO1 antibody. FOXO1-positive was significantly observed in ⁇ -SMA-positive CAFs in the cancerous region. However, no FOXO1-positive cells were found in the non-cancerous fibroblasts of the same patient (Fig. 1a). To generalize this observation, breast cancer sections of 9 more patients were checked (Table 1). Of note, the proportion of FOXO1-positive fibroblasts was significantly increased in CAFs of all breast cancer patients examined (Fig. 1b). Expression at the FOXO1 mRNA level was also increased 4-fold in CAFs compared to the control (Fig. 2a).
  • Example 2 The myofibroblast ability and inflammatory cytokine production ability of CAFs by suppressing FOXO1 expression were investigated. Two different shRNAs capable of significantly suppressing the expression of FOXO1 mRNA and protein were introduced into fibroblasts. CAF into which FOXO1-SHRNA was introduced showed a significant reduction in the expression of myofibroblast markers such as ⁇ -SMA, TGF-b1, SDF-1 mRNA, and pSmad2 protein (Fig. 3). Furthermore, we confirmed the expression level of inflammatory cytokines that contribute to the activation of CAFs and the recruitment of inflammatory immune cells into cancer.
  • Example 3 The specificity of AS1842856 was examined by the FOXO1 luciferase reporter assay using HEK293T cells into which the FOXO1 expression vector or control empty vector was introduced.
  • the cDNA3.11-FOXO1 cDNA vector was introduced into HEK293T cells, AS1842856 (concentration 1.0 ⁇ M) was added 24 hours later, and the transcriptional activity of FOXO1 was measured by Dual-Luciferase TM Reporter Assay System 24 hours later.
  • FIG. 5 it was shown that AS1842856 remarkably suppresses the transcriptional activity of FOXO1.
  • Example 4 It was investigated whether suppression of FOXO1 activity by AS1842856 treatment of CAFs reduced myofibroblast ability.
  • Real-time PCR using a marker gene-specific primer for myofibroblasts was performed using CAFs treated with AS1842856 for 12 hours.
  • CAFs treated with AS1842856 showed a significant decrease in myofibroblast markers.
  • Example 5 Western blot analysis using antibodies against various genes in CAFs treated with AS1842856 was performed. As a result, as shown in FIG. 7, in CAFs treated with AS1842856, the expression of FOXO1, phosphorylated FOXO1, ⁇ -SMA and phosphorylated Smad2 / 3 was observed to be attenuated with time. This result suggests that activation of FOXO1 is essential for the maintenance of CAFs myofibroblast ability and TGF- ⁇ -Smad2 / 3 signal.
  • Example 6 Real-time PCR analysis of CAFs treated with AS18428568 (concentration 1.0 ⁇ M) for 12 hours was performed. As a result, as shown in FIG. 8, the expression of inflammatory cytokines such as CXCL1, CXCL2, IL-1 ⁇ , IL1 ⁇ , IL-8, and LIF in CAFs was remarkably suppressed 24 hours after the treatment with AS1842856. From these results, it was found that treatment with AS18428568, which is a FOXO1 inhibitor, suppresses the myofibroblast ability and inflammatory cytokine production ability of CAFs.
  • AS18428568 which is a FOXO1 inhibitor
  • Example 7 Suppression of CAFs proliferation and induction of cell death by suppression of FOXO1 activity Since the phenotype of activated CAFs was attenuated when FOXO1-SHRNA was introduced, inhibition of FOXO1 activity affects the proliferation and viability of these cells. I checked whether to give it. Compared to the effect of DMSO treatment of the control, CAFs treated with AS1842856 for 72 hours markedly suppressed cell proliferation and increased cell death (FIGS. 9a, 9b), and also controlled human normal mammary fibroblasts. Almost no of these phenomena were observed in cells (Fig. 9b).
  • Example 8 Since FOXO1 is required for promotion of activated fibroblast ability, promotion of proliferation and suppression of cell death of CAFs, it was investigated whether expression of FOXO1 is also necessary for the ability of CAFs to promote migration and proliferation of tumor cells.
  • a Boyden chamber cell migration assay was performed using ductal carcinoma in situ (DCIS) cells from non-invasive human ductal carcinoma in situ. DCIS cells treated with culture supernatants of CAFs introduced with FOXO1-SHRNA showed a significant reduction in migration ability compared to treatment with culture supernatants of CAFs introduced with GFP-SHRNA (Fig.). 11).
  • FOXO1 expression in CAFs affects the in vivo growth of nearby cancer cells.
  • DCIS cells and human normal mammary fibroblasts or CAFs into which GFP-SHRNA or FOXO1-shRNA were introduced were subcutaneously transplanted into immunodeficient nude mice.
  • the volume and weight of tumors containing CAFs whose expression of FOXO1 was suppressed by the introduction of FOXO1-SHRNA was significantly suppressed as compared with the effect of control GFP-SHRNA (Fig. 12). From the above results, it was clarified that the expression of FOXO1 in CAFs is essential for the migration ability and cancer growth ability of nearby DCIS cells.

