WO2016097175A1 - Nouveau procédé de traitement du cancer du pancréas - Google Patents

Nouveau procédé de traitement du cancer du pancréas Download PDF

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WO2016097175A1
WO2016097175A1 PCT/EP2015/080273 EP2015080273W WO2016097175A1 WO 2016097175 A1 WO2016097175 A1 WO 2016097175A1 EP 2015080273 W EP2015080273 W EP 2015080273W WO 2016097175 A1 WO2016097175 A1 WO 2016097175A1
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Prior art keywords
ldlr
pancreatic cancer
cells
expression
expression level
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PCT/EP2015/080273
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English (en)
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Sophie Vasseur
Juan Iovanna
Fabienne GUILLAUMOND
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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 WO2016097175A1 publication Critical patent/WO2016097175A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the inventions relates to a compound which is an antagonist of LDLR or an inhibitor of the LDLR expression for use in the treatment of pancreatic cancer.
  • Pancreatic ductal adenocarcinoma is one of the top cancer killers as it ranks to the 4th leading cause of cancer-related death in United States and Europe, with a 5-year survival rate of about 4% and a median survival less than 6 months [Malvezzi M et al, 2013 and Bosetti C et al, 2012].
  • PDAC pancreatic ductal adenocarcinoma
  • GEM gemcitabine
  • the inventors defined the metabolic fingerprint of advanced PDAC, induced by both pancreas-specific K-Ras G12D mutation and Ink4a/Arf deletion [Aguirre AJ et al, 2003], which demonstrates a strong enrichment of dysregulated genes involved in carbohydrate, amino acid and lipid pathways.
  • the lipid enriched-pathways are the most abundant in tumors and those related to cholesterol synthesis and lipoprotein catabolism are among the most activated and enriched pathways in PDAC compared to non-malignant pancreas.
  • Tumor cells have elevated cholesterol requirements that need to be finely regulated. They can increase their cholesterol pools either through activation of endogenous synthesis (i.e. mevalonate pathway), hydrolysis of cholesterol ester (CE) stores or through receptor- mediated endocytosis of plasma cholesterol-rich low density lipoproteins (LDL) via the LDL receptor (LDLR).
  • Cholesterol is highly represented in membrane, especially in micro- domains, named lipid rafts, wherein reside key cell signaling molecules associated to malignant progression [Staubach S et al., 2011].
  • changes in cholesterol content of lipid rafts modulate growth factor receptors signaling, such as PI3K/Akt- and EGFR-dependent survival pathway.
  • FC free cholesterol
  • the inventors proposed a novel strategy, based on the blockade of LDLR, the main selective route of cholesterol rich- lipoproteins entrance into cancer cells, to limit cholesterol supply to pancreatic tumors. They firstly evaluated whether shRNA- silencing of - -
  • LDLR low-density lipoprotein
  • the inventions relates to a compound which is an antagonist of LDLR or an inhibitor of the LDLR expression for use in the treatment of pancreatic cancer.
  • the invention relates to a compound which is an antagonist of LDLR or an inhibitor of the LDLR expression for use in the treatment of pancreatic cancer.
  • the compound according to the invention is administrated in combination with a chemotherapeutic agent.
  • the invention also relates to i) a compound according to the invention, and ii) a chemotherapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of pancreatic cancer.
  • chemotherapeutic agents may be Gemcitabine, Paclitaxel,
  • the compound according to the invention is administrated in combination with Gemcitabine.
  • the invention also relates to i) compound according to the invention, and ii) the Gemcitabine, as a combined preparation for simultaneous, separate or sequential use in the treatment of pancreatic cancer.
  • the invention also relates to i) compound according to the invention, ii) a chemotherapeutic agent and iii) a radiotherapy, as a combined preparation for simultaneous, separate or sequential use in the treatment of pancreatic cancer.
  • the invention also relates to i) compound according to the invention, ii) a chemotherapeutic agent and iii) a radio therapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of pancreatic cancer. - -
  • the invention also relates to i) compound according to the invention, ii) the Gemcitabine and iii) a radiotherapy, as a combined preparation for simultaneous, separate or sequential use in the treatment of pancreatic cancer.
