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WO2016066671A1 - Procédé pour traiter des cancers résistants à l'aide d'inhibiteurs de la progastrine - Google Patents

Procédé pour traiter des cancers résistants à l'aide d'inhibiteurs de la progastrine Download PDF

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Publication number
WO2016066671A1
WO2016066671A1 PCT/EP2015/074949 EP2015074949W WO2016066671A1 WO 2016066671 A1 WO2016066671 A1 WO 2016066671A1 EP 2015074949 W EP2015074949 W EP 2015074949W WO 2016066671 A1 WO2016066671 A1 WO 2016066671A1
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Prior art keywords
progastrin
cancer
expression
cells
compound
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PCT/EP2015/074949
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English (en)
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Catherine SEVA
Elisabeth MOYAL
Aline KOWALSKI-CHAUVEL
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paul Sabatier Toulouse Iii
Institut Claudius Regaud
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Publication of WO2016066671A1 publication Critical patent/WO2016066671A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/12—Type of nucleic acid catalytic nucleic acids, e.g. ribozymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • the present invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression for use to improve the sensitivity of cancer cells to radiotherapy.
  • Colorectal cancers represent more than 1.2 million of new cases and more than 600000 deaths per year worldwide. Although the survival for patients with metastatic CRC has been improved significantly over the past two decades, the 5-year survival rates still remain low at about 10%. Rectal cancers account for about 40% of the total colorectal cancers.
  • the standard treatment for advanced rectal cancers consists of a preoperative chemoradiotherapy followed by surgery. Although this approach reduces the risk of local recurrence, a high percentage of advanced rectal cancers are resistant to preoperative chemoradiotherapy. At least half the patients fail to achieve sufficient T-stage downstaging. In addition, the risk of metastatic disease in 30-40% of cases remains high. These observations highlight the problem of radioresistance for these patients.
  • the hormone precursor progastrin is a growth factor that can potentially play a prominent role in proliferation of normal and cancerous colorectal cells.
  • Transgenic mice overexpressing progastrin present an increased proliferative index and hyperplasia in colonic mucosa. They also have an increased risk of developing preneoplastic lesions (aberrant crypt foci) and adenocarcinomas in colonic epithelium when treated with a carcinogen, azoxymethane (Singh et al, 2000; Wang et al, 1996).
  • the inventors show that progastrin remains highly expressed after irradiation in rectal tumors of patients resistant to radiotherapy and in residual cancer cells resistant to radiation.
  • the present invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression for use to improve the sensitivity of cancer cells to radiotherapy.
  • the invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression for use to improve the sensitivity of cancer cells to radiotherapy.
  • the invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression for use to enhance the sensitivity of cancer cells to radiotherapy.
  • the invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression to improve the sensitivity of cancer cells to radiotherapy.
  • the invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression to enhance the sensitivity of cancer cells to radiotherapy.
  • the compound according to the invention can be used to reduce the tumoral mass of the cancer before surgery or resection.
  • the invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression for use in the treatment of resistant cancer.
  • the cancer is resistant to radiotherapy or chemotherapy.
  • cancer resistant to radiotherapy denotes a cancer which cannot be cure by using classical radiotherapy.
  • the compound according to the invention is administrated in combination with radiotherapy.
  • the invention also relates to i) compound according to the invention, and ii) a radiotherapy, as a combined preparation for simultaneous, separate or sequential for use in the treatment of resistant cancer.
  • the invention also relates to i) compound according to the invention, and ii) a radiotherapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of resistant cancer.
  • the invention also relates to i) compound according to the invention, and ii) a radiotherapeutic agent, as a combined preparation for simultaneous, separate or sequential use to improve the sensitivity of cancer cells to radiotherapy.
  • the compound according to the invention can be used in association with a radiotherapeutic agent to reduce the tumoral mass of the cancer before surgery or resection.
  • the invention also relates to i) compound according to the invention, and ii) a radiotherapeutic agent, as a combined preparation for simultaneous, separate or sequential to reduce the tumoral mass of the cancer before surgery or resection.
  • 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.
  • Radiotherapy is typically any kind of radiation-based treatment used for solid cancers such as colorectal cancer, prostate cancers, breast cancers, or blood cancer such as Hodgkin's and non-Hodgkin's lymphoma.
  • the compound of the invention antagonizes or inhibits the human progastrin.
