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WO2018167283A1 - Procédés pour le diagnostic et le traitement d'un remodelage neuronal associé à un adénocarcinome canalaire pancréatique - Google Patents

Procédés pour le diagnostic et le traitement d'un remodelage neuronal associé à un adénocarcinome canalaire pancréatique Download PDF

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WO2018167283A1
WO2018167283A1 PCT/EP2018/056706 EP2018056706W WO2018167283A1 WO 2018167283 A1 WO2018167283 A1 WO 2018167283A1 EP 2018056706 W EP2018056706 W EP 2018056706W WO 2018167283 A1 WO2018167283 A1 WO 2018167283A1
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lif
pda
inhibitor
panr
subject
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PCT/EP2018/056706
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Richard TOMASINI
Jérémy NIGRI
Christian BRESSY
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université D'aix Marseille
Institut Jean Paoli & Irene Calmettes
Centre National De La Recherche Scientifique (Cnrs)
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Publication of WO2018167283A1 publication Critical patent/WO2018167283A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease

Definitions

  • the present invention relates to the diagnosis of pancreatic ductal adenocarcinoma (PDA) associated neural remodeling (PANR).
  • PDA pancreatic ductal adenocarcinoma
  • PANR pancreatic ductal adenocarcinoma
  • the present invention also relates to methods and pharmaceutical compositions for the treatment of PDA associated neural remodeling (PANR).
  • Pancreatic ductal adenocarcinoma is considered as one of the most serious cancers, with a quick and asymptomatic evolution leading to a very low survival rate in patients (1,2)
  • current treatments mainly based on surgery and chemotherapies, have a limited impact on the patient's fate, in part due to impaired drug perfusion provoked by the stromal reaction surrounding tumor cells (4,5).
  • PDA is characterized by the presence of a predominant stroma (intra-tumoral microenvironment) composed of cancer associated fibroblasts (CAFs), immune, endothelial and nerve cells.
  • CAFs cancer associated fibroblasts
  • These have all been reported as drastic modifiers of tumor cells' abilities thereby impacting on pancreatic tumor evolution and prognosis (6).
  • recent advances based on the effects of the stromal compartment on PDA are limited, and their clinical translation remains difficult (7).
  • PNI perineural invasion
  • LIF has a direct role on PDA Associated Neural Remodeling.
  • stromal cells mainly macrophages and fibroblasts, have the ability to secrete LIF acting then on pancreatic neural compartment.
  • LIF can induce migration and differentiation of Schwann cells and neural plasticity of dorsal root ganglia (DRG) neurons through modulation of the JAK/STAT3 intracellular signaling.
  • DRG dorsal root ganglia
  • the present invention relates to the diagnosis of pancreatic ductal adenocarcinoma
  • PDA PDA associated neural remodeling
  • PANR PDA associated neural remodeling
  • the inventors investigated the effects of the stromal compartment on pancreatic ductal adenocarcinoma (PDA) and PDA associated neural remodeling (PANR).
  • PDA pancreatic ductal adenocarcinoma
  • PANR PDA associated neural remodeling
  • the inventors also investigated the specific connection between the stromal compartment and the nerve system in PDA.
  • PDA is characterized by a large stroma and important peripheral nervous system modifications.
  • the inventors provide in vitro and in vivo evidences that LIF (leukemia inhibitory factor), a pro-inflammatory cytokine belonging to the IL-6 family, is involved in PDA associated neural remodeling (PANR).
  • LIF leukemia inhibitory factor
  • LIF is overexpressed in PDA tissues compared to healthy pancreas while its receptors, LIFR and gpl30, are expressed in intra-tumoral nerves.
  • both cancer and stromal cells expressed LIF, only stromal cells showed the ability to secrete LIF in the extra-cellular medium.
  • This secreted LIF induced Schwann cell migration, decreased proliferation and modulated their differentiation status, through the activation of the JAK/STAT3/AKT intracellular signaling.
  • LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area.
  • LIF blocking antibody in endogenous PDA mice model reduces intra-tumoral nerve density supporting the important role of LIF in PANR. Furthermore, using human and mouse serum libraries, the inventors showed that LIF titer improves CA19.9 diagnostic value and is positively correlated with intra-tumoral nerve density. Altogether, the present invention highlight the potential use of LIF serum titrating as a valuable diagnostic tool, as well as a therapeutic strategy aiming to limit LIF's impact on PANR.
  • the present invention relates to a LIF inhibitor for use in the treatment of PDA associated neural remodeling (PANR) in a subject in need thereof.
  • PANR PDA associated neural remodeling
  • a subject denotes a mammal.
  • a subject according to the invention refers to any subject (preferably human) afflicted with pancreatic ductal adenocarcinoma (PDA).
  • PDA pancreatic ductal adenocarcinoma
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subjects at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • pancreatic ductal adenocarcinoma or “PDA” has its general meaning in the art and refers to pancreatic ductal adenocarcinoma such as revised in the World Health Organisation Classification C25.
  • PDA associated neural remodeling or "PANR” has its general meaning in the art and refers to conditions resulting in higher nerve densities in PDA due to peripheral nerve fibers infiltration and axonogenesis (9, 10).
  • the term “PDA associated neural remodeling” also refers to alterations caused by the PDA intratumoral microenvironment (11), this includes increased neural density, hypertrophy and pancreatic neuritis, as well as intra and extrapancreatic perineural invasion (PNI) by cancer cells (7, 9).
  • PNI intra and extrapancreatic perineural invasion
  • the term “PDA associated neural remodeling” also refers to neural remodelling which is clinically correlated with neuropathic pain (7). Accordingly, the LIF inhibitor of the present invention is thus particularly suitable for reducing neuropathic pain in a subject suffering from pancreatic ductal adenocarcinoma.
  • LIF has its general meaning in the art and refers to the cytokine leukemia inhibitory factor, a member of interleukin (IL)-6 family (Nicolas and Babon, 2015).
  • the term “LIF” also refers to a glycoprotein synthesised as a 202 amino acid precursor that is post-translationally processed into a 20 kDa form by removal of 22 amino acids from its N-terminus (Nicolas and Babon, 2015).
  • LIF inhibitor has its general meaning in the art and refers to a compound that selectively blocks or inactivates the LIF.
  • LIF inhibitor also refers to a compound that selectively blocks the binding of LIF to its receptors (LIFR and gpl30).
  • LIF inhibitor also relates to LIF complex component inhibitor.
  • LIF inhibitor also refers to a compound able to prevent the action of LIF and LIF complex component for example by inhibiting the LIF controls of downstream effectors such as inhibiting the activation of the JAK/STAT3/AKT intracellular signaling.