  • the invention also relates to i) compound according to the invention, ii) the Gemcitabine and iii) a radio therapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of pancreatic cancer.
  • radiotherapy may consist of gamma-radiation, X-ray radiation, electrons or photons, external radiotherapy or curitherapy.
  • the term "radiotherapeutic agent” is intended to refer to any radio therapeutic agent known to one of skill in the art to be effective to treat or ameliorate cancer, without limitation.
  • the radiotherapeutic agent can be an agent such as those administered in brachytherapy or radionuclide therapy.
  • Such methods can optionally further comprise the administration of one or more additional cancer therapies, such as, but not limited to, chemotherapies, and/or another radiotherapy.
  • LDLR Low-Density Lipoprotein Receptor
  • VLDL Very Low Density Lipoprotein
  • IDL Intermediate-Density Lipoprotein
  • the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC) or an acinar tumor.
  • PDAC pancreatic ductal adenocarcinoma
  • the antagonist according to the invention may be a low molecular weight antagonist, e. g. a small organic molecule (natural or not).
  • small organic molecule refers to a molecule (natural or not) of a size comparable to those organic molecules generally used in pharmaceuticals.
  • Particular small organic molecules range in size up to about 10000 Da, more particularly up to 5000 Da, more particularly up to 2000 Da and most particularly up to about 1000 Da. - -
  • the antagonist may bind to LDLR and block the binding of other compound like the apo lipoprotein B100 or E on LDLR.
  • antagonist of LDLR of the invention may be an anti-LDLR antibody which neutralizes LDLR or an anti-LDLR fragment thereof which neutralizes LDLR.
  • Antibodies directed against LDLR can be raised according to known methods by administering the appropriate antigen or epitope to a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others. Various adjuvants known in the art can be used to enhance antibody production.
  • Antibodies useful in practicing the invention can be polyclonal or monoclonal antibodies. Monoclonal antibodies against LDLR can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture.
  • Techniques for production and isolation include but are not limited to the hybridoma technique originally described by Kohler and Milstein (1975); the human B-cell hybridoma technique (Cote et al., 1983); and the EBV-hybridoma technique (Cole et al. 1985).
  • techniques described for the production of single chain antibodies can be adapted to produce anti-LDLR single chain antibodies.
  • LDLR antagonists useful in practicing the present invention also include anti-LDLR antibody fragments including but not limited to F(ab')2 fragments, which can be generated by pepsin digestion of an intact antibody molecule, and Fab fragments, which can be generated by reducing the disulfide bridges of the F(ab')2 fragments.
  • anti-LDLR antibody fragments including but not limited to F(ab')2 fragments, which can be generated by pepsin digestion of an intact antibody molecule, and Fab fragments, which can be generated by reducing the disulfide bridges of the F(ab')2 fragments.
  • Fab and/or scFv expression libraries can be constructed to allow rapid identification of fragments having the desired specificity to LDLR.
  • Humanized anti-LDLR antibodies and antibody fragments therefrom can also be prepared according to known techniques.
  • “Humanized antibodies” are forms of non-human (e.g., rodent) chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (CDRs) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity and capacity.
  • donor antibody such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity and capacity.
  • framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance.
  • the humanized - - antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the antibody anti-LDLR according to the invention may be an antibody as explained in the patent application WO 2001068710.
  • the antibody anti-LDLR according to the invention may be an antibody as explained in the patent application WO2007014992A2
  • LDLR antagonists may be selected from aptamers.
  • Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition.
  • Aptamers are oligonucleotide or oligopeptide 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).
  • LDLR antagonists may be selected from peptides or peptides mimetic. Such peptides or peptides mimetic can be identified thank to their ability to bind the LDLR to inhibit the binding the apo lipoprotein B100 and E on the LDLR and thus blocking the LDL entry in cells. - -
  • the compound according to the invention is an inhibitor of the LDLR expression.
  • RNAs Small inhibitory R As
  • shRNAs short hairpin RNA
  • LDLR gene expression can be reduced by contacting a 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 LDLR gene 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 for example Tuschl, T. et al. (1999); Elbashir, S. M. et al.
  • Ribozymes can also function as inhibitors of LDLR gene expression 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 endonucleo lytic cleavage.
