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WO2019094613A1 - Procédé de traitement du cancer du sein et de maladies chroniques - Google Patents

Procédé de traitement du cancer du sein et de maladies chroniques Download PDF

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WO2019094613A1
WO2019094613A1 PCT/US2018/059855 US2018059855W WO2019094613A1 WO 2019094613 A1 WO2019094613 A1 WO 2019094613A1 US 2018059855 W US2018059855 W US 2018059855W WO 2019094613 A1 WO2019094613 A1 WO 2019094613A1
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rage
cells
tumor
mice
fps
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Barry Hudson
Marc E. Lippman
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University of Miami
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University of Miami
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    • C—CHEMISTRY; METALLURGY
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    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • the invention relates to materials and methods for treating breast cancer, obesity, nonalcoholic steatohepatitis (NASH), and chronic diseases.
  • NASH nonalcoholic steatohepatitis
  • a method of treating breast cancer comprising administering to a mammalian subject in need thereof an inhibitor of Receptor for Advanced Glycation End-product (RAGE).
  • RAGE Receptor for Advanced Glycation End-product
  • the disclosure further provides a method of inhibiting breast cancer metastasis and/or inhibiting the onset of breast cancer, comprising
  • the disclosure further provides a method of treating obesity, nonalcoholic steatohepatitis (NASH), or chronic disease, the method comprising administering to a mammalian subject in need thereof an inhibitor of RAGE.
  • NASH nonalcoholic steatohepatitis
  • FIG. 1A-1J Increased RAGE expression promotes tumor metastasis.
  • Western blots were performed using anti-RAGE and anti- ⁇ actin antibodies.
  • FIG.lC Western blot analysis of 231 control & RAGE overexpressing cells (using anti-RAGE and anti- ⁇ actin antibodies).
  • FIG. ID Scratch/wound assay of 231 control & RAGE transfected cells at Oh / 16h post wounding.
  • FIGS. 2A-2C RAGE signaling through MAP kinase and EMT drives MDA-MB- 231 cell invasive gene expression and function.
  • FIG.2A Western blot analysis shows EMT markers are increased with RAGE overexpression.
  • FIG.2B Western blot of total and phospho-proteins in 231 & 231-RAGE expressing cells.
  • FIG. 3A-3E RAGE knockdown in human highly metastatic breast cancer cells downregulates cell invasion, anchorage-independent growth in soft agar, and downstream signaling.
  • FIG.3A Western blot analysis of RAGE in shControl and RAGE sh66 231 and
  • RAGE shRNA (and shControl) were quantified for matrigel invasion in transwell chambers after 24h to 1% FBS stimuli, were quantified.
  • Fig.3C Proliferation quantified by crystal violet staining after 48h.
  • FIG.4A-4F Knockdown of RAGE inhibitors tumor progression.
  • Fig.4A 231 parental or
  • FIG.4C-4F Immunohistochemical analysis of tumors for proliferation (Fig.4C. Ki67), angiogenesis (Fig.4D. CD34), and leukocyte (Fig.4E. CD45) and macrophage (Fig.4F. F4/80) infiltration from 4175-shControl and 4175 RAGE sh66 tumors.
  • FIGS 5A-5F RAGE expression in tumor cells is required for breast cancer metastasis in vivo: xenograft models. Lung and liver tissue from 4175 or 231 tumor bearing RAGE sh66 or shControl mice were analyzed for metastasis by immunohistochemistry with anti-human CK7 antibodies. Representative images are shown from tissue for 231 (A&B), 4175 time (Fig.5C and5D) and size (Fig.5E and 5F) -matched mice.
  • FIGS 6A-6F RAGE knockdown in mouse highly metastatic breast cancer cells downregulates cell invasion and breast cancer metastasis in vivo: syngeneic models.
  • Fig.6A Western blot shows knockdown by different RAGE shRNAs (shlO and shl2) compared to shControl in 4T-1 cells, and RAGE overexpression in 67NR cells compared to vector control (using anti-RAGE and anti- ⁇ actin antibodies).
  • FIG.6B 4T-1 cells with RAGE shRNA (and shControl) were quantified for matrigel invasion in transwell chambers after 24h to 1% FBS stimuli, were quantified.
  • FIG.6E 4T-1 cells (lxlO 6 ) with RAGE shlO, RAGE shl2 or shControl were injected into mammary fat pad of BALBc mice. Tumor size was measured over the course of 35 days, and at time of sacrifice (35 days), tumor weight was measured. Data shown are from 8 mice per group.
  • FIG.6F Lung tissue from 4T-1 tumor bearing RAGE shlO, shl2 or shControl mice were analyzed for metastasis by immunohistochemistry with H&E.
  • FIG. 7A-7D RAGE knockout in mice impairs tumor growth in vivo.
  • AT-3 murine mammary tumor cells (0.5xl0 6 ) were injected into mammary fat pad of C57BL6 wild-type and RAGE knockout mice, and
  • Fig.7A tumor progression monitored.
  • Fig.7B and 7C Immunohistochemical analysis of tumors for angiogenesis (Fig.7B, CD34), and leukocyte (Fig.7C, CD45) infiltration from wild-type and RAGE -/- tumors.
