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WO2015158241A1 - Agents thérapeutiques reg3 - Google Patents

Agents thérapeutiques reg3 Download PDF

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Publication number
WO2015158241A1
WO2015158241A1 PCT/CN2015/076513 CN2015076513W WO2015158241A1 WO 2015158241 A1 WO2015158241 A1 WO 2015158241A1 CN 2015076513 W CN2015076513 W CN 2015076513W WO 2015158241 A1 WO2015158241 A1 WO 2015158241A1
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Prior art keywords
disorder
hreg3a
protein
cancer
bmi1
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Rongwen XI
Xicheng LIU
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National Institute of Biological Sciences Beijin
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National Institute of Biological Sciences Beijin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • PcG proteins are known as epigenetic silencers that form chromatin-associated complexes to repress gene transcription and are implicated in diverse cellular functions, including cell fate maintenance, proliferation and survival. They were initially identified in Drosophila as repressors of Hox genes, a function that is essentially conserved in mammals (Schwartz and Pirrotta, 2007) . Subsequent studies also demonstrate important roles of PcG members in stem cell maintenance and tumorigenesis, and many PcG members are frequently unregulated in various cancers and are regarded as proto-oncogenes (Sparmann and van Lohuizen, 2006; Valk-Lingbeek et al., 2004) .
  • Bmi1 is one of the best studied PcG proteins in mammals. It was first identified as a proto-oncogene collaboratively with Myc to initiate lymphoma (Haupt et al., 1991; van Lohuizen et al., 1991) . This oncogenic function on preventing Myc-induced apoptosis is largely due to its repressive effect on the Cdkn2a locus, which contains two tumor suppressor genes, p16 Ink4a and p19 ARF (Jacobs et al., 1999a; Jacobs et al., 1999b) .
  • Bmi1 is frequently overexpressed in many types of human cancers (Valk-Lingbeek et al., 2004) , and is as an important stem cell factor for maintaining self-renewal of both tissue-specific stem cells and cancer-initiating stem cells (Abdouh et al., 2009; Becker et al., 2009; Biehs et al., 2013; Cui et al., 2007; Dovey et al., 2008; Liu et al., 2006; Lukacs et al., 2010; Michael et al., 2008; Molofsky et al., 2005; Molofsky et al., 2003; Park et al., 2003; Proctor et al., 2013; Rizo et al., 2009; Zencak et al., 2005; Zhu et al., 2014) .
  • the mouse model of colitis-associated colorectal cancer has provided important insights into inflammation-associated tumorigenesis. Indeed, inflammation is associated with many types of cancers and may play a causative role in tumor initiation and metastasis (Grivennikov et al., 2010) .
  • IKK ⁇ -dependent activation of NF-kappaB in premalignant epithelial cells prevents apoptosis to facilitate tumor formation, whereas its activation in tumor-associated inflammatory cells promotes production of cytokines, which serve as critical environmental factors to promote tumorigenesis (Greten et al., 2004) .
  • cytokine is IL-6, which activates the receptor gp130 and associated JAK kinases, followed by phosphorylation and activation of STAT3 in malignant cells to promote their proliferation and survival (Bollrath et al., 2009; Grivennikov et al., 2009) .
  • activation of paracrine or autocrine STAT3 regulatory loop appears to be a major driver in various types of cancers.
  • EGFR/Ras-induced pancreatic ductal adenocarcinoma (DPAC) and lung adenocarcinoma EGFR/Ras induces expression of cytokines, which in turn activates STAT3 in an autocrine manner to promote proliferation and survival of tumor cells (Fukuda et al., 2011; Gao et al., 2007; Lesina et al., 2011) .
  • Ras-induced IL-6 expression and STAT3 activation were found in multiple types cancer cell lines (Ancrile et al., 2007) . Therefore, STAT3 may serve as a signaling node that connects autonomous proto-oncogenic stimuli with environmental inflammatory signals to initiate inflammation-associated tumorigenesis.