  • the term “selectively blocks or inactivates” refers to a compound that preferentially binds to and blocks or inactivates LIF with a greater affinity and potency, respectively, than its interaction with the other sub-types of the interleukine family.
  • Compounds that block or inactivate LIF, but that may also block or inactivate other interleukine sub-types, as partial or full inhibitors, are contemplated.
  • the term "LIF inhibitor” also refers to a compound that inhibits LIF complex components expression.
  • a LIF inhibitor is a small organic molecule, a polypeptide, an aptamer, an antibody, an oligonucleotide or a ribozyme.
  • Tests and assays for determining whether a compound is a LIF inhibitor are well known by the skilled person in the art such as described in Vernallis et al., 1997; WO03064463; WO2011124566.
  • LIF inhibitors are well-known in the art as illustrated by Vernallis et al., 1997;
  • LIF inhibitors include but are not limited to the dominant-negative LIF mutant (hLIF-05) (Vernallis et al., 1997; WO03064463) and anti-LIF inhibitory antibodies such as described in WO2011/124566; WO 93/23556.
  • the LIF inhibitor of the invention is a compound inhibiting the
  • LIF complex component such as LIFR and gpl30 antagonists.
  • LIF complex component has its general meaning in the art and refers to the ternary complex or trimer that consists of the LIF bound to gpl30 as well as to LIFR (Nicolas and Babon, 2015).
  • the present invention also relates to a compound which is selected from the group consisting of LIFR antagonist, LIFR expression inhibitor, gpl30 antagonist and gpl03 expression inhibitor for use in the treatment of PDA associated neural remodeling (PANR) in a subject in need thereof.
  • a compound which is selected from the group consisting of LIFR antagonist, LIFR expression inhibitor, gpl30 antagonist and gpl03 expression inhibitor for use in the treatment of PDA associated neural remodeling (PANR) in a subject in need thereof.
  • PANR PDA associated neural remodeling
  • LIFR has its general meaning in the art and refers to the cytokine leukemia inhibitory factor (LIF) receptor.
  • LIF cytokine leukemia inhibitory factor
  • LIFR also refers to LIFRp, a transmembrane signaling subunit that is structurally related to gpl30 (Nicolas and Babon, 2015).
  • LIFR antagonist has its general meaning in the art and refers to compounds such as anti-LIFR antibodies and dominant-negative LIF mutant (hLIF-05) (Vernallis et al., 1997; WO03064463).
  • gpl30 has its general meaning in the art and refers to CD 130, the cytokine leukemia inhibitory factor (LIF) subunit complex receptor (Nicolas and Babon, 2015).
  • gpl30 antagonist has its general meaning in the art and refers to compounds such as quinoxalinhydrazide derivative SC144 having the general formula (I), AG490 having the general formula (II), soluble forms of gpl30 (sgpl30) and compounds described in Seo et al., 2009; Xu et al., 2013; Huang et al., 2010; Fernandez-Botran, 2000; Xu and Neamati, 2013.
  • the LIF inhibitor is a JAK/STAT3/AKT intracellular signaling inhibitor.
  • JAK/STAT3/AKT intracellular signaling inhibitor has its general meaning in the art and refers to compounds such as JAK inhibitors, STAT3 antagonists and AKT inhibitors.
  • JAK inhibitors such as JAK2 inhibitors are well known in the art (Tibes R, Bogenberger JM, Geyer HL, Mesa RA. JAK2 inhibitors in the treatment of myeloproliferative neoplasms. Expert Opin Investig Drugs. 2012 Dec;21(12): 1755-74; Dymock BW, See CS. Inhibitors of JAK2 and JAK3: an update on the patent literature 2010 - 2012. Expert Opin Ther Pat.
  • JAK inhibitor also refers to JAK1 inhibitors such as ruxolitinib (INCB018424); GLPG-0634; Anilinophthalazine-based JAK1 inhibitors and compounds described in Norman, 2012; Nicolas and Babon, 2015; WO2010/135650; WO2011/086053; WO2009/152133; WO2011/068881; WO2011/112662; WO2012/037132.
  • STAT3 antagonists are well-known in the art as illustrated by Yu W., J Med Chem. 2013 May 7; Turkson et al., Mol Cancer Ther. 2004 Mar;3(3):261-9; McMurray JS. Chem Biol. 2006 Nov;13(l l): 1123-4; Liu A, Cancer Sci. 2011 Jul;102(7): 1381-7; Song H., Proc Natl Acad Sci U S A. 2005 Mar 29;102(13); and Wang X., Int J Oncol. 2012 Jul;24.
  • STAT3 antagonists refers to compounds such as compounds that inhibit STAT3 phosphorylation such as PM-73G and pCinn-Leu-cis-3,4-methanoPro-Gln-NHBn (Yu W., J Med Chem. 2013 May 7); and non-peptidomimetic small inhibitors such as 5-hydroxy- 9, 10-dioxo-9,10-dihydroanthracene-l -sulfonamide (LLL12) and a steroidal natural product such as cucurbitacin (McMurray JS. Chem Biol. 2006 Nov;13(l l): 1123-4; Yu W., J Med Chem. 2013 May 7).
  • STAT3 antagonists also refers to compounds that inhibit STAT3 dimerization such as peptidomimetics XZH-5(Yu W., J Med Chem. 2013 May 7); ISS 610; ISS 219 and compounds described in Turkson et al., Mol Cancer Ther. 2004 Mar;3(3):261-9; and small molecules such as Stattic; STA-2; LLL-3; S3I-201 (NSC 74859); S3I-20; S3I- 201.1066; S3I-M200; 5,15-DPP; STX-0119; Niclosamide (Siddiquee KA., ACS Chem Biol. 2007 Dec 21;2(12):787-98; Yu W., J Med Chem.
  • STAT3 antagonists refers to compounds such as 5,8-dioxo-6-(pyridin-3- ylamino)-5,8-dihydronaphthalene- 1-sulfonamide (LY5); Naphthalene-5,8-dione- 1- sulfonamide (Naphthalenesulfonylchloride); 5,8-dioxo-6-(phenylamino)-5,8- dihydronaphthalene- 1-sulfonamide; 5H-Naphth[ 1 ,8-cJJisothiazol-5-one, 1 , l-dioxide,6- (phenylamino); 5H-Naphth[ 1 ,8-cJJisothiazol-5-one, 1 , l-dioxide,6-( 1 ' -chloro-3 ' -nitro-2' - phenylamino); 5H-Naphth[
  • Niclosamide (Yu W., J Med Chem. 2013 May 7); FLLL31; FLLL32 (Liu A, Cancer Sci. 2011 Jul;102(7): 1381-7); NCT00511082; NCT00657176; NCT00955812; NCT01029509; NCT00696176 (Wang X., Int J Oncol. 2012 Jul 24).