  • Fig.7D Immunohistochemical analysis of tumors for angiogenesis
  • Fig.7C, CD45 Fig.7C, CD45
  • FIGs 8A-8H The RAGE inhibitor FPS-ZMl impairs cell invasion and anchorage-independent growth in soft agar.
  • FIG.8 A 231 control & RAGE transfected cells were quantified for Matrigel invasion in transwell chambers after 24h to 1% FBS stimuli in the presence of FPS-ZMl (1 ⁇ ) or DMSO control.
  • FIG.8B 4175 cells with RAGE shRNA (and shControl) were quantified for Matrigel invasion in transwell chambers after 24h to 1% FBS stimuli in the presence of FPS-ZMl (1 ⁇ ) or DMSO control, were quantified.
  • FIG.8C 4T-1 cells were quantified for Matrigel invasion in transwell chambers after 24h to 1% FBS stimuli in the presence of FPS-ZMl ( ⁇ ) or DMSO control.
  • FIG.8D Primary human dissociated tumor (DT28) cells were quantified for Matrigel invasion in transwell chambers after 24h to 1% FBS stimuli in the presence of FPS-ZMl (1 ⁇ ) or DMSO control.
  • FIG.8E Proliferation of 4175 cell treated with FPS-ZMl (1, 10 and 25 ⁇ ) and DMSO control quantified by crystal violet staining after 72h.
  • FIG.8F Proliferation of 4T-1 cell treated with FPS-ZMl (10 ⁇ ) and DMSO control quantified by crystal violet staining after 72h.
  • FIG.8G-8H Soft agar colony formation assays of 4175 (Fig.8G.) and 4T-1 (Fig.8H.) cells treated with FPS-ZMl (1, 10 and 25 ⁇ ) and DMSO control.
  • FIGs 9A-9G The RAGE inhibitor FPS-ZMl reduces tumor progression and metastasis of highly metastatic 4175 cells.
  • 4175 cells were injected into mammary fat pad of NSG mice, and mice treated injected IP with lmg/kg FPS-ZMl or vehicle control twice per week. Tumor size was measured over the course of 35 days, and shown as (Fig.9A) representative mice and (Fig.9B) for tumor size. Data shown are from 5 mice per group.
  • FIG.9C-9F Immunohistochemical analysis of tumors for proliferation (Fig.9C, Ki67), angiogenesis (Fig.9D.
  • FIG.9G Representative images of lung and liver tissues from control (DMSO) and FPS-ZMl treated mice stained with anti-human CK7 antibodies to visualize metastasis. Non-tumor bearing (NTB) controls are shown.
  • Figures 10A-10E RAGE gene expression and clinical outcomes in human breast cancer. Relative expression of RAGE mRNA normalized to beta-actin examined using breast cancer datasets from OncomineTM. Breast cancer stromal datasets (Fig.lOA-lOC) and from metastatic datasets (Fig.lOD and 10E) were compared.
  • FIG. 11 RAGE inhibitors impair tumor growth of 231-4175 human breast cancer cells in NSG immunocompromised mice. 4175 cells were injected into mammary fat pad of NSG mice and mice injected IP with 1 mg/kg FPS-ZMl, TTP488, or vehicle control (DMSO) twice per week. Tumor size (volume, x-axis) was measured over the course of 35 days (y- axis).
  • FIG. 12 Tumor growth of 4T-1 breast cancer cells in BALBc mice. 4T-1 cells were injected into mammary fat pad of BALBc mice, and mice injected IP with 1 mg/kg FPS-ZMl, TTP488, or vehicle control (DMSO) twice per week. Tumor size (volume, x-axis) was measured over the course of 35 days (y-axis).
  • FIG. 13 Mouse weight changes in type 2 diabetic mice on RAGE inhibition. Control (db/m) and diabetic (db/db) mice (5 mice per group) were treated by intraperitoneal (I.P.) injection with 1 mg/kg FPS-ZMl, TTP488, or vehicle control (DMSO) twice per week for 30 days. Mice were weighed weekly. Line graph illustrates weight (g, y-axis) and day (x-axis).
  • FIG. 14 Combination therapy with FPS-ZMl and doxorubicin impairs tumor growth in syngeneic breast cancer models.
  • BALBc mice were injected with 4T-1 cells and treated with control (DMSO), doxorubicin (5 mg/kg), FPS-ZMl (1 mg/kg), or a combination of doxorubicin and FPS-ZMl.
  • Doxorubicin was administered I.P. on days 3 and 7 (post tumor implantation).
  • FPS-ZMl was administered I.P. on days 2, 6, 10, and 13.
  • N 6 mice per group for all experiments.
  • FIG. 15 RAGE inhibition with FPS-ZMl reduces liver inflammation in obese mice.
  • Dbdb mice were treated with FPS-ZMl (1 mg/kg, twice per week I.P.) or vehicle (control).
  • RNA was extracted from liver tissue and QPCR performed to determine gene expression levels.
  • Four sets of bars are provided in the bar graph denoting RNA of four targets (from left to right, x-axis), CDE3, f480, IL6, and TNF, with relative normalized expression denoted on the y-axis. Within each set of bars, the left bar corresponds to treatment with vehicle; the right bar corresponds to treatment with FPS-ZMl.