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Abstract

La présente invention permet d'élucider l'interaction du FOXO1 dans des CAF, et fournit un nouveau médicament thérapeutique.　Cet inhibiteur de croissance cellulaire pour CAF ou cet inducteur de mort cellulaire pour CAF contient un inhibiteur de FOXO1 en tant que principe actif.
PCT/JP2020/039145 2019-10-16 2020-10-16 Inhibiteur de croissance cellulaire ou inducteur de mort cellulaire pour fibroblastes associés au cancer WO2021075559A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076880A1 (fr) * 2021-10-25 2023-05-04 Board Of Regents, The University Of Texas System Thérapie ciblant le foxo1 pour le traitement du cancer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020169707A1 (fr) * 2019-02-21 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteur de foxo1 utilisé pour traiter des infections virales latentes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020169707A1 (fr) * 2019-02-21 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteur de foxo1 utilisé pour traiter des infections virales latentes

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
AKATSU YUICHI, TAKAHASHI NAOYA, YOSHIMATSU YASUHIRO, KIMURO SHIORI, MURAMATSU TOMOKI, KATSURA AKIHIRO, MAISHI NAKO, SUZUKI HIROSHI: "Fibroblast growth factor signals regulate transforming growth factor-beta- induced endothelial-to-myofibroblast transition of tumor endothelial cells via Elkl", MOL. ONCOL., vol. 13, no. 8, August 2019 (2019-08-01), pages 1706 - 1724, XP055819039, DOI: 10.1002/1878-0261.12504 *
GU JIANMEI, QIAN HUI, SHEN LI, ZHANG XU, ZHU WEI, HUANG LING, YAN YONGMIN, MAO FEI, ZHAO CHONGHUI, SHI YUNYAN, XU WENRONG: "Gastric Cancer Exosomes Trigger Differentiation of Umbilical Cord Derived Mesenchymal Stem Cells to Carcinoma-Associated Fibroblasts through TGF-beta/Smad Pathway", PLOS ONE, vol. 7, no. 12, 20 December 2012 (2012-12-20), pages e52465, XP055819036, DOI: https://doi.org/10.1371/journal.pone.0052465 *
GUAN XU-WEN, ZHAO FANG, WANG JING-YA, WANG HAI-YAN, GE SHAO-HUA, WANG XIA, ZHANG LE, LIU RUI, BA YI, LI HONG-LI, DENG TING, ZHOU L: "Tumor microenvironment interruption: a novel anti-cancer mechanism of Proton-pump inhibitor in gastric cancer by suppressing the release of microRNA-carrying exosomes", AM. J. CANCER RES., vol. 7, no. 9, 1 September 2017 (2017-09-01), pages 1913 - 1925, XP055819049 *
TANAKA, H. ET AL.: "Effects of the novel Foxol inhibitor AS1708727 on plasma glucose and triglyceride levels in diabetic db/db mice", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 645, 2010, pages 185 - 191, XP027247568, DOI: https://doi.org/10.1016/j.ejphar. 2010.07.01 8 *
TRUONG THU H, DWYER AMY R, DIEP CAROLINE H, HU HSIANGYU, HAGEN KYLA M, LANGE CAROL A: "Phosphorylated Progesterone Receptor Isoforms Mediate Opposing Stem Cell and Proliferative Breast Cancer Cell Fates", ENDOCRINOLOGY, vol. 160, no. 2, 1 February 2019 (2019-02-01), pages 430 - 446, XP055819032, DOI: 10.1210/en.2018-00990 *
VIVAR RAÚL, HUMERES CLAUDIO, MUÑOZ CLAUDIA, BOZA PÍA, BOLIVAR SAMIR, TAPIA FELIPE, LAVANDERO SERGIO, CHIONG MARIO, DIAZ-ARAYA GUIL: "Fox01 mediates TGF-betal- dependent cardiac myofibroblast differentiation", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1863, no. 1, 2016, pages 128 - 138, XP029306059, DOI: https://doi.org/10.1016/j.bbamcr. 2015.10.01 9 *
ZHANG HONGFANG, HUA YUHUI, JIANG ZHENZHEN, YUE JING, SHI MING, ZHEN XIAOLI, ZHANG XIAOYAN, YANG LING, ZHOU RONGJING, WU SHIXIU: "Cancer-associated Fibroblast- promoted LncRNA DNM30S Confers Radioresistance by Regulating DNA Damage Response in Esophageal Squamous Cell Carcinoma", CLINICAL CANCER RESEARCH, vol. 25, no. 6, 15 March 2019 (2019-03-15), pages 1989 - 2000, XP055819030, DOI: 10.1158/1078-0432.CCR-18-0773 *
ZHANG HONGFANG, XIE CONGHUA, YUE JING, JIANG ZHENZHEN, ZHOU RONGJING, XIE RUIFEI, WANG YAN, WU SHIXIU: "Cancer-associated fibroblasts mediated chemoresistance by a FOX01/TGF beta1 signaling loop in esophageal squamous cell carcinoma", MOLECULAR CARCINOGENESIS, vol. 56, no. 3, March 2017 (2017-03-01), pages 1150 - 1163, XP055819046, DOI: 10.1002/mc.22581 *

Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2023076880A1 (fr) * 2021-10-25 2023-05-04 Board Of Regents, The University Of Texas System Thérapie ciblant le foxo1 pour le traitement du cancer

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