  • the progastrin may be a prograstin like peptide like the glycine-extended gastrin G34-Gly of sequence QLGPQGPPHLVADPSK QGPWLEEEEEAYGWMDFG (SEQ ID NO: 1), the Glycine- extended gastrin G17-Gly of sequence QGPWLEEEEEAYGWMDFG (SEQ ID NO: 2) (see Seva C et al, 1994) or the C-terminal flanking peptide (CTFP) of sequence SAEDEN (SEQ ID NO: 3) (see Smith KA et al, 2006).
  • SEQ ID NO: 1 the Glycine- extended gastrin G17-Gly of sequence QGPWLEEEEEAYGWMDFG
  • CFP C-terminal flanking peptide
  • SAEDEN SEQ ID NO: 3
  • the compound according to the invention may be an antagonist of prograstin like peptide or an inhibitor of the prograstin like peptide.
  • the cancer may be any solid cancer.
  • the cancer may be selected from the group consisting of bile duct cancer (e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, bone cancer (e.g. osteoblastoma, osteochrondroma, hemangioma, chondromyxoid fibroma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, giant cell tumor of the bone, chordoma, lymphoma, multiple myeloma), brain and central nervous system cancer (e.g.
  • bile duct cancer e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer
  • bladder cancer e.g. osteoblastoma, osteochrondroma, hemangioma, chondromyxoid fibroma, osteosarcoma,
  • breast cancer e.g. ductal carcinoma in situ, infiltrating ductal carcinoma, infiltrating, lobular carcinoma, lobular carcinoma in, situ, gynecomastia
  • Castleman disease e.g. giant lymph node hyperplasia, angio follicular lymph node hyperplasia
  • cervical cancer colorectal cancer
  • endometrial cancer e.g.
  • lung cancer e.g. small cell lung cancer, non-small cell lung cancer
  • mesothelioma plasmacytoma, nasal cavity and paranasal sinus cancer (e.g. esthesioneuroblastoma, midline granuloma), nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g.
  • rhabdomyosarcoma embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, skin cancer (e.g. melanoma, nonmelanoma skin cancer), stomach cancer, testicular cancer (e.g. seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer (e.g. follicular carcinoma, anaplastic carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma, thyroid lymphoma), vaginal cancer, vulvar cancer, and uterine cancer (e.g. uterine leiomyosarcoma).
  • skin cancer e.g. melanoma, nonmelanoma skin cancer
  • stomach cancer testicular cancer (e.g. seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer (e.g. follicular carcinoma, anaplastic carcinoma
  • the cancer is a colorectal cancer or a colorectal adenomas.
  • the invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression for use in the treatment of resistant colorectal cancer.
  • the invention relates to a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression for use in the treatment of colorectal cancer resistant to radiotherapy.
  • said antagonist of progastrin 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 progastrin and block the binding of other compound on progastrin or block the binding of progastrin to its receptor.
  • antagonist of progastrin of the invention may be an anti- progastrin antibody which neutralizes progastrin or an anti-progastrin fragment thereof which neutralizes progastrin.
  • Antibodies directed against progastrin 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.
  • 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 progastrin 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-progastrin single chain antibodies.
  • Progastrin antagonists useful in practicing the present invention also include anti-progastrin 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.
  • F(ab')2 fragments which can be generated by pepsin digestion of an intact antibody molecule
  • 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 progastrin.
  • Humanized anti-progastrin 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 binds the N-terminal region of the human progastrin.
  • the antibody anti-progastrin according to the invention may be an antibody as explained in the patent application WO2011045080.
  • progastrin 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).
  • progastrin antagonists may be selected from peptides or peptides mimetic.
  • the peptide can be the peptide JMV1155 (see Litvak DA et al, 1999).
  • the peptide JMV1 155 antagonizes the Gly cine-extended gastrin G17-Gly.
  • the compound according to the invention is an inhibitor of progastrin expression.
  • Small inhibitory R As (siR As) can also function as inhibitors of progastrin gene expression for use in the present invention.
  • Progastrin gene expression can be reduced by contacting a subject or cell with a small double stranded R A (dsR A), or a vector or construct causing the production of a small double stranded RNA, such that progastrin gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsR A small double stranded R A
  • 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.
  • Ribozymes can also function as inhibitors of progastrin 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 endonucleo lytic cleavage of progastrin 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 as inhibitors of progastrin gene expression 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 particularly cells expressing progastrin.