  • Engineered hairpin or hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of LDLR 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.
  • siRNAs siRNAs
  • shRNAs antisense oligonucleotides
  • ribozymes useful as inhibitors of LDLR gene expression
  • siRNAs shRNAs (antisense oligonucleotides)
  • ribozymes useful as inhibitors of LDLR gene expression
  • siRNAs shRNAs (antisense oligonucleotides)
  • ribozymes useful as inhibitors of LDLR gene expression
  • anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule.
  • 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 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 particularly cells expressing LDLR.
  • 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, the siRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a particular 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
  • adenovirus adeno- associated virus
  • SV40-type viruses polyoma viruses
  • Epstein-Barr viruses papilloma viruses
  • herpes virus vaccinia virus
  • polio virus
  • Non-cytopathic viral vectors are based on non-cytopathic eukaryotic viruses in which nonessential genes have been replaced with the gene of interest.
  • 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).
  • retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo.
  • viruses for certain applications are the adeno-viruses and adeno-associated viruses, which 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. Sambrook et al, 1989. In the last few years, 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, eye, 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.
  • the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequence is under the control of a heterologous regulatory region, e.g., a heterologous promoter.
  • a heterologous promoter may be specific for Muller glial cells, microglia cells, - - endothelial cells, pericyte cells and astrocytes.
  • the promoter can also be, e.g., a viral promoter, such as CMV promoter or any synthetic promoters.
  • nucleases, endonucleases or meganucleases which target the gene which codes for the LDLR can be used as compound according to the invention.
  • nuclease or "endonuclease” means synthetic nucleases consisting of a DNA binding site, a linker, and a cleavage module derived from a restriction endonuclease which is used for gene targeting efforts.
  • the synthetic nucleases according to the invention exhibit increased preference and specificity to bipartite or tripartite DNA target sites comprising DNA binding (i.e. TALE recognition site(s)) and restriction endonuclease target site while cleaving at off-target sites comprising only the restriction endonuclease target site is prevented.
  • nucleases which may be used in the present invention are disclosed in WO 2010/079430, WO2011072246, WO2013045480, Mussolino C, et al (Curr Opin Biotechnol. 2012 Oct;23(5):644-50) and Papaioannou I. et al (Expert Opinion on Biological Therapy, March 2012, Vol. 12, No. 3 : 329-342) all of which are herein incorporated by reference.
  • a further object of the invention relates to a method for treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound which is an antagonist of LDLR or an inhibitor of the LDLR expression.
  • the invention in another embodiment, relates to a method for treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective amount of i) compound according to the invention, and ii) a chemotherapeutic agent, as a combined preparation for simultaneous, separate or sequential.
  • Compounds of the invention may be administered in the form of a pharmaceutical composition, as defined below.
  • said compound is an antagonist of LDLR.
  • a “therapeutically effective amount” is meant a sufficient amount of compound to treat pancreatic cancer.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of - - the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific antagonist 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 active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, particularly from 1 mg to about 100 mg of the active ingredient.
  • 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 present invention also provides a pharmaceutical composition comprising an effective dose of an antagonist of LDLR and/or compound according to the invention.
  • Any therapeutic agent 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” refers 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.
  • compositions for example, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc.
  • compositions of the invention can be formulated for a topical, oral, intranasal, parenteral, intraocular, intravenous, intramuscular or subcutaneous administration and the like.
  • 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, potassium, 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 doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.
  • compositions include, e.g. tablets or other solids for oral administration; time release capsules; and any other form currently can be used.
  • compositions of the present invention may comprise a further therapeutic active agent.
  • the present invention also relates to a kit comprising a compound according to the invention and a further therapeutic active agent.
  • the pharmaceutical composition is administrated in combination with radiotherapy and/or chimiotherapy.
  • said therapeutic active agent is an anticancer agent.