  • Three sets of bars are provided in the bar graph denoting RNA of three targets (from left to right, x-axis), RAGE, S 10048, and S 10049, with relative normalized expression denoted on the y-axis. Within each set of bars, the left bar
  • FIGs 17A-17B The RAGE inhibitor FPS-ZMl displays a dose dependent effect on tumor metastasis.
  • DMSO DMSO
  • FPS-ZMl DMSO
  • FPS-ZMl FPS-ZMl
  • FIGs 18A-18B Frequency and dose effects of the RAGE inhibitor FPS-ZMl on tumor metastasis.
  • FPS-ZMl was given to mice either twice per week (lmg/kg), or every day (lmg/kg or 2mg/kg).
  • FIGs 19A-19B The RAGE inhibitor TTP488 displays a dose dependent effect on tumor metastasis.
  • DMSO DMSO
  • FIG. 20 FPS-ZMl impairs tumor cell invasion.
  • Cell invasion assays were performed using a Matrigel transwell invasion system.
  • X-axis cell line and treatment;
  • y- axis relative invasion (%).
  • FIG. 21 RAGE inhibitors (FPS-ZMl and TTP488) impair tumor cell invasion.
  • Cell invasion assays were performed as in Figure 20.
  • Cells (4T-1) were treated with either FPS-ZMl (5 ⁇ ), TTP488 (5 ⁇ ) or DMSO control.
  • FIGS. 24A-24B RAGE knockout in MMTV-PyMT mice impairs tumor initiation and metastasis.
  • Tumor latency (Fig. 24A) and tumor metastasis (Fig. 24B) were measured for MMTV-WT and MMTV-PyMT RAGE KO (RKO) mice.
  • FIG. 25 RAGE inhibitors FPS-ZM1 impairs NASH in db/db mice.
  • Db/db mice were treated with FPS-ZM1 (lmg/kg, twice per week) or DMSO control.
  • NASH was assessed by histology of liver and serum analysis of the liver enzyme ALT.
  • the Receptor for Advanced Glycation End-product is a multiligand cell surface molecule of the immunoglobulin superfamily. RAGE binds multiple ligands including, e.g., the non-enzymatic protein- adducts (AGEs) that form in the hyperglycemic state of diabetes (Siegel et al. (2013). CA Cancer J Clin, 63, 11-30; Taguchi et al. (2000). Nature, 405, 354-360)), various members of the S lOO/calgranulins (S 100A4, A6-9, S 100B and S 100P) (Kalea et al. (2010). Cancer Res, 70, 5628-5638; Kang et al. (2010).
  • S 100A4, A6-9, S 100B and S 100P various members of the S lOO/calgranulins
  • the disclosure provides a method of treating breast cancer, the method comprising administering to mammalian subject in need thereof an inhibitor of Receptor for Advanced Glycation End-product (RAGE).
  • the disclosure also provides a method of inhibiting breast cancer metastasis, the method comprising administering to mammalian subject in need thereof an inhibitor of RAGE.
  • the subject is a human.
  • the RAGE inhibitor is a small molecule.
  • a RAGE inhibitor suitable for use in the context of the disclosure is TTP-488 (chemical name 3-(4- ⁇ 2- butyl- 1 -[4-(4-chlorophenoxy)-phenyl] - lH-imidazole-4-yl ⁇ -phenoxy)-propyl] -diethylamine), also known as azeliragon or PF-04494700).
  • TTP-488 chemical name 3-(4- ⁇ 2- butyl- 1 -[4-(4-chlorophenoxy)-phenyl] - lH-imidazole-4-yl ⁇ -phenoxy)-propyl] -diethylamine
  • TTP-488 is an orally active, antagonist of RAGE-RAGE ligand interaction, which has shown reduction of amyloid accumulation in the brains of mice. In human clinical trials, TTP-488 did not display any adverse effects in both in Phase I and II trials. Low dose treatment with TTP-488 in Alzheimer patients demonstrated slower decline in cognitive function compared to controls.
  • the RAGE inhibitor is FPS-ZM1, the structure of which is provided below.
  • the disclosure provides a method of treating breast cancer or inhibiting breast cancer metastasis in a subject in need thereof.
  • "Treating" breast cancer does not require a 100% abolition of cancer in the subject. Any decrease in tumor load, tumor burden, or tumor volume; inhibition of tumor cell proliferation; eradication of tumor cells; and the like constitutes a beneficial biological effect in a subject.
  • the progress of the method in treating breast cancer e.g., reducing tumor size or eradicating cancerous cells
  • Tumor size can be figured using any suitable technique, such as measurement of dimensions or estimation of tumor volume.
  • Tumor size can be determined by tumor visualization using, for example, CT, ultrasound, SPECT, spiral CT, MRI, photographs, and the like. Measurement of tumor size, detection of new tumors, biopsy, surgical downstaging, PET scans, and the like can point to the overall progression (or regression) of cancer in a human. Similarly, "inhibiting metastasis” does not require a complete blockage of metastasis; any degree of preventing, suppressing, delaying the onset, or slowing metastasis in the subject is contemplated.