  • the LIF inhibitor of the invention is an aptamer.
  • Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition.
  • Aptamers are oligonucleotide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.
  • Such ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library, as described in Tuerk C. and Gold L., 1990.
  • the random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence.
  • Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli Thioredoxin A that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996). Then after raising aptamers directed against LIF of the invention as above described, the skilled man in the art can easily select those blocking or inactivating LIF.
  • a platform protein such as E. coli Thioredoxin A
  • the LIF inhibitor of the invention is an antibody (the term including "antibody portion") directed against LIF, LIFR, gpl30, or LIF complex component.
  • the antibody is a monoclonal antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a polyclonal antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a humanized antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a chimeric antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a light chain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a heavy chain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fab portion of the antibody.
  • the portion of the antibody comprises a F(ab')2 portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fc portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fv portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a variable domain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises one or more CDR domains of the antibody.
  • antibody includes both naturally occurring and non-naturally occurring antibodies. Specifically, “antibody” includes polyclonal and monoclonal antibodies, and monovalent and divalent fragments thereof. Furthermore, “antibody” includes chimeric antibodies, wholly synthetic antibodies, single chain antibodies, and fragments thereof. The antibody may be a human or nonhuman antibody. A nonhuman antibody may be humanized by recombinant methods to reduce its immunogenicity in man.
  • Antibodies are prepared according to conventional methodology. Monoclonal antibodies may be generated using the method of Kohler and Milstein (Nature, 256:495, 1975). To prepare monoclonal antibodies useful in the invention, a mouse or other appropriate host animal is immunized at suitable intervals (e.g., twice-weekly, weekly, twice-monthly or monthly) with antigenic forms of LIF, LIFR, gpl30, or LIF complex component. The animal may be administered a final "boost" of antigen within one week of sacrifice. It is often desirable to use an immunologic adjuvant during immunization.
  • Suitable immunologic adjuvants include Freund's complete adjuvant, Freund's incomplete adjuvant, alum, Ribi adjuvant, Hunter's Titermax, saponin adjuvants such as QS21 or Quil A, or CpG-containing immunostimulatory oligonucleotides.
  • Other suitable adjuvants are well-known in the field.
  • the animals may be immunized by subcutaneous, intraperitoneal, intramuscular, intravenous, intranasal or other routes. A given animal may be immunized with multiple forms of the antigen by multiple routes.
  • the antigen may be provided as synthetic peptides corresponding to antigenic regions of interest in LIF, LIFR, or gpl30.
  • lymphocytes are isolated from the spleen, lymph node or other organ of the animal and fused with a suitable myeloma cell line using an agent such as polyethylene glycol to form a hydridoma.
  • cells are placed in media permissive for growth of hybridomas but not the fusion partners using standard methods, as described (Coding, Monoclonal Antibodies: Principles and Practice: Production and Application of Monoclonal Antibodies in Cell Biology, Biochemistry and Immunology, 3rd edition, Academic Press, New York, 1996).
  • cell supernatants are analyzed for the presence of antibodies of the desired specificity, i.e., that selectively bind the antigen.
  • Suitable analytical techniques include ELISA, flow cytometry, immunoprecipitation, and western blotting. Other screening techniques are well-known in the field. Preferred techniques are those that confirm binding of antibodies to conformationally intact, natively folded antigen, such as non- denaturing ELISA, flow cytometry, and immunoprecipitation.
  • an antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc' region designated an F(ab')2 fragment, retains both of the antigen binding sites of an intact antibody.
  • an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region designated an Fab fragment, retains one of the antigen binding sites of an intact antibody molecule.
  • Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd.
  • the Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation.
  • CDRs complementarity determining regions
  • FRs framework regions
  • CDR1 through CDRS complementarity determining regions
  • compositions and methods that include humanized forms of antibodies.
  • humanized describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules.
  • Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference.
  • the above U.S. Pat. Nos. 5,585,089 and 5,693,761, and WO 90/07861 also propose four possible criteria which may used in designing the humanized antibodies.
  • the first proposal was that for an acceptor, use a framework from a particular human immunoglobulin that is unusually homologous to the donor immunoglobulin to be humanized, or use a consensus framework from many human antibodies.
  • the second proposal was that if an amino acid in the framework of the human immunoglobulin is unusual and the donor amino acid at that position is typical for human sequences, then the donor amino acid rather than the acceptor may be selected.
  • the third proposal was that in the positions immediately adjacent to the 3 CDRs in the humanized immunoglobulin chain, the donor amino acid rather than the acceptor amino acid may be selected.
  • the fourth proposal was to use the donor amino acid reside at the framework positions at which the amino acid is predicted to have a side chain atom within 3A of the CDRs in a three dimensional model of the antibody and is predicted to be capable of interacting with the CDRs.
  • the above methods are merely illustrative of some of the methods that one skilled in the art could employ to make humanized antibodies.
  • One of ordinary skill in the art will be familiar with other methods for antibody humanization.
  • humanized forms of the antibodies some, most or all of the amino acids outside the CDR regions have been replaced with amino acids from human immunoglobulin molecules but where some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they would not abrogate the ability of the antibody to bind a given antigen.
  • Suitable human immunoglobulin molecules would include IgGl, IgG2, IgG3, IgG4, IgA and IgM molecules.
  • a "humanized" antibody retains a similar antigenic specificity as the original antibody.
  • Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and references cited therein, the contents of which are incorporated herein by reference.
  • mice have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies.
  • the animals are further modified to contain all or a portion of the human germ-line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human antibodies to the antigen of interest.
  • monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies will have human immunoglobulin amino acid sequences and therefore will not provoke human anti-mouse antibody (KAMA) responses when administered to humans.
  • KAMA human anti-mouse antibody
  • the present invention also provides for F(ab') 2 Fab, Fv and Fd fragments; chimeric antibodies in which the Fc and/or FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; chimeric F(ab')2 fragment antibodies in which the FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; chimeric Fab fragment antibodies in which the FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; and chimeric Fd fragment antibodies in which the FR and/or CDR1 and/or CDR2 regions have been replaced by homologous human or non-human sequences.
  • the present invention also includes so-called single chain antibodies.
  • the various antibody molecules and fragments may derive from any of the commonly known immunoglobulin classes, including but not limited to IgA, secretory IgA, IgE, IgG and IgM.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4.
  • the LIF inhibitor of the invention is a Human IgG4.
  • the antibody according to the invention is a single domain antibody.
  • the term “single domain antibody” (sdAb) or "VHH" refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains.
  • VHH refers to the single heavy chain having 3 complementarity determining regions (CDRs): CDRl, CDR2 and CDR3.
  • CDR complementarity determining region
  • CDR refers to the hypervariable amino acid sequences which define the binding affinity and specificity of the VHH.