  • said anticancer agents include but are not limited to fludarabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, platinum complexes such as cisplatin, carboplatin and oxaliplatin, mitomycin, dacarbazine, procarbazine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L- asparaginase, doxorubicin, epimbicm, 5-fluorouracil, taxanes such as docetaxel and paclitaxel, leucovor
  • additional anticancer agents may be selected from, but are not limited to, one or a combination of the following class of agents: alkylating agents, plant alkaloids, DNA topoisomerase inhibitors, anti-folates, pyrimidine analogs, purine analogs, DNA antimetabolites, taxanes, podophyllotoxin, hormonal therapies, retinoids, photosensitizers or photodynamic therapies, angiogenesis inhibitors, antimitotic agents, isoprenylation inhibitors, cell cycle inhibitors, actinomycins, bleomycins, anthracyclines, MDR inhibitors and Ca2+ ATPase inhibitors.
  • alkylating agents include plant alkaloids, DNA topoisomerase inhibitors, anti-folates, pyrimidine analogs, purine analogs, DNA antimetabolites, taxanes, podophyllotoxin, hormonal therapies, retinoids, photosensitizers or photodynamic therapies, angiogenesis inhibitors, antimitotic agents, isopre
  • Additional anticancer agents may be selected from, but are not limited to, cytokines, chemokines, growth factors, growth inhibitory factors, hormones, soluble receptors, decoy receptors, monoclonal or polyclonal antibodies, mono-specific, bi-specific or multi-specific antibodies, monobodies, polybodies.
  • Additional anticancer agent may be selected from, but are not limited to, growth or hematopoietic factors such as erythropoietin and thrombopoietin, and growth factor mimetics thereof.
  • the further therapeutic active agent can be an antiemetic agent.
  • Suitable antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine monoemanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dunenhydrinate, diphenidol, dolasetron, meclizme, methallatal, metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols, thiefhylperazine, thioproperazine and tropisetron.
  • the further therapeutic active agent can be an hematopoietic colony stimulating factor.
  • Suitable hematopoietic colony stimulating factors include, but are not limited to, filgrastim, sargramostim, molgramostim and epoietin alpha.
  • the other therapeutic active agent can be an opioid or non-opioid analgesic agent.
  • opioid analgesic agents include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, nomioiphine, etoipbine, buprenorphine, mepeddine, lopermide, anileddine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazodne, pemazocine, cyclazocine, methadone, isomethadone and propoxyphene.
  • Suitable non-opioid analgesic agents include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.
  • the further therapeutic active agent can be an anxiolytic agent.
  • Suitable anxiolytic agents include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam. - -
  • the invention also relates to an in vitro method for the prognosis of the survival time of a patient suffering from a pancreatic cancer comprising the steps consisting of i) determining the expression level of LDLR in a sample from said patient, ii) comparing said expression level with a predetermined reference value and iii) providing a good outcome prognosis when the expression level is lower than the predetermined reference value and a poor outcome prognosis when the expression level is higher than the predetermined reference value.
  • the sample according to the invention may be a blood, plasma, serum sample or a cancer biopsy.
  • said sample is a pancreatic cancer biopsy.
  • the invention relates to a method for predicting the overall survival (OS) of a patient suffering from a pancreatic cancer comprising the steps consisting of i) determining the expression level of LDLR in a sample from said patient, ii) comparing said expression level with a predetermined reference value and iii) providing a good outcome prognosis when the expression level is lower than the predetermined reference value and a poor outcome prognosis when the expression level is higher than the predetermined reference value.
  • the invention in another embodiment, relates to a method for predicting the disease- free survival (EFS) of a patient suffering from a pancreatic cancer comprising the steps consisting of i) determining the expression level of LDLR in a sample from said patient, ii) comparing said expression level with a predetermined reference value and iii) providing a good outcome prognosis when the expression level is lower than the predetermined reference value and a poor outcome prognosis when the expression level is higher than the predetermined reference value.
  • EDS disease- free survival
  • the invention relates to a method for predicting the recurrence of a patient which has suffered of a pancreatic cancer, to have a tumor relapse comprising the steps consisting of i) determining the expression level of LDLR in a sample from said patient, ii) comparing said expression level with a predetermined reference value and iii) providing a good outcome prognosis when the expression level is lower than the predetermined reference - - value and a poor outcome prognosis when the expression level is higher than the predetermined reference value.
  • OS Overall survival
  • the overall survival rate is often stated as a twelve months survival rate, which is the percentage of people in a study or treatment group who are alive twelve months after their diagnosis or the start of treatment.