  • the disclosure further provides a method of inhibiting the onset of breast cancer.
  • the method comprises administering to a mammalian subject in need thereof an inhibitor of Receptor for Advanced Glycation End-product (RAGE).
  • RAGE Receptor for Advanced Glycation End-product
  • “Inhibiting the onset of breast cancer” does not require 100% prevention of the disease, although complete prevention is contemplated.
  • “Inhibiting the onset” when used in the context of a disease or disorder also includes lessening the likelihood of the disease or disorder onset or slowing the onset of the disease or disorder.
  • the disclosure also provides a method of treating chronic disease, optionally associated with inflammation, comprising administration to a subject in need thereof a RAGE inhibitor, such as a RAGE inhibitor described herein.
  • the chronic disease is obesity, non-alcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).
  • NAFLD non-alcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • the subject has a body mass index of 30 or greater.
  • NAFLD is characterized by the presence of steatosis
  • NASH is characterized by the histologic presence of steatosis, cytological ballooning, inflammation, and fibrosis. "Treating" the chronic disease, such as obesity or NASH does not require a 100% abolition of the disorder in the subject.
  • the method reduces the risk of developing the chronic disease (e.g., NAFLD or NASH), arrests or slows the development of the disease or clinical symptoms thereof, or ameliorates the chronic disease (e.g., promotes regression or reversal of the disease state or symptoms thereof).
  • the disclosure contemplates a method of reducing liver inflammation comprising administering to a subject in need thereof a RAGE inhibitor, such as a RAGE inhibitor described herein.
  • Liver inflammation and steatosis are detected using any of a number of techniques including, but not limited to, blood tests (to detect, e.g., elevated liver enzymes), ultrasound, computerized tomography (CT) scans, Magnetic resonance imaging (MRI), and biopsy.
  • blood tests to detect, e.g., elevated liver enzymes
  • CT computerized tomography
  • MRI Magnetic resonance imaging
  • the RAGE inhibitor is provided in a composition (e.g., a pharmaceutical composition) comprising a physiologically-acceptable (i.e., a physiologically-acceptable) i.e., a physiologically-acceptable (i.e., a physiologically-acceptable) i.e., a physiologically-acceptable (i.e., a physiologically-acceptable) i.e., a physiologically-acceptable (i.e., a physiologically-acceptable)
  • physiologically-acceptable (e.g., pharmaceutically acceptable) carrier can be used within the context of the disclosure, and such carriers are well known in the art.
  • carrier will be determined, in part, by the particular site to which the composition is to be
  • composition formulations include aqueous and non-aqueous solutions, isotonic sterile solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the composition can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials.
  • a particular administration regimen for a particular subject will depend, in part, upon the amount of RAGE inhibitor administered, the route of administration, and the cause and extent of any side effects.
  • the amount administered to a subject e.g., a mammal, such as a human
  • the administration regimen for TTP488 may, in various aspects, comprise daily administration of about 10 mg to about 60 mg to a subject in need thereof.
  • the disclosure further contemplates administering the RAGE inhibitor in combination with one or more additional therapeutics.
  • the therapeutic regimen for the subject may include administration of one or more cytotoxic agents or chemotherapeutic agents.
  • additional therapeutic agents include, but not limited to, 5-azacytidine, actinomycin D, amanitin, aminopterin, anguidine, anthracycline, anthramycin (AMC), auristatin, bevacizumab, bleomycin, busulfan, butyric acid,
  • camptothecin carboplatin, carmustine, cemadotin, cisplatin, colchicin, a combretastatin, cyclophosphamide, cytarabine, cytochalasin B, dactinomycin, daunorubicin, decarbazine, diacetoxypentyldoxorubicin, dibromomannitol, dihydroxy anthracin dione, a disorazole, docetaxel, dolastatin (e.g., dolastatin 10), doxorubicin, daunorubicin, duocarmycin, echinomycin, emetine, epothilones, esperamicin, ethidium bromide, etoposide, fluorouracil, gemcitabine, geldanamycin, glucocorticoid, irinotecan, lapatinib, melphalan, mercatopurine,
  • the RAGE inhibitor is administered in combination with doxorubicin. It will be appreciated that "in combination” does not restrict the timing or order in which the RAGE inhibitor and one or more additional therapies are administered to the subject.
  • the administration of different therapeutic agents can occur simultaneously or sequentially, and by the same or different routes of administration.
  • This example demonstrates inhibition of breast cancer cell proliferation and metastasis in vivo using RAGE inhibitors.
  • RAGE overexpression and gene knockdown cells Lentiviral vectors encoding human RAGE cDNA (Precision LentiORF; Thermo Scientific) and human / mouse RAGE shRNA (pGIPZ; Thermo Scientific) were used for RAGE overexpression and silencing.
  • Human RAGE cDNA POHS_100006205
  • empty vector pLOC control were used.