  • VHH according to the invention can readily be prepared by an ordinarily skilled artisan using routine experimentation.
  • VHH variants and modified form thereof may be produced under any known technique in the art such as in-vitro maturation.
  • VHHs or sdAbs are usually generated by PCR cloning of the V-domain repertoire from blood, lymph node, or spleen cDNA obtained from immunized animals into a phage display vector, such as pHEN2.
  • Antigen- specific VHHs are commonly selected by panning phage libraries on immobilized antigen, e.g., antigen coated onto the plastic surface of a test tube, biotinylated antigens immobilized on streptavidin beads, or membrane proteins expressed on the surface of cells.
  • immobilized antigen e.g., antigen coated onto the plastic surface of a test tube, biotinylated antigens immobilized on streptavidin beads, or membrane proteins expressed on the surface of cells.
  • VHHs often show lower affinities for their antigen than VHHs derived from animals that have received several immunizations.
  • VHHs from immune libraries are attributed to the natural selection of variant VHHs during clonal expansion of B-cells in the lymphoid organs of immunized animals.
  • the affinity of VHHs from non-immune libraries can often be improved by mimicking this strategy in vitro, i.e., by site directed mutagenesis of the CDR regions and further rounds of panning on immobilized antigen under conditions of increased stringency (higher temperature, high or low salt concentration, high or low pH, and low antigen concentrations).
  • VHHs derived from camelid are readily expressed in and purified from the E. coli periplasm at much higher levels than the corresponding domains of conventional antibodies.
  • VHHs generally display high solubility and stability and can also be readily produced in yeast, plant, and mammalian cells.
  • the "Hamers patents” describe methods and techniques for generating VHH against any desired target (see for example US 5,800,988; US 5,874, 541 and US 6,015,695).
  • the "Hamers patents” more particularly describe production of VHHs in bacterial hosts such as E. coli (see for example US 6,765,087) and in lower eukaryotic hosts such as moulds (for example Aspergillus or Trichoderma) or in yeast (for example Saccharomyces, Kluyveromyces, Hansenula or Pichia) (see for example US 6,838,254).
  • the LIF inhibitor of the invention is a LIF complex components expression inhibitor such as LIF expression inhibitor, LIFR expression inhibitor and gpl30 expression inhibitor.
  • a gene product can be the direct transcriptional product of a gene (e.g., mRNA, tRNA, rRNA, antisense RNA, ribozyme, structural RNA or any other type of RNA) or a protein produced by translation of a mRNA.
  • Gene products also include messenger RNAs, which are modified, by processes such as capping, polyadenylation, methylation, and editing, and proteins (e.g., LIF complex components such as LIF, LIFR and gpl30) modified by, for example, methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, myristilation, and glycosylation.
  • proteins e.g., LIF complex components such as LIF, LIFR and gpl30
  • an “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • LIF complex component expression inhibitors for use in the present invention may be based on antisense oligonucleotide constructs.
  • Anti-sense oligonucleotides including anti- sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of LIF complex components mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of LIF complex components proteins, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding LIF complex components can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion.
  • Small inhibitory RNAs can also function as LIF complex component expression inhibitors for use in the present invention.
  • LIF complex component gene expression can be reduced by contacting the subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that LIF complex component expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference
  • Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. see Tuschl, T. et al. (1999); Elbashir, S. M. et al. (2001); Hannon, GJ. (2002); McManus, MT.
  • Ribozymes can also function as LIF complex component expression inhibitors for use in the present invention.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA.
  • the mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
  • Engineered hairpin or hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of LIF complex component mRNA sequences are thereby useful within the scope of the present invention.
  • ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
  • antisense oligonucleotides and ribozymes useful a LIF complex component expression inhibitors can be prepared by known methods. These include techniques for chemical synthesis such as, e.g., by solid phase phosphoramadite chemical synthesis. Alternatively, anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Various modifications to the oligonucleotides of the invention can be introduced as a means of increasing intracellular stability and half-life.
  • Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2'-0-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone.
  • Antisense oligonucleotides siRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
  • a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide siRNA or ribozyme nucleic acid to the cells and preferably cells expressing LIF complex component.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide siRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus
  • adenovirus adeno
  • Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo.
  • adeno-viruses and adeno-associated viruses are double-stranded DNA viruses that have already been approved for human use in gene therapy.
  • the adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hemopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions.
  • the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection.
  • adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event.
  • the adeno- associated virus can also function in an extrachromosomal fashion.
  • Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g., SANBROOK et al., "Molecular Cloning: A Laboratory Manual," Second Edition, Cold Spring Harbor Laboratory Press, 1989.
  • plasmid vectors have been used as DNA vaccines for delivering antigen-encoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors.
  • These plasmids however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid.
  • Plasmids may be delivered by a variety of parenteral, mucosal and topical routes.
  • the DNA plasmid can be injected by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally.
  • the plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and microencapsulation.
  • inhibitors according to the invention as described above are administered to the subject in a therapeutically effective amount.
  • a “therapeutically effective amount” of the inhibitor of the present invention as above described is meant a sufficient amount of the inhibitor for treating PDA associated neural remodeling (PANR) at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the inhibitors and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • PANR PDA associated neural remodeling
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific inhibitor employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific inhibitor employed; the duration of the treatment; drugs used in combination or coincidential with the specific inhibitor employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the inhibitor of the present invention for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the inhibitor of the present invention, preferably from 1 mg to about 100 mg of the inhibitor of the present invention.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the LIF inhibitor of the present invention is administered to the subject in combination with anti-PDA treatment.
  • PDA treatment has its general meaning in the art and refers to any type of pancreatic cancer therapy undergone by the pancreatic cancer subjects including surgical resection of pancreatic cancer, and any type of agent conventional for the treatment of PDA.
  • the LIF inhibitor of the present invention is administered to the subject in combination with at least one compound selected from the group consisting of gemcitabine, fluorouracil, FOLFIRINOX (fluorouracil, irinotecan, oxaliplatin, and leucovorin), nab-paclitaxel, inhibitors of programmed death 1 (PD-1), PD-1 ligand PD-L1, anti-CLA4 antibodies, EGFR inhibitors such as erlotinib, chemoradiotherapy, inhibitors of PARP, inhibitors of Sonic Hedgehog, gene therapy and radiotherapy.
