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WO2017089347A1 - Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf - Google Patents

Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf Download PDF

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WO2017089347A1
WO2017089347A1 PCT/EP2016/078448 EP2016078448W WO2017089347A1 WO 2017089347 A1 WO2017089347 A1 WO 2017089347A1 EP 2016078448 W EP2016078448 W EP 2016078448W WO 2017089347 A1 WO2017089347 A1 WO 2017089347A1
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Prior art keywords
melanoma
braf
pde4
treatment
inhibitors
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PCT/EP2016/078448
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English (en)
Inventor
Nicolas DUMAZ
Armand Bensussan
Julie DELYON
Samia Mourah
Celeste Lebbe
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Inserm (Institut National De La Sante Et De La Recherche Medicale)
Université Paris Diderot– Paris 7
Assistance Publique-Hôpitaux de Paris
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Publication of WO2017089347A1 publication Critical patent/WO2017089347A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • 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
    • 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
    • C12N15/1137—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 enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/04—Phosphoric diester hydrolases (3.1.4)
    • C12Y301/04017—3',5'-Cyclic-nucleotide phosphodiesterase (3.1.4.17)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/04—Phosphoric diester hydrolases (3.1.4)
    • C12Y301/04053—3',5'-Cyclic-AMP phosphodiesterase (3.1.4.53)
    • 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 N.A.
    • C12N2310/141—MicroRNAs, miRNAs

Definitions

  • the present invention relates to methods and pharmaceutical compositions for the treatment of BRAF inhibitor resistant melanomas.
  • Melanoma is the most aggressive skin cancer. It often induces metastasis and its incidence is rapidly growing and continues to rise alarmingly. Surgery is curative in nearly all cases before metastatic stage, but when metastasis appears, surgery, radiotherapy and conventional chemotherapy have little curative effects and patient survival is usually short. Molecular alterations are frequent in melanomas. Activating mutations in the serine/threonine kinase BRAF and in particular the BRAFV600E mutation occurs in about 50% of melanomas. This BRAF mutation induces activation of the MAPK pathway, which is involved in the tumoral development.
  • Vemurafenib (PLX4032) and Dabrafenib.
  • PLX4032 specific anti-BRAFV600E inhibitors
  • Dabrafenib Preclinical studies indicate that Vemurafenib and Dabrafenib block the mutated BRAF protein, inducing cell growth arrest and cell death in tumors carrying this mutation.
  • Clinical trials of Vemurafenib and Dabrafenib have shown therapeutic effect in more than 50% of patients with BRAFV600E positive metastatic melanomas.
  • BRAFV600E positive metastatic melanomas.
  • identification and characterization of unknown pathways mediating resistance to BRAF inhibitors are essential for the rational design of targeted strategies to prevent and overcome said resistance across this entire population of patients.
  • the present invention relates to methods and pharmaceutical compositions for the treatment of BRAF inhibitor resistant melanomas.
  • the present invention is defined by the claims.
  • Phosphodiesterases are enzymes, which modulate the cAMP pathway that plays a major role in melanocyte differentiation.
  • the inventors have previously shown that in RAS-mutated melanoma (20% of melanoma), the overexpression of PDE4 enzymes was critical for the MAPK activation by oncogenic RAS, and that PDE4 inhibition induced cell death in melanoma cells (Marquette et al. Nat Struct Mol Biol 201 1).
  • the inventors have shown that PDE4D is overexpressed in melanoma tumours and that inhibiting PDE4D inhibited melanoma proliferation in clonogenic assays and in melanoma grown in 3D as spheroids. Moreover, the inventors demonstrated that PDE4 inhibitors inhibited the proliferation of melanoma cell lines resistant to BRAF inhibitors used to treat BRAF-mutated melanoma. The results demonstrate that PDE4 inhibitors could be used to treat melanoma resistant to BRAF inhibitors.
  • an object of the present invention relates to a method of treating a melanoma resistant to BRAF inhibitors in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a PDE4 inhibitor.