  • DFS Disease-Free Survival
  • the term "Good Prognosis” denotes a patient with more than 50% chance of survival for the next 2 years after the treatment after surgery.
  • detecting includes qualitative and/or quantitative detection (measuring levels) with or without reference to a control.
  • LDLR expression may be measured for example by enzyme-labeled and mediated immunoassays (such as ELISA), flow cytometry assessment or qRT-PCR performed on the sample.
  • the "reference value" may be a healthy subject, i.e. a subject who does not suffer from any cancer and particularly pancreatic cancer. Particularly, said control is a healthy subject.
  • Detection of LDLR expression in the sample may be performed by measuring the level of LDLR protein or the Ldlr gene.
  • the methods may comprise contacting a sample with a binding partner capable of selectively interacting with LDLR protein present in the sample.
  • the binding partner is generally an antibody that may be polyclonal or monoclonal, particularly monoclonal.
  • the presence of the protein can be detected using standard electrophoretic and immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays.
  • immunoassays such as competition, direct reaction, or sandwich type assays.
  • assays include, but are not limited to, Western blots; agglutination tests; enzyme-labeled and mediated immunoassays, such as ELISAs; - - biotin/avidin type assays; radioimmunoassays; Immunoelectrophoresis; immunoprecipitation, etc.
  • the reactions generally include revealing labels such as fluorescent, chemiluminescent, radioactive, enzymatic labels or dye molecules, or other methods for detecting the formation of a complex between the antigen and the antibody or antibodies reacted therewith.
  • the aforementioned assays generally involve separation of unbound protein in a liquid phase from a solid phase support to which antigen-antibody complexes are bound.
  • Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like.
  • an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies against the proteins to be tested. A sample containing or suspected of containing the marker protein is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labeled secondary binding molecule is added. The secondary binding molecule is allowed to react with any captured sample marker protein, the plate is washed and the presence of the secondary binding molecule is detected using methods well known in the art.
  • immunoenzymatic staining methods are known in the art for detecting a protein of interest. For example, immunoenzymatic interactions can be visualized using different enzymes such as peroxidase, alkaline phosphatase, or different chromogens such as DAB, AEC, or Fast Red; or fluorescent labels such as FITC, Cy3, Cy5, Cy7, Alexafluors, etc.
  • Counterstains may include H&E, DAPI, Hoechst, so long as such stains are compatable with other detection reagents and the visualization strategy used.
  • amplification reagents may be used to intensify staining signal.
  • tyramide reagents may be used.
  • the staining methods of the present invention may be accomplished using any suitable method or system as would be apparent to one of skill in the art, including automated, semi-automated or manual systems.
  • the method of the invention may comprise a further step consisting of comparing
  • the term "expression level of LDLR" refers to an amount or a concentration of a transcription product, for instance mRNA coding for Ldlr - - gene.
  • a level of mRNA expression can be expressed in units such as transcripts per cell or nanograms per microgram of tissue.
  • a level of protein can be expressed as nanograms per microgram of tissue or nanograms per milliliter of a culture medium, for example. Alternatively, relative units can be employed to describe an expression level. Methods to detect a level of mRNA are well known in the state of art.
  • a “threshold value”, “threshold level”, “reference 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. Particularly, the person skilled in the art may compare the expression levels of LDLR obtained according to the method of the invention with a defined threshold value.
  • said threshold value is the mean expression level of LDLR of a population of healthy individuals.
  • the term "healthy individual” denotes a human which is known to be healthy, i.e. which does not suffer from a cancer and in particular from a pancreatic cancer and does not need any medical care.
  • the skilled person in the art may determine the expression level of LDLR in a biological sample, particularly a biopsy of a pancreatic cancer, of 100 individuals known to be healthy.
  • the mean value of the obtained expression levels is then determined, according to well known statistical analysis, so as to obtain the mean expression level of LDLR. Said value is then considered as being normal and thus constitutes a threshold value. By comparing the expression levels of LDLR to this threshold value, the physician is then able to classify and prognostic the cancer.
  • the physician would be able to adapt and optimize appropriate medical care of a subject in a critical and life-threatening condition suffering from cancer.