  • Indicated shRNAs are as follows: shControl (RHS4346), human RAGE sh65
  • V3LHS_316665; TGGACTTGGTCTCCTTTCC (SEQ ID NO: 1)
  • human RAGE sh66 (V3LHS_316666; TACACTTCAGCACCAGTGG (SEQ ID NO: 2))
  • mouse RAGE shlO (V3LMM_430610; TGACCTCCTTCCCTCGCCT (SEQ ID NO: 3))
  • mouse RAGE shl2 (V3LMM_430612; TATTAGGGACACTGGCTGT (SEQ ID NO: 4)).
  • Human RAGE cDNA (PLOHS_100006205) and empty vector control.
  • lentiviral vectors were co-transfected with psPAX2 and pMD2.G (Addgene) into HEK-293T cells (ATCC) with Lipofectamine 2000 (Lifetech). Supernatants were collected at 48 hours and cell debris pelleted. MDA-MB-231, 4175. 4T-1, and 67NR were infected with viral supernatant with 4 ⁇ g/ml polybrene and stable expression selected with blasticidin (pLOC) or puromycin (pGIPZ). Stably transduced cells were tested for RAGE overexpression or knockdown by Western blotting (see below).
  • Wound healing assays To assess cell migration, wound-healing (scratch) assays were used. Cells were plated in 6 well plates at 2.5 x 105 cells / well and grown to confluence to form a monolayer and serum starved overnight. A single scratch was made per well with a 200 ⁇ pipette tip, and the cell media changed to 1% FBS. Cells were fixed at 0 and 16 h after wounding and images acquired with a light microscope at lOx magnification.
  • Cell invasion assays were performed using transwell migration chambers as previously described; 17. 5 x 10 cells were seeded in the upper chamber of 8- ⁇ porous transwell inserts (ThinCerts, Greiner) coated with 12.5 ⁇ g of Growth Factor Reduced Matrigel (BD Biosciences) in serum-free DMEM, and incubated in 24 well plates with 1% FBS as a chemoattractant for 24 hours (48 hours for DT28 cells). Following incubation cells were fixed with methanol for 10 minutes and stained with 2% crystal violet in 2% ethanol solution. Non-migrated cells were removed from transwell chambers with a cotton swab.
  • the cell stain was extracted with 10% acetic acid, transferred to a 96 well plate and measured at 595 nm using an iMark Microplate Reader (Biorad).
  • iMark Microplate Reader Biorad
  • cells were pre- treated for lh prior to assays and re-added during invasion assays (both upper and lower chambers) with either FPS-ZM1 (1 ⁇ ; Millipore) or equal volume DMSO control.
  • Proliferation assays Cells were counted and plated in triplicate at 35,000 cells per well of a 12 well plate and grown for 48-72 hours. Cells were fixed with 4%
  • Soft agar assay Cells (5 x 10 cells/well) were resuspended in 0.4% agarose (Sigma) in Iscove's Modified Dulbecco's Medium (IMDM) with 10% FBS and seeded on top of a 0.8% agarose layer (IMDM with 10% FBS) in 6 well plates and cultured for 14 days (4T-1, 67NR cells) or 21 days (231, 4175 cells). Tumor colonies were stained with 0.05% INT (Iodonitrotetrazolium chloride) in PBS overnight at 37 °C and representative images (5 per well) were acquired using a Nikon Eclipse TS 100 microscope. The assay was performed in triplicate and repeated independently three times.
  • mice with tumor growth in exceeding 5% of body weight or exhibiting 20% weight loss were terminated early and excluded from the study.
  • Animals were randomized to each experimental group (RAGE shRNA vs. scramble shRNA; FPS-ZMl vs. vehicle). Injections and measurements were performed by different investigators, and mice injected/measured in a random manner.
  • Syngeneic drug models 100,000 luciferase labelled 4T1 cells, were injected into the 4th mammary fat pad (anatomical right) of BALBc mice. Drug treatments (FPS-ZM1 or TTP488) during the study were given LP. and varied on dosage schedule and amount of drug administered. Tumor size after initial palpability was measured twice weekly by calipers. In vivo imaging was performed using the Xenogen IVIS-200, which allowed for quantitative primary tumor and metastasis measurements. A luminoscore based on average radiance and total photon flux (photons/sec) was generated by drawing regions of interest (ROIs) around the lungs of each mouse.
  • ROIs regions of interest
  • MMTV-PyMT male mice were bred with either C57BL6 wild-type or RAGE knockout mice.
  • Mouse genotype was confirmed by PCR for both MMTV transgene and knockout of the RAGE gene. Tumor palpability was monitored in mice and at time of sacrifice, lungs were isolated to identify metastasis.
  • In vitro assays Invasion assays: cellular invasion was tested using transwell Matrigel invasion assays. Cells (50,000) were seeded in the upper chamber of a transwell insert coated with Matrigel. Cells were allowed to invade toward a lower chamber with 1% FBS as stimulant for 24 hours. For inhibitor studies, cells were incubated with either FPS- ZM1, TTP488 or DMSO control.
  • Cytokine arrays cell were grown on 100mm dishes and treated with either FPS-ZM1, TTP488 or DMSO control for 24 hours. Conditioned media was collected and cytokine release assessed using the Proteome Profiler Mouse XL Cytokine array.