  • melanoma refers to a condition characterized by the growth of a tumor arising from the melanocytic system of the skin and other organs. Most melanocytes occur in the skin, but are also found in the meninges, digestive tract, lymph nodes and eyes. When melanoma occurs in the skin, it is referred to as cutaneous melanoma. Melanoma can also occur in the eyes and is called ocular or intraocular melanoma. Melanoma occurs rarely in the meninges, the digestive tract, lymph nodes or other areas where melanocytes are found.
  • BRAF serine-threonine protein kinase B-RAF
  • resistant refers to the repeated outbreak of melanoma, or a progression of the melanoma independently of whether the disease was cured before said outbreak or progression.
  • BRAF inhibitor refers to an agent that is capable of inhibiting BRAF kinase or mutated BRAF kinase activity (one or more mutated forms of serine-threonine protein kinase B-RAF (BRAF)) (e.g. BRAFV600E). Accordingly, the term “BRAF inhibitors” encompasses within its scope a compound that is capable of inhibiting BRAF or its mutated form; or a compound that is capable of inhibiting V600 mutated form of BRAF.
  • BRAF inhibitors include but are not limited to BAY43-9006 (sorafenib, Bayer), vemurafenib (PLX4032, Plexxikon; RG7204, R05185426, Hofmann-LaRoche), GDC-0879 (GlaxoSmithKline), dabrafenib (GSK21 18436, GlaxoSmithKline), PLX4720 (Hofmann-LaRoche), BMS-908662 (XL281 , Bristol-Myers Squibb), LGX818 (Novartis), PLX3603 (RO5212054, Hofmann-LaRoche), ARQ-736 (ArQule), DP-4978 (Deciphera) or RAF265 (Novartis).
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • PDE4 inhibitor has its general meaning in the art and refers to any compound which inhibits selectively the type 4 phosphodiesterase.
  • the PDE4 inhibitor of the present invention when compared to other known types of phosphodiesterases, e.g. type 1, 2, 5 etc., whereby the compound has a lower IC50 for the type 4 phosphodiesterase by a factor of 10 compared to the IC50 for the inhibition of other known phosphodiesterases, e.g. type 1 , 2, 5, etc.
  • PDE4 inhibitors are well known in the art (see e.g.
  • PDE4 inhibitors are disclosed in the following patent application publications: EP2070913; EP2196465; EP2226323; EP2380890; EP2394998;
  • WO2010147922 WO2011018510; WO2011073231; WO2011092547; WO2011114103; WO2011134468; WO2011136192; WO2011160632; WO2012016845; WO2012016889; WO2012040258; WO2012083153; WO2012097116; WO2012133492; and WO2012168226.
  • the PDE4 inhibitor of the present invention is selected from the group consisting of:
  • Methanesulfonic acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN: LIRIMILAST]; the preparation of this compound and its pharmaceutically acceptable salts as well as their use as PDE4 inhibitors is disclosed in the European patent application EP0731099.
  • the PDE4 inhibitor of the present invention is selected from the group consisting of:
  • the PDE4 inhibitor is an inhibitor of PDE4 expression.
  • An "inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme.
  • anti- sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of PDE4 mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of PDE4, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding PDE4 can be synthesized, e.g., by conventional phosphodiester techniques.
  • Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).
  • Small inhibitory RNAs siRNAs
  • siRNAs can also function as inhibitors of expression for use in the present invention.
  • PDE4 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 PDE4 gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • Antisense oligonucleotides, siRNAs, shRNAs 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, shRNA or ribozyme nucleic acid to the cells and typically cells expressing PDE4.
  • 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, shRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous 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 rous sarcoma virus
  • adenovirus adeno-associated virus
  • SV40-type viruses polyoma viruses
  • Epstein-Barr viruses Epstein-Barr viruses
  • papilloma viruses herpes virus
  • vaccinia virus
  • the expression "therapeutically effective amount” meant a sufficient amount of the active ingredient (i.e. the PDE4 inhibitor) for treating or reducing the symptoms at reasonable benefit/risk ratio applicable to any medical treatment. 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 subject 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 subject; 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 with the active ingredients; 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 subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, typically 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 active ingredient of the present invention e.g.