  • Bmi1 and Mel18 are critically required for tumor initiation and development in the experimental model of CAC.
  • the invention provides methods and compositions for attenuating IL-6 or STAT3 signaling or inhibiting IL-6 mediated STAT3 activation in a person in need thereof.
  • the invention provides a therapeutic method for treating a person determined to have a disorders are associated with STAT3 mis-or dysfunctional signaling, undesirable STAT3 signaling, dysregulation of IL-6 signaling, or IL6-mediated STAT3 activation.
  • the invention provides a method of attenuating IL-6 or STAT3 signaling or inhibiting IL-6 mediated STAT3 activation in a person in need thereof, the method comprising administering to a person a hREG3A protein (SEQ ID NO: 01) or, or an expression vector encoding said hREG3A protein.
  • the person is determined to have a disorder associated with dysfunctional IL-6 or STAT3 signaling, wherein the disorder is an autoimmune disease or inflammation-associated cancer.
  • the autoimmune disease is rheumatoid arthritis
  • the inflammation associated cancer is colitis-associated colorectal cancer (CAC) .
  • the hREG3A protein in the administering step, is administered parenterally by injection, such as intravenously, intratumor, subcutaneous, intramuscular, etc.
  • the method further comprises the prior step of determining hREG3A expression in cells of the person, and/or the subsequent step of determining a resultant therapeutic efficacy, such as an interruption or reduction in development of the cancer or autoimmune disease.
  • the administering step comprises administering the hREG3A protein, or expression vector encoding said hREG3A protein, with a second, different drug for treating the disorder associated with dysfunctional IL-6 or STAT3 signaling, such as those particular disorders described herein.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a hREG3A protein, or an expression vector encoding said hREG3A protein, and a pharmaceutical excipient, copackaged or coformulated with a second, different drug for treating a disorder associated with dysfunctional IL-6 or STAT3 signaling, wherein pharmaceutical composition may be in unit dosage.
  • the disorder is an autoimmune disease or inflammation-associated cancer, and preferably labeled or government (e.g. FDA) approved for such purpose.
  • the disorder is an inflammation-associated cancer
  • the second drug is selected from Fluorouracil, Bevacizumab, Irinotecan Hydrochloride, Capecitabine, Cetuximab, Leucovorin Calcium, Oxaliplatin, Panitumumab, Regorafenib, and Ziv-Aflibercept.
  • the disorder is an autoimmune disease
  • the second drug is selected from acetylsalicyclate, ibuprofen, naproxen, prednisone, methotrexate, leflunomide, hydroxychloroquine sulfasalazine, azathioprine, cyclophosphamide, chloambucil, cyclosporine, gold salts, D-penicillamine, etanercept, infliximab, anakinra, adalimumab, rituximab, abatacept, golimumab , certolizumab pegol, tocilizumab, and tofacitinib.
  • the invention encompasses all combination of the particular embodiments recited herein, such as wherein the disorder is colitis-associated colorectal cancer (CAC) and wherein the administering step, the hREG3A protein is administered parenterally by injection.
  • CAC colitis-associated colorectal cancer
  • the invention provides methods and compositions for attenuating IL-6 or STAT3 signaling in a person in need thereof, particularly wherein the person is determined to have a disorder associated with dysfunctional IL-6 or STAT3 signaling, particularly wherein the disorder is an autoimmune disease or inflammation-associated cancer.
  • the methods generally comprises administering to a person a hREG3A protein (SEQ ID NO: 01) or, or an expression vector encoding said hREG3A protein, optionally in conjunction, or mixed, coformulated or copackaged a second, different chemotherapeutic drug for treating the disorder.
  • hREG3A protein has the sequence: MLPPMALPSV SWMLLSCLML LSQVQGEEPQ RELPSARIRC PKGSKAYGSH CYALFLSPKS WTDADLACQK RPSGNLVSVL SGAEGSFVSS LVKSIGNSYS YVWIGLHDPT QGTEPNGEGW EWSSSDVMNY FAWERNPSTI SSPGHCASLS RSTAFLRWKD YNCNVRLPYV CKFTD (SED ID NO: 01) .