  • OncomineTM analysis of RAGE mRNA expression The OncomineTM database was used for initial analysis and extraction of RAGE expression from three breast cancer stromal datasets (Finak, Ma-4, and Karnoub) and two invasive breast cancer datasets (Sorlie-2 and TCGA). Finak et al. (2008). Nat Med, 14, 518-527; Karnoub et al. (2007). Nature, 449, 557- 563; Ma et al. (2009). Breast Cancer Res, 11, R7; Sorlie et al. (2003). Proc Natl Acad Sci U S A, 100, 8418-8423; (2012). Nature, 490, 61-70.
  • Log2 median-centered intensity values for RAGE gene expression were compared between normal breast stroma and stroma from primary breast lesions: invasive breast cancer (Finak), invasive ductal carcinoma (Karnoub), and DCIS (Ma-4). Log2 median-centered intensity values for RAGE gene expression were also compared between primary breast lesions and metastatic breast lesions (Sorlie-2 and TCGA). Comparisons of RAGE expression between groups were performed using one-sided Student's t-test.
  • Metastatic human and mouse breast cancer cells show increased RAGE expression: To investigate the role of RAGE in driving breast cancer metastasis, RAGE protein levels were compared by immunoblotting in breast cancer lines with low and high metastatic ability; MDA-MB-231 (hereafter 231) and in highly metastatic variants of 231, MDA-MB- 231-4175 and MDA-MB-231-1833 (hereafter 4175 and 1833), previously selected for increased metastasis to lung and bone in xenograft models, respectively. Minn et al. (2005). Nature, 436, 518-524; Kang et al. (2003). Cancer Cell, 3, 537-549.
  • the highly metastatic 4175 and 1833 cells displayed greater RAGE protein than parental 231 cells ( Figure 1A).
  • the murine mammary metastatic 4T1 model which spontaneously metastasizes from the primary site in vivo in syngeneic hosts, and an isogenic variant thereof, 67NR, with reduced metastatic potential was studied. Aslakson et al. (1992). Cancer Res, 52, 1399-1405;
  • RAGE signaling drives cellular invasion through a MEK-dependent expression of EMT regulators: Since RAGE expression is linked to poor breast cancer survival, and since RAGE is overexpressed in metastatic lines and mediates increased tumor cell invasion and soft agar colony formation, the effects of RAGE on signaling pathways and epithelial to mesenchymal transition (EMT) mediators implicated in metastasis was studied.
  • EMT epithelial to mesenchymal transition
  • RAGE overexpression in 231 cells increased expression of EMT markers including matrix metalloproteins, MMP-2, MMP-9, and vimentin, whilst concurrently reducing expression of epithelial markers, E-cadherin and ZO-1 (Figure 2A).
  • RAGE overexpression increased expression of EMT transcription factors Slug and Twistl and increased ⁇ -catenin, while Snail and Zebl levels were unchanged ( Figure 2B).
  • RAGE knockdown in highly metastatic breast cancer cells impairs Matrigel invasion and anchorage-independent growth: Since RAGE overexpression increased migration and invasion of 231 cells, the ability of RAGE gene knockdown to impair these effects in highly metastatic lines was tested.
  • RAGE shRNA decreased RAGE protein levels in 231 and 4175 to >75% of shControl ( Figure 3A). Cell invasion assays showed shControl highly metastatic 4175 cells showed greater invasion than shControl parental 231 transwell Matrigel invasion assays as expected ( Figure 3B). RAGE knockdown dramatically reduced Matrigel invasion by 4175 cells, and impaired that of the less metastatic parental 231 line ( Figure 3B).
  • RAGE knockout in mice impairs tumor growth and progression: The role of RAGE expression in non-tumor cells of the tumor microenvironment was tested. Syngeneic studies with AT-3 cells (MMTV-PyMT spontaneous BC cell model) injected into the mammary fat pad of wild-type and RAGE knockout C57BL6 immunocompetent mice were performed. RAGE knockout mice (RAGE -/-) displayed striking impairment of tumor cell growth with AT3 cells compared to wild-type (RAGE +/+) mice ( Figure 7A). Furthermore, IHC analysis of tumor tissue revealed that RAGE -/- mice had decreased vessel formation ( Figure 7B) and a significant decrease in leukocyte recruitment (Figure 7C) to the tumor.
  • FPS-ZM1 The RAGE antagonist, FPS-ZM1, impairs breast cancer cell invasion and anchorage-independent growth: FPS-ZM1 is a RAGE antagonist that interacts with the ligand binding domain of the receptor to block RAGE signaling. Deane et al. (2012). J Clin Invest, 122, 1377-1392. This drug has been tested for potential effects in Alzheimer's disease, but has not been explored as an anticancer agent.
  • FPS-ZM1 did not affect cell proliferation or viability in any of the cells tested even at high doses (data shown for 4175 at 1, 10 and 25 ⁇ and for 4T-1 at 10 ⁇ , Figure 8E&F). RAGE inhibitor effects on colony formation in soft agar assays also were tested. In both 4175 and 4T-1 cells, FPS-ZM1 significantly impaired colony number and size in a dose- dependent manner (Figure 8G&H). These data support a role for RAGE as a therapeutic target for breast cancer.