  • PDE4 inhibitor is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the active ingredients of the invention can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • FIGURES are a diagrammatic representation of FIGURES.
  • PDE4D is overexpressed in human melanoma tumors.
  • PDE4D mRNA expression assessed by qRT-PCR in 43 melanoma tumor samples (related to housekeeping mRNA PPIA).
  • FIG. 1 PDE4 inhibition significantly reduces growth of BRAF-mutated melanoma cell line.
  • A Clonogenic assay in BRAF-mutated SkMel28 treated with BRAF inhibitor vemurafenib 3 ⁇ , PDE4 inhibitor rolipram ⁇ + forskolin ⁇ , or DMSO as a control. Bars represent mean +-SD.
  • B Size of SkMel28 and M74 melanospheres treated with PDE4 inhibitor rolipram ⁇ + forskolin ⁇ , or DMSO in spheroid culture medium for 2 weeks. Bars represent mean +-SD.
  • FIG. 3 PDE4D inhibition by RNA interference significantly BRAF-mutated melanoma cell lines.
  • A Clonogenic assay in WM266.4 silenced for PDE4D (mil or mi2PDE4D) or not (miCTL). Bars represent mean +-SD.
  • B Proliferation assay of melanospheres dissociated after 2 weeks of culture in spheroid culture medium. Luminescence was measured after 96. Bars represents mean +-SD.
  • FIG. 4 PDE4 inhibition significantly reduces growth of BRAF-mutated melanoma cell lines resistant to BRAF inhibitors.
  • A Clonogenic assay in SkMel28 resistant to vemurafenib (BRAF Res. and BRAF RAS) treated with BRAF inhibitor vemurafenib 3 ⁇ , vemurafenib 10 ⁇ , PDE4 inhibitor rolipram 10 ⁇ + forskolin ⁇ , or DMSO as a control. Bars represent mean +-SD.
  • B Clonogenic assay in SkMel28 resistant to vemurafenib (BRAF Res.
  • BRAF RAS BRAF RAS treated with BRAF inhibitor vemurafenib 10 ⁇ , PDE4 inhibitor rolipram ⁇ + forskolin ⁇ , PDE4 inhibitors (rolipram, apremilast, roflumilast ⁇ ) or DMSO as a control. Bars represent mean +-SD.
  • FFPE paraffin-embedded
  • RNA from paraffin-embedded (FFPE) tissue sections was extracted from five ⁇ sections using RNeasy FFPE extraction kit (Qiagen) after xylene treatment according to the manufacturer's protocol. RNA quantity and quality was assessed using the Nanodrop-ND- 1000 (Nanodrop Technologies, Wilmington). First-strand cDNA was synthesized using a High-Capacity cDNA Archive Kit (Applied-Biosystems) according to the manufacturer's protocol. Transcript levels were measured by qRT-PCR using Perfect Master Mix-Probe (AnyGenes, France) on LightCycler-480 (Roche). Transcript levels were normalized to the housekeeping PPIA (peptidylprolyl isomerase A) and ⁇ -ACTIN transcripts.
  • PPIA peptidylprolyl isomerase A
  • BRAF-mutated melanoma cell lines human melanoma cell lines SkMel28 and WM266.4 were cultured in respectively RPMI or DMEM supplemented with 10% fetal calf serum (FCS).
  • FCS fetal calf serum
  • PDEs inhibitors (rolipram, apremilast, roflumilast) and BRAF inhibitor (vemurafenib) were obtained from Selleckchem and dissolved in dimethylsulphoxide (DMSO).