  • gemcitabine fluorouracil
  • FOLFIRINOX fluorouracil, irinotecan, oxaliplatin, and leucovorin
  • nab-paclitaxel inhibitors of programmed death 1 (PD-1), PD-1 ligand PD-L1, anti-CLA4 antibodies
  • EGFR inhibitors such as erlotinib, chemoradi
  • the present invention relates to a method of screening a candidate compound for use as a drug for treating PDA associated neural remodeling (PANR) in a subject in need thereof, wherein the method comprises the steps of:
  • a candidate compound such as a small organic molecule, a polypeptide, an aptamer, an antibody or an intra-antibody,
  • measuring LIF activity involves determining a Ki on the LIF cloned and transfected in a stable manner into a CHO cell line, measuring neuronal plasticity, measuring Schwann cell migration, measuring Schwann cell proliferation, measuring Schwann cell differentiation status and measuring JAK/STAT3/AKT intracellular signaling in the present or absence of the candidate compound.
  • Tests and assays for screening and determining whether a candidate compound is a LIF inhibitor are well known in the art (Vernallis et al., 1997; WO03064463; WO2011124566). In vitro and in vivo assays may be used to assess the potency and selectivity of the candidate compounds to inhibit LIF activity.
  • Activities of the candidate compounds, their ability to bind LIF, LIFR or gpl30 and their ability to inhibit LIF activity may be tested using isolated Schwann cell or CHO cell line cloned and transfected in a stable manner by the human LIF, LIFR and gpl30.
  • Activities of the candidate compounds and their ability to bind to the LIF, LIFR or gpl30 may be assessed by the determination of a Ki on the LIF, LIFR and gpl30 cloned and transfected in a stable manner into a CHO cell line, measuring neuronal plasticity, measuring Schwann cell migration, measuring Schwann cell proliferation, and measuring Schwann cell differentiation status in the present or absence of the candidate compound.
  • the ability of the candidate compounds to inhibit LIF activity may be assessed by measuring LIF complex component formation, and measuring JAK/STAT3/AKT intracellular signaling such as described in the example.
  • Cells expressing another cytokine than LIF may be used to assess selectivity of the candidate compounds.
  • the inhibitors of the invention may be used or prepared in a pharmaceutical composition.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the inhibitor of the invention and a pharmaceutical acceptable carrier for use in the treatment of PDA associated neural remodeling (PANR) in a subject of need thereof.
  • PANR PDA associated neural remodeling
  • the inhibitor of the invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • “Pharmaceutically” or “pharmaceutically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, intramuscular, intravenous, local or rectal administration, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, intraperitoneal, intramuscular, intravenous and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising inhibitors of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the inhibitor of the invention can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active inhibitors in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • aqueous solutions for parenteral administration in an aqueous solution
  • the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; liposomal formulations; time release capsules; and any other form currently used.
  • compositions of the invention may include any further compound which is used in the treatment of pancreatic ductal adenocarcinoma.
  • said additional active compounds may be contained in the same composition or administrated separately.
  • the pharmaceutical composition of the invention relates to combined preparation for simultaneous, separate or sequential use in the treatment of PDA associated neural remodeling (PANR) in a subject in need thereof.
  • PANR PDA associated neural remodeling
  • kits comprising the inhibitor of the invention.
  • Kits containing the inhibitor of the invention find use in therapeutic methods.
  • a further aspect of the invention relates to a method of identifying a subject having or at risk of having or developing PDA associated neural remodeling (PANR), comprising a step of measuring in a biological sample obtained from said subject the expression level of LIF.
  • PANR PDA associated neural remodeling
  • biological sample refers to any biological sample derived from the subject such as blood sample, plasma sample, serum sample or PDA sample.
  • the method of the invention may further comprise a step consisting of comparing the expression level of LIF in the biological sample with a reference value, wherein detecting differential in the expression level of LIF between the biological sample and the reference value is indicative of subject having or at risk of having or developing PDA associated neural remodeling (PANR).
  • PANR PDA associated neural remodeling
  • the "reference value” refers to a threshold value or a cut-off value.
  • a “threshold value” or “cut-off value” can be determined experimentally, empirically, or theoretically.
  • a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skilled in the art.
  • the threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative).
  • the optimal sensitivity and specificity (and so the threshold value) can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • the person skilled in the art may compare the expression level (obtained according to the method of the invention) with a defined threshold value.
  • the threshold value is derived from the expression level (or ratio, or score) determined in a biological sample derived from one or more subjects having PDA associated neural remodeling (PANR). Furthermore, retrospective measurement of the expression level (or ratio, or scores) in properly banked historical subject samples may be used in establishing these threshold values.
  • the reference value may correspond to the expression level of LIF determined in a biological sample associated with a subject not afflicted with PDA associated neural remodeling (PANR). Accordingly, a higher expression level of LIF than the reference value is indicative of a subject having or at risk of having or developing PDA associated neural remodeling (PANR), and a lower or equal expression level of LIF than the reference value is indicative of a subject not having or not at risk of having or developing PDA associated neural remodeling (PANR).
  • PANR PDA associated neural remodeling
  • the reference value may correspond to the expression level of LIF determined in a biological sample associated with a subject afflicted with PDA associated neural remodeling (PANR). Accordingly, a higher or equal expression level of LIF than the reference value is indicative of a subject having or at risk of having or developing PDA associated neural remodeling (PANR), and a lower expression level of LIF than the reference value is indicative of a subject not having or not at risk of having or developing PDA associated neural remodeling (PANR).
  • PANR PDA associated neural remodeling
  • Analyzing the LIF expression level may be assessed by any of a wide variety of well- known methods for detecting expression of a transcribed nucleic acid or translated protein.
  • the LIF expression level is assessed by analyzing the expression of mRNA transcript or mRNA precursors, such as nascent RNA, of LIF gene. Said analysis can be assessed by preparing mRNA/cDNA from cells in a biological sample from a subject, and hybridizing the mRNA/cDNA with a reference polynucleotide. The prepared mRNA/cDNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses, such as quantitative PCR (TaqMan), and probes arrays such as GeneChip(TM) DNA Arrays (AFFYMETRIX).
  • mRNA transcript or mRNA precursors such as nascent RNA
  • the analysis of the expression level of mRNA transcribed from the gene encoding for LIF involves the process of nucleic acid amplification, e. g., by RT-PCR (the experimental embodiment set forth in U. S. Patent No. 4,683, 202), ligase chain reaction (Barany, 1991), self sustained sequence replication (Guatelli et al., 1990), transcriptional amplification system (Kwoh et al., 1989), Q-Beta Replicase (Lizardi et al., 1988), rolling circle replication (U. S. Patent No. 5,854, 033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art.
  • RT-PCR the experimental embodiment set forth in U. S. Patent No. 4,683, 202
  • ligase chain reaction Barany, 1991
  • self sustained sequence replication (Guatelli et al., 1990)
  • transcriptional amplification system Kwoh et
  • amplification primers are defined as being a pair of nucleic acid molecules that can anneal to 5' or 3' regions of a gene (plus and minus strands, respectively, or vice-versa) and contain a short region in between.