  • the RAGE inhibitor FPS-ZMl displays a dose dependent effect on tumor metastasis.
  • Treatment of FPS-ZMl led to a significant reduction in tumor growth ( Figure 17A).
  • Assessment of metastasis showed a more striking effect of RAGE inhibitors and a dose-dependent effect of FPS-ZMl on lung metastasis ( Figure 17B).
  • the RAGE antagonist FPS-ZMl impairs in vivo tumor progression and metastasis of highly metastatic 4175 cells:
  • the data in this study show both in vitro and in vivo that targeting RAGE in both tumor cells and non-tumor cells of the tumor microenvironment are critical for tumor progression and metastasis.
  • the effects of FPS-ZMl on 4175 tumor formation and metastasis from orthotopic primary tumors in NSG also were tested.
  • mice with FPS-ZMl (1 mg/kg injection twice per week, intraperitoneally started 1 day after tumor cell implantation) impaired 4175 tumor growth compared to vehicle controls ( Figure 9A&B). Next the effects of FPS-ZMl were assessed by tumor
  • the RAGE inhibitor TTP488 displays a dose dependent effect on tumor metastasis. Mice treated with TTP488 showed impaired tumor growth compared to DMSO treated mice. Metastasis in mice was impaired with TTP488 treatment ( Figure 19A and 19B).
  • FPS-ZMl impair tumor cell invasion. Treatment of cells with FPS-ZMl (2 ⁇ ) impaired invasion of 4T-1, E0771 and Py8119 mouse breast cancer cell lines, compared to DMSO control ( Figure 20). In addition, both FPS-ZMl and TTP488 impaired tumor cell invasion, with TTP488 displaying a greater degree of inhibition than FPS-ZMl ( Figure 21).
  • RAGE inhibitors (FPS-ZMl and TTP488) impair tumor cell inflammation.
  • RAGE knockout in mice impairs tumor progression.
  • RAGE knockout mice RKO
  • WT mice wild-type mice
  • RAGE knockout in MMTV-PyMT mice impairs tumor initiation and metastasis.
  • wild-type and RAGE knockout (RAGE KO) mice were crossed with the MMTV-PyMT spontaneous BC model.
  • MMTV-PyMT mice are a well-established mouse model that displays widespread transformation of the mammary epithelium resulting in rapidly forming mammary tumors and metastatic lesions primarily in lymph nodes and lung, closely mimicking the human clinical state.
  • MMTV-PyMT RAGE KO displayed impaired tumor initiation and growth compared to MMTV-PyMT wild-type mice ( Figure 24 A).
  • MMTV-PyMT RAGE KO mice had little or no metastatic lesions on the surface of the lungs, whereas MMTV- PyMT wild-type mice displayed extensive metastatic lesions ( Figure 24B).
  • RAGE inhibitors FPS-ZMl impair experimental metastasis.
  • RAGE is overexpressed in human breast cancer and is associated with increased metastasis: To determine whether RAGE is differentially expressed in breast cancer tissues from human subjects, microarray data from breast cancer patient samples in the OncomineTM database was examined. Datasets were assessed that include breast stroma from human subjects. In the Finak, Karnoub and Ma-4 datasets, RAGE overexpression in breast stroma was associated with breast cancer compared to normal breast stroma ( Figure lOA-C). To correlate these findings with outcomes in breast cancer, datasets were examined that compared the expression of genes in primary tumors versus distant metastases. In both the Sorlie-2 and TCGA datasets, increased RAGE expression was associated with the metastatic site versus primary tumor ( Figures 10D and 10E). These data together demonstrate that increased RAGE expression is associated with invasive breast cancer and at the metastatic site.
  • FPS-ZMl and TTP-448 The activity of FPS-ZMl and TTP-488 was compared in various animal models including xenograft and syngeneic breast cancer. For these studies, TTP488 and FPS-ZMl were reconstituted in DMSO, and mice were injected twice per week with lmg/kg of FPS-ZMl, TTP-488 or vehicle control (DMSO). TTP-488 impaired tumor growth to a similar degree compared to FPS-ZMl ( Figure 11). FPS-ZMl injection into mice strongly impaired tumor cell metastasis to both lung and liver. TTP-488 also impaired metastasis (especially to liver).
  • TTP-488 The activity of TTP-488 compared to FPS- ZMl also was tested in the syngeneic immunocompetent 4T-l/BALBc model. Similar to NSG mice, treatment of tumor bearing mice with either FPS-ZMl or TTP-488 impaired tumor growth (Figure 12).
  • DOX RAGE inhibitor and doxorubicin
  • a major issue with DOX is its cytotoxicity and the ability of breast cancer cells to become chemoresistant.
  • Combination therapy with multiple cytotoxic agents have greater anti-tumor effects than DOX alone, but are associated with greater side-effects and reduced quality of life for women with breast cancer.
  • the effect of combination therapy with DOX and FPS-ZMl was examined. Using the BALBc/4T-l syngeneic model, mice were treated with either DMSO (control), doxorubicin (5mg/kg on days 3 and 7), FPS-ZMl (lmg/kg on days 2, 6, 10 and 13) or combination DOX & FPS-ZMl.