  • the determination of said prognosis is highly appropriate for follow-up care and clinical decision making.
  • kits useful for the methods of the invention comprising means for detecting LDLR expression.
  • kits of the invention may comprise an anti- LDLR protein antibody; and another molecule coupled with a signalling system which binds to said LDLR protein antibody or any molecule which bind to the mRNA of Ldlr gene like a probe.
  • the antibodies or combination of antibodies are in the form of solutions ready for use.
  • the kit comprises containers with the solutions ready for use. Any other forms are encompassed by the present invention and the man skilled in the art can routinely adapt the form to the use in immunohistochemistry.
  • the invention in another embodiment, relates to an in vitro method for monitoring a patient's response cancer treatment which comprises a step of measuring the level of LDLR expression, in a sample from a patient.
  • the present invention relates to the use of LDLR as a biomarker for the monitoring of anti pancreatic cancer therapies.
  • the expression level of LDLR may be determined to monitor a patient's response to pancreatic cancer treatment.
  • Another aspect of the invention relates to a compound which is an antagonist of LDLR or an inhibitor of the LDLR expression for use in the treatment of patient suffering of a pancreatic cancer with a high expression level of LDLR.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 Up-regulation of cholesterol uptake correlates to cholesterol overload in PDAC.
  • data are mean ⁇ SEM, *P ⁇ 0.05, Student's t-test or Mann- Whitney U- test.
  • Figure 3 Cutpoints, relative to disease-free survival (DFS) and overall survival (OS), determined using maximally selected rank statistics which allow partition of the patient cohort into two groups (low and high Ldlr expression).
  • Figure 4. A high expression of Ldlr in human PDAC is associated with an increased risk of recurrence.
  • EXAMPLE Material & Methods Human PDAC samples. Tumor specimens from 23 patients (54-79 years old) were taken, with patient consent, during surgery (Tissue collection: DC-2013-1857). PDAC stages were classified according to the American Joint Committee on Cancer staging system. A postoperative follow-up including clinical, biochemical and radiological assessment was performed for all patients.
  • Expression array data (Mouse Transcriptome Assay 1.0, Affymetrix,) were normalized with standard RMA (Bioconductor, Package Affy) and filtered from a pre-compiled GO terms list, annotated with the term "metabolic" (NCBI GO-gene association file downloaded the 1st of April, 2013), to restrain analysis to metabolic transcripts.
  • Significant PDAC dysregulated transcripts and enriched pathways were determined by the SAM method (MeV software) and a Bonferroni-corrected hypergeometric distribution, respectively. Results can be accessed from the GEO database (http://www.ncbi.nlm.nih.gov/geo/, accession number: GSE61412). Human tumor collection and mRNA extraction.
  • RNA quality was verified on RNA Nano chips (Agilent, Santa Clara, CA, USA). Establishment of stable shRNA PK4A cell lines.
  • 293T cells were cotransfected with lentiviral vectors expressing shRNA targeting LDLR (Ldlrl, clone ID: NM O 10700.1 - 1457slcl; Ldlr2, clone ID: NM_010700.1-2457slcl; Ldlr3, clone ID: M_010700.2- 3407s21cl, Ldlr4, clone ID: NM_010700.1-1304slcl; Ldlr5, clone ID: NM 010700.1- 1864slcl, Ldlr6, clone ID: NM_010700.2-1124s21cl and clone ID: M_010700.2- 642s21cl; Sigma- Aldrich) or a non-mammalian control shRNA (SHC202V, Sigma- Aldrich), together with pCMV-delta helper and pCMV-VsVg plasmids
  • PK4A cells (1.3.106), were infected twice at 24h intervals with shRNA- expressing lentiviruses. Puromycin selected cells were grown in glutamax high glucose DMEM medium (Life Technologies), supplemented with 10% fetal bovine serum GOLD (PAA Laboratories), 1% antibiotic-antimycotic solution (Life Technologies) and puromycin (0.2 ⁇ g/ml).