  • amplification primers are from about 10 to 30 nucleotides in length and flank a region from about 50 to 200 nucleotides in length. Under appropriate conditions and with appropriate reagents, such primers permit the amplification of a nucleic acid molecule comprising the nucleotide sequence flanked by the primers.
  • the LIF expression level is assessed by analyzing the expression of the protein translated from said gene. Said analysis can be assessed using an antibody (e.g., a radio-labeled, chromophore- labeled, fluorophore-labeled, or enzyme-labeled antibody), an antibody derivative (e.g., an antibody conjugate with a substrate or with the protein or ligand of a protein of a protein/ligand pair (e.g., biotin-streptavidin)), or an antibody fragment (e.g., a single-chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically to the protein translated from the gene encoding for LIF.
  • an antibody e.g., a radio-labeled, chromophore- labeled, fluorophore-labeled, or enzyme-labeled antibody
  • an antibody derivative e.g., an antibody conjugate with a substrate or with the protein or ligand of a protein of a
  • EIA enzyme immunoassay
  • RIA radioimmunoassay
  • RIA Western blot analysis
  • the method of the invention is performed by measuring LIF activation level.
  • Analyzing the LIF activation level may be assessed by any of a wide variety of well- known methods (Vernallis et al., 1997; WO03064463; WO2011124566).
  • the LIF activation level is assessed by measuring LIF, LIFR and pgl30 heterodimerization or measuring JAK/STAT3/AKT intracellular signalling.
  • a further aspect of the invention relates to a method of monitoring PDA progression by performing the method of the invention.
  • the present invention relates to a method of treating PDA associated neural remodeling (PANR) in a subject in need thereof comprising the steps of:
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 LIF secretion is driven by stromal compartment and mainly by CAFs.
  • A Human (top panel) and mouse (bottom panel) LIF mRNA expression levels (mean + SD).
  • B Human LIF mRNA expression levels (mean + SD).
  • PDA#1 to 4 represents human PDA primary tumor cells.
  • C LIF immunoblots. Quantifications noted are expressed as fold changes compared to macrophages (Raw) or fibroblasts (CAF).
  • D LIF immunoblots. Quantifications noted are expressed as fold changes compared to fibroblasts co-cultivated with macrophages (FHN+RAW).
  • E Quantification of secreted LIF, by ELISA assay, in various stromal cells conditioned media (mean + SD).
  • F Quantification of secreted LIF, by ELISA assay, in conditioned media from stromal and tumor cells (mean + SD). Each experiment was reproduced at least three times. *, P ⁇ 0.05; **, P ⁇ 0.01.
  • FIG. 3 LIF-triggered signaling enhance migratory capacities of Schwann nerve cells.
  • a to C Effects of stromal cells conditioned media on sNF96.2 migration ability (A) (mean + SD) using Ab-LIFR/Ab-Ctrl (B) or AG490/SC144 (30 ⁇ /2 ⁇ respectively, preincubation for 2h) (C).
  • D Effects of various doses (0-320ng/ml) of LIF recombinant protein on sNF96.2 migration (mean + SD).
  • E Impact of Ab-LIFR on sNF96.2 migration (mean + SD), using 50ng/ml of LIF and various doses of Ab-LIFR (upper panel) or 4 ⁇ g/ml of Ab- LIFR compared to Ab-Ctrl (lower panel).
  • F Impact of AG490/SC144 on sNF96.2 migration (mean + SD), using 50ng/ml of LIF.
  • G pSTAT3 and pAKT immunoblots in sNF96.2 cells following CM incubations and AG490/SC144 treatments. Quantifications noted are expressed as fold changes compared with sNF96.2 cells under sNF96.2 media. Each experiment was reproduced at least three times. *, P ⁇ 0.05; **, P ⁇ 0.01; P ⁇ 0.001.
  • FIG. 4 LIF reduces Schwann cells proliferation.
  • a to C Cell count of sNF96.2 cells incubated with stromal conditioned media (A) together with Ab-LIFR (B) or LIF recombinant protein (C) (mean + SD).
  • D Effect of LIF recombinant protein (50ng/ml) on p21 mPvNA expression in sNF96.2 cells (mean + SD).
  • E p21 immunoblots from sNF96.2 incubated for 36 (top panel) or 48 (down panel) hours with 50ng/ml of LIF. Quantifications noted are expressed as fold changes compared with sNF96.2 cells not incubated with LIF recombinant protein.
  • F and G p21 immunoblots from sNF96.2 incubated for 36 hours with 50ng/ml of LIF (F) or various conditioned media (G) together with AG490 (F and G) or SC144 (F) treatments. Each experiment was reproduced at least three times. *, P ⁇ 0.05.
  • LIF induces Schwann cell differentiation and neural plasticity.
  • A S100 and Pou3F2 immunoblots in sNF96.2 cultured cells.
  • B S100 and Pou3F2 mRNA expression levels in sNF96.2 cells incubated with 50ng/ml of LIF recombinant protein (mean + SD).
  • C SI 00 and Pou3F2 immunoblots from sNF96.2 cells incubated for 48 hours with LIF (50ng/ml).
  • LIF is a potent diagnostic and predictive biomarker for PDA.
  • G Graphical representation summarizing the impact of stromal secreted LIF on PANR and its potent use as a biomarker.
  • FIG. 8 Graphical representations of co-culture method and migration assay.
  • A Method of cell co-culture in order to produce specific conditioned media (CM). Those CM are used in the following migration assay or for LIF ELISA tittering while cells from the co- culture are then recovered for protein or mRNA extracts.
  • B Migration assay method for the measurement of migration ability of sNF96.2 cells using various conditioned media (CM).
  • FIG. 9 LIF induces activation of AKT/STAT3 signaling pathways in Schwann cells.
  • A pSTAT3 immunoblot in sNF96.2 cells following incubations with human LIF recombinant protein. Quantifications noted are expressed as fold changes compared with sNF96.2 cells untreated.
  • B pAKT immunoblot in sNF96.2 cells following incubations with human LIF recombinant protein. Quantifications noted are expressed as fold changes compared with sNF96.2 cells untreated.
  • C pSTAT3 and pAKT immunoblots in sNF96.2 cells following incubations with human LIF recombinant protein and treatments with AG490 or Ab-LIFR. Quantifications noted are expressed as fold changes compared with sNF96.2 cells untreated. Each experiment was reproduced at least three times.
  • FIG. 10 LIF do not modify Schwann cell survival.
  • A Quantification of caspase positive sNF96.2 cells following 48 hours incubation with human LIF recombinant protein (mean + IQR). Quantifications noted are expressed as fold increase compared with untreated cells.