  • RAGE knockdown in 4T-1 cells impaired invasion and soft agar colony formation, whereas overexpression of RAGE in 67NR increased colony formation in soft agar.
  • the in vivo studies described herein revealed that RAGE knockdown in the 4175 cells decreased tumor growth at the orthotopic site, but did not affect tumor growth of 231 cells. Further, RAGE knockdown prevented the emergence of distant metastasis of 231 and 4175 cells in both lung and liver, in both a time and tumor size matched manner.
  • the data provided herein further show for the first time that the use of small molecule RAGE antagonists is an effective treatment in multiple breast cancer models.
  • RAGE plays a role in both the tumor cell (shRNA knockdown) and non- tumor cells of the tumor microenvironment (RAGE host knockout).
  • FPS-ZMl is a highly attractive therapeutic approach to target multiple mechanisms that promote progression and metastasis.
  • the data show FPS-ZMl inhibits cell invasiveness and soft agar colony formation, but does not appear to inhibit tumor cell viability or proliferation. These effects were demonstrated not only in the 4175, 231 parental, and 4T-1 cells, but also primary DT28 breast cancer cells dissociated from a patient with triple negative breast cancer.
  • RAGE is a key mediator of breast cancer metastasis in the models evaluated and strongly implicate it as a mediator of metastasis in vivo.
  • the Example demonstrates a clear tumor cell intrinsic role of RAGE in affecting breast cancer cell invasion and metastasis.
  • RAGE knockout mice demonstrate a role of RAGE in breast cancer through cells of the breast tumor microenvironment.
  • RAGE knockdown in 4175 cells and treatment with the RAGE inhibitor reduces angiogenesis and recruitment of inflammatory cells to the tumor.
  • the data implicate RAGE as a mediator of breast malignancy through effects on both the tumor cell itself and the associated tumor microenvironment.
  • mice Liver from mice was used for histology. H&E was performed to visualize gross changes in liver. Trichrome staining was performed to visualize changes in collagen / liver fibrosis. Oil-red O staining was performed to assess fat content / accumulation in liver. F4/80 staining by IHC was performed to assess macrophage accumulation / inflammation in liver. Serum: mouse serum was analyzed for the liver enzyme ALT.
  • NASH Nonalcoholic Steatohepatitis
  • RAGE inhibitor FPS-ZMl impairs NASH in mice on a high-fat diet. Mice were fed a HFD for 32 weeks to induce fat accumulation in the liver and NASH. Mice were treated throughout the study with either FPS-ZMl, TTP488 (lmg/kg / twice per week), or DMSO control. Liver histology demonstrated less fat accumulation in both TTP488 and FPS-ZMl treated mice compared to controls. Trichrome staining revealed less fibrosis in RAGE inhibitor treated mice. F4/80 staining also demonstrated less inflammation in RAGE inhibitor treated mice. Data also showed that TTP488 displayed a greater inhibitory effect than FPS- Zml (data not shown).

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Abstract

L'invention concerne un procédé de traitement du cancer du sein, le procédé comprenant l'administration à un Sujet mammifère Qui En a besoin d'un inhibiteur du récepteur Pour un produit final de Glycation avancée (RAGE). L'invention concerne en outre un procédé d'inhibition de la métastase du cancer du sein, le Procédé comprenant l'administration à un sujet mammifère qui en a besoin d'un inhibiteur de RAGE.
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WO2020190984A1 (fr) * 2019-03-19 2020-09-24 City Of Hope Composés pour le traitement de la douleur neuropathique
CN115594642A (zh) * 2021-06-28 2023-01-13 广西医科大学（Cn） 阿齐瑞格三氮唑衍生物及其抗乳腺癌用途
US11648235B1 (en) 2022-12-30 2023-05-16 Cantex Pharmaceuticals, Inc. Treatment of glioblastoma
CN117427068A (zh) * 2023-11-15 2024-01-23 广州医科大学 阿齐瑞格在治疗奥希替尼耐药的肺腺癌中的应用

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TAKEUCHI ET AL.: "Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis : Novel treatment strategies", WORLD J HEPATOL., vol. 6, no. 12, 27 December 2014 (2014-12-27), pages 880 - 993, XP055608547, ISSN: 1948-5182, DOI: 10.4254/wjh.v6.i12.880 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020190984A1 (fr) * 2019-03-19 2020-09-24 City Of Hope Composés pour le traitement de la douleur neuropathique
CN115594642A (zh) * 2021-06-28 2023-01-13 广西医科大学（Cn） 阿齐瑞格三氮唑衍生物及其抗乳腺癌用途
CN119350257A (zh) * 2021-06-28 2025-01-24 广西医科大学 三氮唑化合物
CN119350257B (zh) * 2021-06-28 2025-11-18 广西医科大学 三氮唑化合物
US11648235B1 (en) 2022-12-30 2023-05-16 Cantex Pharmaceuticals, Inc. Treatment of glioblastoma
CN117427068A (zh) * 2023-11-15 2024-01-23 广州医科大学 阿齐瑞格在治疗奥希替尼耐药的肺腺癌中的应用

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