  • 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 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 Epstein-Barr viruses
  • papilloma viruses herpes 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.
  • the promoter may be specific for Muller glial cells, microglia cells, endothelial cells, pericyte cells and astrocytes
  • a specific expression in Muller glial cells may be obtained through the promoter of the glutamine synthetase gene is suitable.
  • 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 progastrin 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.
  • a further object of the invention relates to a method of improving the sensitivity of cancer cells to radiotherapy comprising administering to a subject in need thereof a therapeutically effective amount of compound which is an antagonist of progastrin or an inhibitor of the progastrin expression.
  • the invention in another embodiment, relates to a method of improving the sensitivity of cancer cells to radiotherapy comprising administering to a subject in need thereof a therapeutically effective amount of i) compound according to the invention, and ii) a radio therapeutic agent, as a combined preparation for simultaneous, separate or sequential.
  • the invention in another embodiment, relates to a method of treating resistant cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound which is an antagonist of progastrin or an inhibitor of the progastrin expression.
  • Compounds of the invention may be administered in the form of a pharmaceutical composition, as defined below.
  • said compound is an antagonist of progastrin.
  • a “therapeutically effective amount” is meant a sufficient amount of compound to improve the sensitivity of cancer cells to radiotherapy. It will be understood that 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 progastrin 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 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.
  • said therapeutic active agent is an anticancer agent.
  • said anticancer agents include but are not limited to fludarabine, gemcitabine, 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
  • 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.
  • 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, diclofmac, 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.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1A shows mRNA progastrin relative expression, measured by RT- QPCR, in different human colorectal cancer cell lines (DLD1, HCT116, sw620, Sw837) in basal condition. Results are expressed relative to the expression in DLD1 cell line set at 1.
  • Figure IB shows mRNA progastrin expression, measured by RT-QPCR, in different human colorectal cancer cell lines after irradiation. NIR: non-irradiated cells, IR: irradiated cells (72h post-radiation, 10 Gy). Quantifications of 3 experiments are presented as means ⁇ S.E.M.
  • Figure 2 shows the inhibition of the expression of progastrin in 4 different human colorectal cancer cell lines stably transfected with a scramble sh-RNA (negative control, sh- Scr) or a specific progastrin sh-RNA (sh-PG) in basal condition (Fig 2A) or after irradiation (72h post-radiation, 10 Gy) (fig 2B). Quantifications of 3 experiments are presented as means ⁇ S.E.M.
  • Figure 3 shows for different human colorectal cancer cell lines (DLD1, HCT116, sw620, Sw837) the survival fraction after 2 Gy of radiation (in clonogenic assays) as a function of progastrin relative expression.
  • Figure 4 illustrates the effects of the inhibition of progastrin expression on the sensitivity of colorectal cancer cells to radiations. Clonogenic assays have been performed with increasing doses of radiations (1 to 8 Gy) in 4 different colorectal cancer cell lines stably transfected with a scramble sh-RNA or a specific progastrin sh-RNA.
  • the best fit survival curve was generated according to the linear quadratic model and the mean inactivation dose (MID) calculated to compare the radiosensitivity of the different cell lines (HCT116, DLD1, SW620, SW837). Quantifications of 3 experiments are presented as means ⁇ S.E.M.
  • Figure 5 shows that progastrin targeting with a specific shRNA increases apoptotic cell death induced by radiation in colorectal cancer cells.
  • shRNA in 2 colorectal cancer cell lines, HCT116 and sw837) after radiation is shown on the activation of the effector caspase 7 (fig. 5A, 5B) and on the cleavage and inactivation of an enzyme involved in DNA repair, the poly. (ADP-ribose) polymerase (PARP) (fig. 5C, 5D), measured by western-blot.
  • Western-blots are representative of at least 3 experiments. Quantifications of 3 experiments are presented as means ⁇ S.E.M
  • Figure 6 shows the effect of the inhibition of progastrin expression by a specific shRNA in the rectal cancer cell line SW837 on the activation of the ERK (A) or AKT (B) pathway after irradiation measured by western blot.
  • Western-blots are representative of at least 3 experiments. Quantifications of 3 experiments are presented as means ⁇ S.E.M.
  • Figure 7 shows the effects of the inhibition of progastrin expression on the growth of transplanted human rectal cancer cells in vivo in response to irradiation.