  • Applicable inflammation-associated cancers include breast, liver, prostate, colon, rectal, bladder, esophageal, stomach, mouth and lung cancer, or mesothelioma, Hodgkin lymphoma, and papillary thyroid cancer
  • second drugs applicable thereto include chemotherapeutic drugs like Fluorouracil, Bevacizumab, Irinotecan Hydrochloride, Capecitabine, Cetuximab, Leucovorin Calcium, Oxaliplatin, Panitumumab, Regorafenib, and Ziv-Aflibercept.
  • Applicable autoimmune diseases or disorders include osteoporosis, neoplasia, aging, rheumatoid arthritis (RA) , juvenile idiopathic arthritis (JIA) , systemic JIA (sJIA) , polyarticular course JIA (pcJIA) , psoriatic arthritis, Castleman's disease, Crohn's disease, multiple myeloma, polymyalgia rheumatica, glomerulonephritis, plasmacytoma or plasmacytosis, myeloma (including multiple myeloma) , hyperimmunoglobulinemia, anemia, nephritis (such as mesangium proliferative nephritis) , cachexia (including cancerous cachexia) , tumors, T cell mediated disease (e.g.
  • uveitis chronic thyroiditis, delayed hypersensitivity, contact dermatitis, or atopic dermatitis
  • lupus including lupus nephritis and systemic lupus erythmatosus
  • inflammatory bowel disease including Crohn's disease and ulcerative colitis
  • pancreatitis pancreatic islet transplantation
  • myocardial infarction heart failure, ischemia-induced severe arrhythmia
  • heart transplantation prostate cancer
  • choroidal neovascularization e.g.
  • idiopathic choroidal neovascularization e.g., idiopathic choroidal neovascularization, cyopic choroidal neovascularization, idiopathic choroidal neovascularization
  • muscle atrophy e.g., muscle atrophy, chronic rejection, ocular inflammatory disease (e.g.
  • panuveitis anterior aveitis, intermediate uveitis, scleritis, keratitis, orbital inflammation, optic neuritis, dry eye, diabetic retinopathy, proliferative vitreoretinopathy, postoperative inflammation) , graft versus host disease (GVHD) , fibrotic disorders (such as systemic sclerosis) , giant cell arteritis (GCA) , Takayasu’s arteritis (TA) , arteritis nodosa, ankylosing spondylitis, etc.
  • GVHD graft versus host disease
  • fibrotic disorders such as systemic sclerosis
  • GCA giant cell arteritis
  • TA Takayasu’s arteritis
  • arteritis nodosa ankylosing spondylitis, etc.
  • the disorder is rheumatoid arthritis or juvenile idiopathic arthritis (JIA) , systemic JIA (sJIA) , polyarticular course JIA (pcJIA) , giant cell arteritis (GCA) , or systemic sclerosis.
  • JIA juvenile idiopathic arthritis
  • sJIA systemic JIA
  • pcJIA polyarticular course JIA
  • GCA giant cell arteritis
  • systemic sclerosis rheumatoid arthritis or juvenile idiopathic arthritis
  • sJIA systemic JIA
  • pcJIA polyarticular course JIA
  • GCA giant cell arteritis
  • Second drugs for such autoimmune disorders include nonsteroidal anti-inflammatory drugs (NSAIDs, like acetylsalicyclate, ibuprofen and naproxen and etodolac; steroids, like prednisone; Disease-modifying antirheumatic drugs (DMARDs) , such as methotrexate, leflunomide, hydroxychloroquine and sulfasalazine; immunosuppressants, like azathioprine, cyclophosphamide, chloambucil and cyclosporine, gold salts, D-penicillamine, and biologic RA drugs like etanercept, infliximab, anakinra, adalimumab, rituximab, abatacept, golimumab , certolizumab pegol, tocilizumab, and tofacitinib.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • DMARDs disease-
  • compositions at typically administered in a therapeutically effective amount, which elicits, to a significant extent, a chemotherapeutic (anti-cancer) response.