  • B Quantification of caspase positive sNF96.2 cells following 48 hours incubation with conditioned media from FHN+RAW or FHN+RAW+HMC- 1 (mean + IQR). Quantifications noted are expressed as fold increase compared with cells incubated with sNF96.2 media. Each experiment was reproduced at least three times, ns, not significant.
  • Human pancreatic cancer cell lines (PANC-1, MIApaCa-2, BxPC-3, Capan-2) and Schwann cells (sNF96.2) as well as murine macrophage (RAW264.7) were obtained from American Type Culture Collection (ATCC) and cultivated in DMEM medium supplemented with 10% fetal bovine serum (Life Technologies) and 1% of antibiotic/antimycotic (Invitrogen, 15240-062).
  • Human mast cells (HMC-1) were provided by Professor Michel Arock (ENS Cachan, France) and cultivated in RPMI-1640 medium, supplemented with 10% fetal bovine serum and 1% of antibiotic/antimycotic.
  • Human primary fibroblasts were a kind gift from Dr Cedric Gaggioli (IRCAN, Nice, France) and CAF cells (produced from freshly resected human PDA) (25) were cultivated in DMEM medium and DMEM/F12 medium respectively.
  • PDA-1 to 4 are human pancreatic primary cancer cells derived from freshly resected PDA samples (26). All patients gave their consent and are included in the clinical trial number 2011-A01439-32 (26). Expert clinical centers collaborated on this project after approval from their respective ethics review board (approval number 11-61).
  • Sera from healthy and PDA bearing mice were obtained after intra-cardiac puncture and separation between plasma and blood cells by centrifugation. Mice developing PDA were euthanized when they were moribund (average of 8.5 weeks old).
  • mice were obtained by crossing the following strains: Pdxl-cre, Kras G12D and Ink4A fl/fl mice kindly provided by Dr. D Melton (Harvard Stem Cell Institute, Cambridge, MA, USA), Dr. R Depinho (Dana-Farber Cancer Institute, Boston, MA, USA) and Dr T Jacks (David H Koch Institute for Integrative Cancer Research, Cambridge, MA, USA), respectively. Pieces of tumor pancreas were fixed in 4% (wt/vol) formaldehyde for further immunostaining analysis or prepared for RNA extraction. All animal care and experimental procedures were performed in agreement with the Animal Ethics Committee of Marseille.
  • Acute pancreatitis in mice was realized by injection of Caerulein (50 ⁇ g/kg/100 ⁇ l, from AnaSpec As-24252) by intraperitoneal mode 6 times per hour during 6 hours. Sera and pancreas was removed 2 hours after the last injection. Chronic pancreatitis was induced by twice a week injection of Caerulein (50 ⁇ g/kg/100 ⁇ l) by intraperitoneal mode for 10 weeks.
  • LIF Human recombinant leukemia inhibitory factor
  • Prospec CYT-644, 25 ⁇ g
  • LIF pathway inhibitors were used: Ab-LIFR, a LIF receptor blocking antibody (Santa-cruz biotechnology: sc-659, C19 clone) used at 4 ⁇ g/ml; tyrphostin (AG490), a JAK-2 protein tyrosine kinase (Sigma-Aldrich, T3434-5MG) used at 30 ⁇ ; and SC144 hydrochloride (Sigma-Aldrich, SML0763-5MG), an inhibitor of glycoprotein gpl30 (gpl30) used at 2 ⁇ .
  • a control polyclonal antibody from rabbit anti-rat IgG (Bal042.5 Boster biological technology) was used for in vitro experience at 4 ⁇ g/ml.
  • an anti-LIF neutralizing antibody produced in goat, IgG fraction of antiserum was used (L9152, Sigma-Aldrich).
  • Antibody was injected (20 ⁇ g/kg/souris/IP/100 ⁇ l) by intraperitoneal mode twice a week during 4 weeks in PDAC mice aged of 4 weeks old.
  • CM Conditioned media
  • sNF96.2 cells 1.5xl0 5 were plated on 6-well plates. The next day, normal medium was changed with either various conditioned media from stromal or nerve cells (FHN, RAW, HMC-1 or sNF96.2) in a DMEM medium containing 0.5% FBS supplemented, or not, with LIF (50ng/ml). Cell proliferation was measured at different time points (24h or 48h later) by trypan blue counting using a ViCELL XR (Beckman Coulter).
  • LIF titration in cell supernatant or in serum, was performed with the LIF ELISA Kit according to the supplier's instructions (Raybiotech, ELH-LIF-001). Sera from patients or PDA mice were diluted 1:2. Titration of IL-6 and CA19.9 in serum was performed with the IL-6 ELISA Kit (D6050, R&D systems) and the CA19.9 ELISA Kit (abl08642, Abeam), respectively, as instructed by the suppliers.
  • cDNA was obtained after the reverse transcription of ⁇ g of total RNA using the
  • GoSCRIPT Tm Reverse Transcription system (Promega) according to the manufacturer's procedure. Specific genes were amplified from this cDNA by real time PCR with the GoTAQ qPCR Master Mix kit (Promega), using an Mx3000P Stratagene system. Relative expression was calculated as a ratio of the particular gene expression to a housekeeping gene expression (TBP). Different primers were used: human LIF; murine LIF; human p21 ; human POU3F2; human S100; and human/murine TBP.
  • Protein extracts from sNF96.2 cells, different stromal cells (FHN, RAW, HMC-1) or cancer cells (PANC-1, MIAPACA-2, BXPC-3, HN-14, B-TIM TUM, J-IPC, L-IPC, HN-14) were prepared with RIPA buffer (Hepes 50mM, Nacl 150mM, EDTA lmM, EGTA lmM, 10% glycerol, 1% TritonX-100, ⁇ ZnC12 with protease inhibitors cocktail). Proteins were titrated using the Bradford Protein Assay Reagent (Biorad).
  • Proteins were separated on gels by electrophoresis: protein extracts (20 ⁇ g) were run on 12% NuPAGE Novex Tris-glycine Mini Gels and electrotransferred onto nitrocellulose membranes using an electrophoretic transfer system (Invitrogen). A classical procedure was then used as reported earlier (12).
  • the primary antibodies used were: anti-LIF antibody (Santa-Cruz, Clone N18, sc-1336, 1/200), anti-S-100 Protein (Millipore, clone 15E2E2, MAB079-1, 1/1000), anti-Pou3F2 (Abgent, clone AP16803C, AP16803C, 1/1000), anti-P21 Wafl/Cipl (Cell Signaling, DCS60, 2946S, 1/1000), anti-pAKT (Cell Signaling, clone D9E, 4060S, 1/1000), anti-STAT3 (Cell Signaling, clone 79D7, 4904S, 1/1000), anti-p-STAT3 (Cell Signaling, clone D3A7, 9145S, 1/1000), and anti-P-actin (Sigma-Aldrich, clone AC-74, A2228, 1/2000).