  • Figure 7A shows a flow chart of the in vivo experiment.
  • Figure 7B shows the growth curve for the human rectal cancer cell line sw837, stably transfected with a scramble sh-RNA or a specific progastrin shRNA, transplanted into nude mice and submitted to radiations or not as described in A. All experimental groups consisted of 5-8 mice. Quantifications are presented as means ⁇ S.E.M.
  • HCT116 Human colorectal cancer cell lines (HCT116, DLD1, SW620, SW837) were obtained from the American Type Culture Collection (ATCC) and cultured in RPMI supplemented with 10% fetal bovine serum at 37°C in a humidified atmosphere containing 5% C02.
  • shRNA transfection RNA extraction, reverse-transcription and Real-time PCR.
  • the shR A directed against PG (sh-PG: ATGCAGCGACTATGTGTGTATGT, SEQ ID NO: 4), or a non target shRNA control (sh-control: GGAATCTCATTCGATGCATAC, SEQ ID NO: 5) cloned in the SureSilencing shRNA plasmid (SuperArray, Bioscience corporation) were transfected into cells using Attractene Transfection Reagent (Qiagen) and selected in a polyclonal background with neomycin.
  • Tumor cells growing in log-phase were seeded as single cell suspension (500 cells/mL) into T25 flasks. After attachment cells were irradiated with a single dose of 1 to 8 Gy of gamma-rays (GammaCell Irradiator), and a standard colony- forming assay was performed to determine the respective surviving fractions. After 15 days, cells were fixed with paraformaldehyde and stained with Crystal Violet. Colonies with more than 50 cells were scored as survivors. Non- irradiated cultures were used for data normalization. The best fit survival curve was generated according to the linear quadratic model and the mean inactivation dose (MID) calculated to compare the radiosensitivity of the different cell lines.
  • MID mean inactivation dose
  • mice All procedures were approved by animal facility care committee. Eight-week old athymic nude mice (Charles River, France) were inoculated subcutaneously with 2x 106 cells. Tumor volume was measured every two days with a digital calliper using the following formula: (width2 x length)/2. At a volume of- 150 mm3 tumors were irradiated every 3 days with 2.5 Gy for 9 days (total dose of 10 Gy) as described in figure 9 A using a gamma-ray irradiator (GammaCell irradiator). Four to five weeks after the randomization at 150 mm3 mice were euthanized. All experimental groups consisted of 5-8 mice.
  • the present invention discloses that progastrin remains highly expressed after irradiation of rectal tumors of patients resistant to radiotherapy and in residual cancer cells resistant to radiation (data not shown) indicating that progastrin is overexpressed in radioresistant colorectal cancer cells.
  • the present invention compared the expression levels of progastrin mRNA in different colorectal cancer cell lines, DLDl, HCTl 16, sw620, Sw837 measured by RT-QPCR and the radiosensitivity of the cell lines measured by clonogenic assays (sf2, survival fraction at 2 Gy).
  • the present invention confirmed first that the basal expression of the progastrin gene (fig. 2A) as well as the expression of the prohormone induced by radiations (fig. 2B)were significantly inhibited by stable transfection of a specific progastrin Sh-R A in all colorectal cancer cell lines tested.
  • the present invention discloses that survival of cancer cells after irradiation, measured by clonogenic assays was significantly decreased in all cells in which the progastrin gene has been inhibited (Sh-PG) as compared to cells transfected with a scramble control and overexpressing progastrin (Sh-Scr) (fig. 4). In other words, radiation- induced cytotoxicity was enhanced when progastrin expression was blocked. It is important to notice that radiosensibilization of cancer cells by inhibiting progastrin was also observed in cell lines harbouring p53 mutations (SW620 and SW837) since this mutation has been particularly associated with radioresistance.
  • progastrin expression is correlated to cancer cell radioresistance
  • progastrin plays a direct role in mediating radioresistance
  • progastrin inhibition can lead to a radiosensitization of cancer cells.
  • the inhibition of progastrin expression increases radiation-induced apoptosis which is one of the main cell death induced by radiations.
  • radiations are used in treatment of cancer cells they induce apoptosis through the activation of pro-apoptotic factors including the initiator caspases 8 and 9 (data not shown), the effector caspase 7 (fig.