  • DMSO dimethylsulphoxide
  • SkMel28 were transfected with plasmid containing the cDNA of oncogenic RAS (G12V) (SkMel28RAS) or the empty vector (SkMel28Res) and selected by exposure to increased doses of vemurafenib concentration over 2 months.
  • G12V oncogenic RAS
  • SkMel28RAS oncogenic RAS
  • SkMel28Res empty vector
  • miR-PDE4D containing vectors were obtained by cloning two complementary oligonucleotides specifics of PDE4D into a BLOCK-iTTM Pol II miR RNAi Expression Vector with EmGFP, according to manufacturer instructions (Life technologies, Carlsbad, CA, USA).
  • WM266.4 melanoma cell lines stably expressing a miRNA control (mi-CTL) or targeting PDE4D (mil-PDE4D and mi2-PDE4D) were obtained by transfection with JetPEI (Polyplus-transfection, Illkirch, France) according to the manufacturer's instructions and selection by blasticidin (10 ⁇ g ml-1; GE Healthcare Europe GmbH, Velizy-Villacoublay, France).
  • Resistant cells were then sorted by fluorescence with an ARIA III cell sorter from Becton Dickinson (BD Biosciences, Franklin Lakes, NJ, USA), the most fluorescent cells (about 1%) were amplified.
  • mi-CTL and mi-PDE4D cells were cultured in complete medium and expression of PDE4D and actin were analysed by Western Blotting.
  • Cells were plated at low density (2000 cells per well in 6-well tissue culture plates) in fresh medium. Cells were treated every 48 hours with DMSO or inhibitors at the indicated concentrations, in duplicate. After 10 days, cells were stained with 0.5%> crystal violet, and the number of colonies was counted.
  • Melanoma sphere culture SkMel28, M74 and WM266.4 were seeded at a concentration of 2000 cells/ml in DMEM/F12 serum free medium supplemented with B27, 5 ⁇ / ⁇ 1 insulin, 20 ng/ml epidermal growth factor, 20 ng/ml fibroblast growth factor and 1% penicillin-streptomycine on ultra low-attachment 6-well plates. Cells were treated every 48 hours with DMSO or inhibitors. Medium was replaced weekly. To analyse sphere- forming capacity, the largest sphere diameters were measured after 1 week and 2 weeks of treatment on light microscope images of each well at lOx magnification.
  • PDE4D is expressed in human melanoma tumours
  • PDE4 inhibitor rolipram significantly reduces clone formation in BRAF-mutated melanoma cell lines
  • BRAF-mutated cell line SkMel28 was cultured at low density in the presence of inhibitors for 10 days to assess cell clone formation in comparison with DMSO as a control ( Figure 2A).
  • the BRAF inhibitor vemurafenib at 3 ⁇ , significantly inhibited SkMel28 clone formation.
  • Re-activation of the cAMP pathway with rolipram 10 ⁇ , a PDE4 inhibitor, and a sub-optimal dose forskolin, an adenylyl cyclase activator, ( ⁇ ) reduced the ability of SkMel28 to form clones by 82%.
  • SkMel28, M74 and WM266.4 were cultured in a three-dimensional melanospheres that in vitro partially recapitulate tumorigenic melanoma growth and that are known to contain an increased proportion of melanoma-initiating cells (Sette 2013, Perego 2010).
  • PDE4 inhibition with rolipram 1 ⁇ + forskolin 1 ⁇ significantly reduced the growth of SkMel28 and M74 melanosphere ( Figure 2B).
  • Cell viability was assessed in SkMel28 and WM266.4 melanospheres using a proliferation assay after 2 weeks of treatment with rolipram ⁇ + forskolin ⁇ in spheroid culture medium.

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Abstract

La présente invention concerne des procédés et des compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de BRAF. La présente invention concerne en particulier un procédé de traitement d'un mélanome résistant aux inhibiteurs de BRAF chez un sujet le nécessitant, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un antagoniste de PDE4.
PCT/EP2016/078448 2015-11-25 2016-11-22 Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf WO2017089347A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
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US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
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