  • the therapeutically effective amount will vary depending on the formulation, the disease and its severity and the age, weight, etc., of the person to be treated.
  • compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage, a physically discrete unit suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material (s) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Suitable excipients or carriers and methods for preparing administrable compositions are known or apparent to those skilled in the art and are described in more detail in such publications as Remington's Pharmaceutical Science, Mack Publishing Co, NJ (2012) .
  • the compounds may be advantageously used in conjunction with other therapeutic, analgesic, etc. agents as described herein or otherwise known in the art.
  • the amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target disease, patient, the route of administration, etc.
  • mice containing floxed alleles of Bmi1 and/or Mel18 and a transgene expressing Cre recombinase under the control of villin gene promoter (villin-cre) , an intestine-specific promoter (Madison et al., 2002) . These mice hereafter referred to as Bmi1 col-/- , Mel18 col-/- and DKO mice, respectively.
  • mice of appropriate genotypes were injected with the colonphilic mutagen theazoxymethane (AOM) followed by three cycles of the luminal toxin dextran sodiumsulfate (DSS) treatment to trigger chronic inflammation, as previously described ( Greten et al., 2004 ) . After the AOM-DSS treatment, upon gross inspection, the WT mice gradually developed intestinal polyps.
  • AOM colonphilic mutagen theazoxymethane
  • DSS luminal toxin dextran sodiumsulfate
  • Bmi1 col-/- or Mel18 col-/- mice also gradually developed polyps.
  • DKO mice exhibited significantly fewer polyps compared to WT, Bmi1 col-/- or Mel18 col-/- mice. Histological analysis revealed that the DKO mice had markedly decreased tumor incidence and tumor load.
  • adenomas observed in the colons of DKO mice generally showed only low-grade dysplasias, but adenomas with high grade dysplasia characterized by aggressive invasion of the muscularis mucosa were frequently observed in WT, Bmi1 col-/- or Mel18 col-/- colons.
  • mice containing the floxed alleles of Bmi1 and Mel18 and the Villin-Cre-ERT2 driver el Marjou et al., 2004 .
  • mice containing the floxed alleles of Bmi1 and Mel18 and the Villin-Cre-ERT2 driver el Marjou et al., 2004 .
  • mice of appropriate genotypes were allowed to develop tumors after the AOM-DSS treatment and tamoxifen was delivered 3 days after the last DSS treatment. The mice were cultured for additional 20 days before analysis.
  • Bmi1 is known as a proto-oncogene that positively regulate cell proliferation, we reasoned that the decreased tumorigenesis in DKO mice could be due to reduced cell proliferation and/or increased cell death.
  • immunohistochemical analysis of Ki-67 revealed impaired proliferation of the colonic enterocytes of DKO mice compared to colonic crypts of WT, or single KO mice.
  • Staining for active caspse-3 revealed a reciprocal increase in apoptosis of IECs in DKO mice. Therefore, simultaneous depletion of Bmi1 and Mel18, but not either alone, reduces cell proliferation and increases cell death in IECs during CAC tumorigenesis, phenotypes that can explain the tumor suppression effect.
  • the Cdkn2a locus which encodes p16 Ink4a and p19 Arf tumor suppressors, is known as a Bmi1 targeting locus ( Jacobs et al., 1999a ) .
  • Significant up-regulation of p16 mRNA levels was also observed in Mel18 -/- MEFs ( Jacobs et al., 1999a ) . It is therefore reasonable to speculate that the failed CAC tumorigenesis in DKO mice could be due to the autonomous activation of the Ink4a/Arf locus and consequently cell cycle arrest and apoptosis in premalignant cells.
  • TKO vilin-cre
  • Bmi1 col-/- Mel18 col-/- Cdkn2a col-/- triple deficient mice referred to as TKO hereafter mice.