  • protein extracts of pancreas from PDA or healthy mouse were obtained after organ crushing and preparation with RIPA-2 buffer (Nacl 150mM, Tris-base pH8 20mM, 1% NP40, EDTA 5mM with protease inhibitors cocktail).
  • the quantity of protein run was 20 ⁇ g, and the following western blot steps were the same as with in vitro samples.
  • Immunofluorescence experiments were performed either on cultured cells or on murine pancreas samples previously fixed in paraformaldehyde 4%, paraffin embedded and cut. Concerning PDA patients, immunofluorescence was performed on tissue microarray slides.
  • the antibodies used were: anti-Pou3F2 (Abgent, clone AP16803C, AP16803C, 1/100), anti-LIF (Santa-Cruz, Clone N18, sc-1336, 1/50), and anti-SlOO (Millipore, clone 15E2E2, MAB079-1, 1/100).
  • Additional primaries antibodies were used to detect CD68 (Abeam, Ab845, 1/50), cdl l7/c-kit (Abeam, Ab5505, 1/100), a-SMA (Sigma-Aldrich, A2547, 1/200), cytokeratin 19 (Dako, M-0888, 1/50), marking respectively macrophages, mast cells, fibroblasts and epithelial pancreatic cancer cells.
  • Primary antibody labeling was followed by Alexa Fluor (488nm or 568nm)-conjugated secondary antibody staining (Invitrogen, 1/500). Nucleic contrast was achieved with DAPI staining and slides were observed using a Nikon eclipse 90i fluorescence microscope. Image quantification was performed using the ImageJ software.
  • DRG dorsal root ganglia
  • HBSS Hank's Balanced Salt Solution
  • HEPES HEPES 4.76 g/1, D-glucose 1,8 g/1, which allowed for neuron protection and blood removal during dissection.
  • neurons present in the DRG were released by a collagenase/dispase (Liberase, n°05401160001, Roche) treatment supplemented with Cacl2 1M and dissociated by several passages through a 26G needle.
  • Neurobasal medium (Life Technologies) containing NGF (lOng/ml), GDNF (2ng/ml), B27 (0.02 ⁇ g/ ⁇ l), Glutamine (2mM), and Penicillin-Streptomycin (O.O ⁇ g ⁇ l).
  • NGF laminin-Lysine
  • laminin Invitrogen
  • LIF Leukemia Inhibitory Factor
  • LIFR LIFR
  • gpl30 was found in 4 out of 12 nerves but with a stronger mean expression (20%). These changes in LIF expression were confirmed in PDA mouse model with a strong increase in LIF mRNA (Fig. 1C) and protein (Fig. ID and IE) level in PDA samples compared to healthy pancreas. Altogether, these data reveal the presence of LIF and its receptors, LIFR and gpl30, in PDA samples. Moreover, the expression patterns of LIFR and gpl30 support the hypothesis of LIF implication in PDA associated neural remodeling.
  • Table2 Representative images of co-localization of LIF, LIFR or gpl30 with neurofilament on human PDA. The table indicates the percentage of expression of the markers in nerves, and the fraction of nerves containing them. SD (+/-); p-values compared LIF-R or gpl30 expression in nerves compared to LIF.
  • LIF is referenced as a secreted cytokine
  • ELISA the amount of LIF secreted in media and observed a higher LIF concentration in media from fibroblasts co-cultured with macrophages compared to other stromal cell cultures.
  • amount of LIF secreted by CAF was higher than by FHN, we observed that amounts of LIF secreted were not different between CAF and FHN when co-cultured with RAW.
  • LIF was either undetectable or present in small amount in media from various tumor cells (Fig. 2F).
  • Table 3 Co-localization of LIF with Cytokeratin-19, CD117, CD68 or a-SMA on human PDA sections.
  • CM stromal conditioned media
  • FHN+RAW and FHN+RAW+HMC 1 LIF titer
  • LIFR and gpl30, STAT3 and AKT are two of the main pathways known to be induced (34).
  • LIF can trigger STAT3 and AKT phosphorylation/activation (Fig. 9A and 9B).
  • Fig. 9C shows that such signaling activation is mediated by LIF receptors, LIFR and gpl30, as AG490 or LIFR blocking antibody were able to inhibit STAT3 and AKT phosphorylation.
  • stromal cells CM could induce STAT3 or AKT phosphorylation/activation.
  • LIF induces Schwann cell differentiation and neuronal plasticity
  • the inventors performed SI 00 and Pou3F2 staining on human PDA and Pou3F2 and S100 dual-staining in sNF96.2 cells incubated for 48 hours with control (sNF96.2) or stromal (FHN+RAW or FHN+RAW+HMC-1) conditioned media (CM), in the absence or presence of AG490 or SC144.
  • LIF titer in serum as a diagnostic and prognostic biomarker for PDA patients
  • Demir IE Friess H, Ceyhan GO. Neural plasticity in pancreatitis and pancreatic cancer. Nature reviews Gastroenterology & hepatology 2015;12:649-59.
  • Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer research 2012;72:5733-43.
  • Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis. PloS one 2013;8:e60529.
  • ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer.

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Abstract

La présente invention concerne le diagnostic et le traitement d'un PANR (remodelage neuronal associé à un PDA (adénocarcinome canalaire pancréatique)). Les inventeurs ont étudié les effets du compartiment stromal sur PDA et PANR et la connexion spécifique entre le compartiment stromal et le système nerveux dans un PDA. A l'aide d'échantillons de PDA provenant de modèles humains et de souris endogènes, les inventeurs ont démontré que le LIF (facteur inhibiteur de la leucémie) est surexprimé dans les tissus de PDA par comparaison avec le pancréas sain tandis que ses récepteurs, LIFR et gp130 sont exprimés dans des nerfs intra-tumoraux. Les inventeurs ont démontré que l'expression et la sécrétion de LIF induit une migration de cellules de Schwann, une prolifération réduite et une modulation de leur état de différenciation. Le LIF induit également une plasticité neuronale. L'injection d'anticorps bloquant le LIF dans un modèle de souris PDA endogène réduit la densité du nerf intra-tumoral. En outre, à l'aide de bibliothèques de sérum humain et de souris, les inventeurs ont montré que le titre de LIF améliore la valeur de diagnostic de CA19,9 et est corrélé positivement à la densité de nerf intra-tumorale. Ainsi, la présente invention concerne un inhibiteur de LIF destiné à être utilisé dans le traitement du PANR et un procédé d'identification d'un sujet ayant ou présentant un risque d'avoir ou de développer un PANR, comprenant la mesure du niveau d'expression de LIF.
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