  • Dil-LDL uptake Control and Ldlr3 shRNA PK4A cells (1.106) were seeded in 6-well culture plates and cultured in standard medium overnight. After 1 hour of serum starvation, cells were incubated with Dil-LDL (5 ⁇ g/ml, Molecular Probes) for 30min. Trypsinized cells were then resuspended in IX PBS and Dil-LDL uptake was analyzed in 1.104 cells using a MACSQuant VYB instrument (Miltenyi Biotec). Untreated cells were used as negative controls for background fluorescence.
  • Control and Ldlr3 shRNA PK4A cells (1.106) were fixed in 70% ethanol. After RNA removal by RNase digestion (100 ⁇ g/ml), cells were stained with propidium iodide (50 ⁇ g/ml, Sigma-Aldrich) and analyzed by flow cytometry using a - -
  • Control and Ldlr3 shRNA PK4A cells (1.105) were grown in High glucose DMEM supplemented with 5% FBS and 1% antibiotic- antimycotic solution for 24, 48 or 72 hours.
  • the concentrations of L-lactate and D-glucose (mmol/1) from cultured-cell supernatants were determined electro-enzymatically using an YSI 2950 Biochemistry Analyzer (Yellow Springs Instruments, USA). Each metabolite concentration was normalized to viable cells number determined using the Vi-Cell cell counter (Beckman Coulter).
  • Doxorubicin uptake Control and Ldlr3 shRNA PK4A cells (1.106) were seeded in 6- well culture plates and cultured in standard medium overnight. Cells were then treated with doxorubicin (DOX, lmg/ml) for 15, 30, 60, 120 or 240 min. Trypsinized cells were then resuspended in IX PBS and DOX uptake was analyzed in 1.104 cells using a MACSQuant VYB instrument (Miltenyi Biotec). Untreated cells were used as negative controls for background fluorescence.
  • DOX doxorubicin
  • Immunohisto chemistry with an anti-human LDLR antibody (LifeSpan Biosciences, CI 93443) was performed on formalin- fixed and paraffin-embedded human PDAC sections using the Ventana Discovery XT automated stainer (Ventana Medical Systems, Arlington, USA) in the Pathology Department (Hopital Nord, Marseille). Antigen retrieval was performed with CCl buffer (Cell Conditioning 1; citrate buffer pH 6.0, Ventana Medical Systems). Immunofluorescence. Cryostat tumor and control pancreas sections (8 ⁇ ) were fixed in cold acetone and pre incubated in blocking solution (3% BSA, 10% donkey serum).
  • Tissue- sections were then incubated with primary antibody(ies), followed by incubation with alexa fluor 568 and/or alexa fluor 488-conjugated secondary antibodies (Molecular probes, 1 :500). Stained tissue sections were mounted using Prolong Gold Antifade reagent with DAPI (Life Technologies).
  • Tissue sections were incubated overnight at 4°C with filipin (200 ⁇ g/ml, Sigma- Aldrich, F4767) and then with anti-Lamin A/C antibody (1 : 100, Cell Signalling Technology) for 1 hour at room temperature. Lamin A/C staining was revealed with alexa fluor 568- conjugated secondary antibody (Molecular probes, 1 :500). Tissue sections were mounted using Prolong Gold Antifade reagent without DAPI (Life Technologies).
  • PathScan signaling antibody array analysis An antibody array for simultaneous detection of 18 well characterized intracellular signaling molecules was used (Cell Signaling Technology, 7323). Control and Ldlr3 shRNA PK4A cells were washed with ice-cold IX PBS and lysed in the IX Cell Lysis buffer provided. Total protein extracts were then hybridized, to the slide containing pre-spotted target-specific antibodies, overnight at 4°C. A cocktail of biotinylated detection antibodies was then added to each well and incubated for lh at room temperature and Horseradish peroxidase (HRP)-conjugated streptavidin was then added for 30 min. The slide was covered with the LumiGLO/Peroxide reagent provided and chemiluminescent signals were detected with a Fusion Fx7 imager.
  • HRP horseradish peroxidase
  • RNA quality was verified with the RNA Nano Chip kit (Agilent) on an Agilent Bioanalyzer and treatment with DNase was systematically performed using the RNase-free DNase set (Qiagen). Then, 5 ⁇ g of total RNA from each sample was used to synthesize the first-strand cDNA by using the PrimeScript RT reagent kit (Promega) and the provided oligo-dT primers, according to manufacturer's instructions. Quantitative PCR reactions were performed with specific primers (Table S7) and the GoTaq qPCR master mix kit (Promega) using the Mx3000P Stratagene system. Differential expressions of transcripts of interest were calculated in relation to the RplpO housekeeping transcript.