  • TKO triple deficient mice
  • the DKO mice exhibited greater body weight loss than WT or single KO mice. Histologically, these mice showed a significantly higher degree of mucosa damage and an increased incidence of ulcerations. Along with increased inflammatory cell infiltration, these are typical phenotypes of hyper inflammatory response.
  • proinflammatory genes including IL-6, IL-1 ⁇ , IL-11, TNF ⁇ and Cox-2 were significantly elevated in the colonic mucosa. Again, these inflammatory cytokines were not up-regulated in Bmi1 col-/- or Mel18 col-/- mice, further supporting that Bmi1 and Mel18 have redundant roles in this process.
  • the proapoptotic gene Bcl10, and several cell-cycle inhibitors were significantly up-regulated in DKO mice compared to control ones.
  • the altered STAT3 activation therefore provides a molecular explanation for the tumor suppression effect caused by Bmi1 and Mel18 ablation during CAC tumorigenesis.
  • Reg family genes in human colorectal cancers.
  • hREG1A hREG1A
  • REG1B REG3A
  • REG3G REG3G
  • REG4 Parikh et al., 2012
  • hREG3A showed robust STAT3 inhibition.
  • hREG3A has the closest similarity to, and is the human ortholog for mouse Reg3b ( Liu and Cui, 2007 ) .
  • Collagen Induced Arthritis is an established experimental model of Rheumatoid Arthritis (RA) .
  • RA Rheumatoid Arthritis
  • rats are administered recombinant Reg3b by intraperitoneal injection at early and late time points in the CIA model described by Hu et al. Biomed Res Int. 2014; 2014: 325875.
  • bovine collagen-II (CII) Chondrex, 2002, USA, dissolved in 0.05 M acetic acid) is emulsified with an equal volume of incomplete Freund's adjuvant ( (IFA) Chondrex, 7002, USA) .
  • This CII-IFA emulsified liquid is administered as a 0.2 mL intradermal injection at the dorsum of each rat's tail, approximately 2 cm distal from the base.
  • each rat receives 0.1 mL of CII-IFA booster via intradermal injection on the tail's ventral side.
  • rats are monitored three times a week by the same person blinded to the treatment group, and the incidence of arthritis and clinical score are evaluated.
  • This model demonstrates that administration of recombinant Reg3b significantly attenuates progression of (CIA) , indicating its therapeutic application to rheumatoid arthritis.
  • Reg3b belongs to a family of small secreted proteins that contain a single C-type (calcium-dependent) lectin domain. Reg proteins, or named also pancreatitis-associated proteins (PAP) , were initially discovered as proteins strongly induced by pancreatitis or during islet regeneration ( Parikh et al., 2012 ) . Later studies have revealed that Reg proteins are also expressed in a number of physiological or pathological processes. For instance, in the gut, it has been suggested that Reg3g could serve as a carbohydrate-binding bactericidal lectin to maintain microbial integrity ( Cash et al., 2006 ) .
  • PAP pancreatitis-associated proteins
  • Reg proteins In addition to a role in pancreatic beta cell proliferation, Reg proteins have been implicated as modulators of inflammation, but many observed correlations could not be ambiguously confirmed by the vivo knock out studies, possibly due to functional redundancies among the Reg family members.
  • STAT3 activity is enhanced during liver regeneration ( Lieu et al., 2006 ) .
  • STAT activation is reduced during caerulein-induced pancreatitis ( Gironella et al., 2007 ) .
  • Reg3b, 3g are all targeted by Bmi1 and Mel18, only Reg3b, but not Reg3g, shows robust anti-STAT3 activity.
  • REG3A which shows the highest structural similarity to Reg3b, shows robust anti-STAT3 activity.
  • the expression of hREG3A is inversely correlated with the grade or invasiveness of colorectal cancers.
  • Reg3b and hREG3A are highly expressed in small intestine but not colon ( Parikh et al., 2012 ) , consistent with their expression in small intestine providing a tumor suppressive environment, which explains the strikingly distinct incidences of carcinomas in small intestine and colon.
  • BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29, 8884-8896.
  • Polycomb group protein Bmi1 is required for growth of RAF driven non-small-cell lung cancer.
  • BMI1 represses Ink4a/Arf and Hox genes to regulate stem cells in the rodent incisor. Nat Cell Biol 15, 846-852.
  • Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12, 328-341.
  • Bmi-1 is essential for the tumorigenicity of neuroblastoma cells.
  • RNAi screen for BMI1 targets identifies TGF-beta/BMP-ER stress pathways as key regulators of neural-and malignant glioma-stem cell homeostasis. Cancer Cell 23, 660-676.
  • IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285-296.
  • IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103-113.
  • Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation.
  • Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19, 1432-1437.
  • Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302-305.
  • Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma.
  • Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci. Cell Stem Cell 9, 272-281.
  • Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation. J Neurosci 25, 5774-5783.

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Abstract

La présente invention concerne l'atténuation de la voie de signalisation IL-6 ou STAT3, et le traitement de troubles associés au moyen d'une protéine hREG3A ou d'un vecteur d'expression codant pour ladite protéine hREG3A, et éventuellement d'un second médicament différent pour le trouble concerné.
PCT/CN2015/076513 2014-04-18 2015-04-14 Agents thérapeutiques reg3 Ceased WO2015158241A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019012128A1 (fr) * 2017-07-13 2019-01-17 Institut National De La Sante Et De La Recherche Medicale (Inserm) Reg3alpha destiné à être utilisé dans la protection de bactéries gram-positives sensibles à l'oxygène
WO2023023256A1 (fr) * 2021-08-18 2023-02-23 Oculogenex Inc. Transfert de gènes médié par aav pour une rétinopathie

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896499A (zh) * 2007-08-30 2010-11-24 库尔Dm股份有限公司 使用前胰岛肽及其类似物的组合物和方法
US20110229435A1 (en) * 2007-02-12 2011-09-22 The Board Of Regents Of The University Of Texas System Expression and purification of hip/pap and uses therefor
EP2687225A1 (fr) * 2012-07-19 2014-01-22 Alfact Innovation Protéine HIP/PAP et ses dérivés pour une utilisation dans le traitement du cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110229435A1 (en) * 2007-02-12 2011-09-22 The Board Of Regents Of The University Of Texas System Expression and purification of hip/pap and uses therefor
CN101896499A (zh) * 2007-08-30 2010-11-24 库尔Dm股份有限公司 使用前胰岛肽及其类似物的组合物和方法
EP2687225A1 (fr) * 2012-07-19 2014-01-22 Alfact Innovation Protéine HIP/PAP et ses dérivés pour une utilisation dans le traitement du cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GAO YANG ET AL.: "Expression and functional characterization of Rge3A protein in Escherichia coli", MICROBIOLOGY CHINA, vol. 38, no. 8, 20 August 2011 (2011-08-20), pages 1249 - 1255 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019012128A1 (fr) * 2017-07-13 2019-01-17 Institut National De La Sante Et De La Recherche Medicale (Inserm) Reg3alpha destiné à être utilisé dans la protection de bactéries gram-positives sensibles à l'oxygène
CN112004549A (zh) * 2017-07-13 2020-11-27 国家健康与医学研究院 用于保护氧敏感革兰氏阳性菌的REG3α
EP4019036A1 (fr) * 2017-07-13 2022-06-29 The Healthy Aging Company Reg3alpha pour utilisation dans la protection de bactéries à gram positif sensibles à l'oxygène
US11484569B2 (en) 2017-07-13 2022-11-01 Institut National De La Sante Et De La Recherche Medicale (Inserm) Polypeptide for use in the protection of oxygen sensitive gram-positive bacteria
WO2023023256A1 (fr) * 2021-08-18 2023-02-23 Oculogenex Inc. Transfert de gènes médié par aav pour une rétinopathie

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