  • PARP poly (ADP-ribose) polymerase
  • the sensitivity of cancer cells to the death by irradiation may be enhanced by inhibiting the expression or activity of progastrin. It was also demonstrated that the inhibition of progastrin in combination with irradiation increases the expression of pro-apoptotic genes including, BIM, TRAIL, TNF-alpha (data not shown). A synergic effect of the combined treatment was also observed. For BIM and TRAIL in both cell line tested (HCT116 and SW837). The expression of these two pro-apoptotic factors was not increased by radiations alone but significantly enhanced by combination of both progastrin inhibition and irradiation.
  • the present invention also discloses that in addition to an increase in radio- induced apoptosis progastrin blocking by specific shRNA also lead to an inhibition of survival pathways which are activated after irradiation in cells resistant to radiations particularly, the AKT and the ERK pathways.
  • survival pathways which are activated after irradiation in cells resistant to radiations particularly, the AKT and the ERK pathways.
  • the two survival pathways are activated by irradiation.
  • the increase in AKT and ERK activation by radiations was completely blocked.
  • the present inventors examined the effect of radiation alone, progastrin inhibition alone or in combination on the growth of subcutaneous SW837 xenograft in nude mice (fig. 7B). From the sixteenth days after rendomization and the first irradiation, the tumors volume in the combined treatment group (radiation + progastrin inhibition by a specific shRNA, sh-PG IR) was significantly lower than in the radiation only group (radiation + control shRNA, Sh-control IR).
  • progastrin expression enhances the radioresistance of cancer cells in vivo and that the inhibition of progastrin expression or activity can enhance the radiosensitivity of cancer cells in vivo.
  • CM Jr. JMV1155 a novel inhibitor of glycine-extended progastrin-mediated growth of a human colon cancer in vivo. Anticancer Res. 1999 Jan-Feb;19(lA):45-9.
  • the wnt target jagged- 1 mediates the activation of notch signaling by progastrin in human colorectal cancer cells. Cancer Res 69: 6065-73.
  • Precursor peptide progastrin(l-80) reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP.

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Abstract

La présente invention concerne un composé qui est un antagoniste de la progastrine ou un inhibiteur de l'expression de la progastrine, destiné à être utilisé pour améliorer la sensibilité de cellules cancéreuses à la radiothérapie.
PCT/EP2015/074949 2014-10-29 2015-10-28 Procédé pour traiter des cancers résistants à l'aide d'inhibiteurs de la progastrine WO2016066671A1 (fr)

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Cited By (4)

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CN110662769A (zh) * 2017-03-30 2020-01-07 普莱戈斯瑞恩癌症有限责任公司 使用前胃泌素结合分子检测和治疗前列腺癌的组合物和方法
JP2022064969A (ja) * 2015-12-31 2022-04-26 プロガストリン、エ、カンセル、エス、アー エル、エル 食道癌の検出および治療のための組成物および方法
CN114438216A (zh) * 2022-03-16 2022-05-06 上海市东方医院（同济大学附属东方医院） m6A甲基转移酶WTAP在制备用于诊断直肠癌新辅助放疗抵抗标记物中的用途
US11561225B2 (en) * 2017-03-30 2023-01-24 Progastrine Et Cancers S.À R.L. Compositions and methods for treating lung cancer

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022064969A (ja) * 2015-12-31 2022-04-26 プロガストリン、エ、カンセル、エス、アー エル、エル 食道癌の検出および治療のための組成物および方法
JP7363007B2 (ja) 2015-12-31 2023-10-18 プロガストリン、エ、カンセル、エス、アー エル、エル 食道癌の検出および治療のための組成物および方法
CN110662769A (zh) * 2017-03-30 2020-01-07 普莱戈斯瑞恩癌症有限责任公司 使用前胃泌素结合分子检测和治疗前列腺癌的组合物和方法
US11561225B2 (en) * 2017-03-30 2023-01-24 Progastrine Et Cancers S.À R.L. Compositions and methods for treating lung cancer
CN110662769B (zh) * 2017-03-30 2023-10-20 普莱戈斯瑞恩癌症有限责任公司 使用前胃泌素结合分子检测和治疗前列腺癌的组合物和方法
CN114438216A (zh) * 2022-03-16 2022-05-06 上海市东方医院（同济大学附属东方医院） m6A甲基转移酶WTAP在制备用于诊断直肠癌新辅助放疗抵抗标记物中的用途

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