  • PDAC metabolic signature was highly enriched in up- and down-regulated pathways associated with amino acid, carbohydrate and lipid metabolism.
  • the lipid class contained the greatest number of disrupted pathways in PDAC.
  • pathways associated with lipoprotein catabolism and its negative regulation, and those involved in regulating cholesterol homeostasis were the most highly enriched in PDAC (enrichment of 100%).
  • Biosynthetic lipoprotein and retinoic acid pathways and glycosphingo lipid metabolism were also over-represented in PDAC (enrichment ranging from 57 to 75%).
  • LDLR is expressed in the epithelial compartment of PDAC
  • LDLR spatial LDLR expression in stromal and epithelial PDAC compartments.
  • LDLR was restricted to PDAC, since no specific staining was observable in controls.
  • pan-cytokeratin pan-KRT
  • LDLR was also present in undifferentiated cancer cells, which were disseminated into the stroma. Although these LDLR-undifferentiated cells were stained with pan-KRT marker, they had lost the E-Cadherin epithelial marker, and acquired the N-Cadherin mesenchymal marker.
  • LDLR is present in the epithelial compartment of the tumor, both in differentiated and aggressive cells which exhibit an epithelial to mesenchymal transition phenotype.
  • LDLR silencing by modifying cholesterol distribution, inhibits ERK survival pathway and reduces the proliferative and clonogenic potential of pancreatic cancer cells
  • PK4A cells established from Pdxl-Cre; LSL-Kras G12D ; Ink4a/Arf a/fl tumors, were used to investigate the impact of LDLR inhibition on tumorigenic properties of PDAC cells.
  • PK4A cells expressing shRNA which targeted different Ldlr sequences, were established and validated for LDLR knock-down (data not shown). Successful LDLR knockdown was achieved with Ldlr3 shRNA (i.e.
  • LDLR silencing did not disturb TC content, but modified its distribution, as the CE content was reduced by 46%, while the FC fraction was 1.9-fold increased and detected in membrane and cytoplasm of PDAC cells.
  • LDLR silencing significantly decreased the proliferation rate as well as the number of colonies formed, by 50%. Importantly, the morphology and size of PDAC cells were not impacted by LDLR silencing. We then investigated which survival signaling pathways are disturbed in LDLR-depleted cells.
  • pancreatic syngeneic tumor graft mice we then evaluated whether LDLR inhibition potentiates GEM-dependent tumor regression.
  • LDLR inhibition potentiates GEM-dependent tumor regression.
  • One week after tumor establishment half of the Ldlr3 and control shRNA PK4A implanted-mice were treated, twice weekly, with GEM.
  • tumor growth was reduced by 50% in GEM treated Ldlr3 shRNA mice when compared to GEM treated control shRNA mice ( Figure 2A), along with a 2.3-fold reduction in tumor weight in GEM-treated Ldlr3 shRNA mice when compared to GEM treated control shRNA mice ( Figure 2B).
  • LDLR protein levels remain efficiently reduced in Ldlr3 shRNA implanted-tumors when compared to control shRNA tumors, and HMGCR expression was not disturb by LDLR silencing, as previously shown in vitro.
  • LDLR silencing associated or not with GEM, did not modify TC content when compared to control shRNA tumors.
  • GEM altered the cholesterol distribution (i.e. the FC:CE ratio).
  • FC:CE ratio of 0.5:0.5 in untreated vs 0.9:0.1 in GEM treated Ldlr3 shRNA tumors.
  • LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Blood, 1 august 2005.

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Abstract

La présente invention concerne un composé qui est un antagoniste du LDLR ou un inhibiteur de l'expression du LDLR s'utilisant dans le traitement ou la prévention du cancer du pancréas.
PCT/EP2015/080273 2014-12-18 2015-12-17 Nouveau procédé de traitement du cancer du pancréas WO2016097175A1 (fr)

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