WO2020193746A1 - Méthodes de prédiction de la survie de patients atteints de mélanome - Google Patents

Méthodes de prédiction de la survie de patients atteints de mélanome Download PDF

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WO2020193746A1
WO2020193746A1 PCT/EP2020/058682 EP2020058682W WO2020193746A1 WO 2020193746 A1 WO2020193746 A1 WO 2020193746A1 EP 2020058682 W EP2020058682 W EP 2020058682W WO 2020193746 A1 WO2020193746 A1 WO 2020193746A1
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melanoma
patient
expression
sgms1
sms1
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PCT/EP2020/058682
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Bruno SEGUI
Thierry Levade
Anne Montfort
Joelle RIOND
Nicolas Meyer
Nathalie ANDRIEU-ABADIE
Céline COLACIOS
Fatima BILAL
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paul Sabatier Toulouse Iii
Centre Hospitalier Universitaire De Toulouse
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Publication of WO2020193746A1 publication Critical patent/WO2020193746A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
    • C12Y207/08—Transferases for other substituted phosphate groups (2.7.8)
    • C12Y207/08027—Sphingomyelin synthase (2.7.8.27)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/5743—Specifically defined cancers of skin, e.g. melanoma
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to methods for predicting the survival of patients suffering from melanoma.
  • sphingosine 1 -phosphate behaves as an oncometabolite, enhancing tumor angiogenesis, stromagenesis and modulating tumor-associated macrophages.
  • GCS glucosylceramide synthase
  • GlcCer glucosylceramide synthase
  • the present invention relates to methods for predicting the survival of patients suffering from melanoma.
  • the present invention is defined by the claims.
  • SM sphingolipid
  • GlcCer glucosylceramide
  • the first object of the present invention relates to a method for predicting the survival of a patient suffering from melanoma comprising i) determining the expression level of SGMS1 , which encodes SMS1, in a tumor sample obtained from the patient, ii) comparing the expression level determined at step i) with a predetermined reference value and iii) and concluding that the patient will have short survival time when the level determined at step i) is lower than the predetermined reference value or concluding that the patient will have long survival time when the expression level determined at step i) is higher than the predetermined reference value.
  • 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
  • OS survival time is generally based on and expressed as the percentage of people who survive a certain type of cancer for a specific amount of time. Cancer statistics often use an overall five-year survival rate. In general, OS rates do not specify whether cancer survivors are still undergoing treatment at five years or if they've become cancer-free (achieved remission). DSF gives more specific information and is the number of people with a particular cancer who achieve remission.
  • progression-free survival (PFS) rates (the number of people who still have cancer, but their disease does not progress) includes people who may have had some success with treatment, but the cancer has not disappeared completely.
  • the expression“short survival time” indicates that the patient will have a survival time that will be lower than the median (or mean) observed in the general population of patients suffering from said cancer.
  • the expression “long survival time” indicates that the patient will have a survival time that will be higher than the median (or mean) observed in the general population of patients suffering from said cancer.
  • tumor tissue sample has its general meaning in the art and encompasses pieces or slices of tissue that have been removed including following a surgical tumor resection.
  • the tumor tissue sample can be subjected to a variety of well-known post collection preparative and storage techniques (e.g., fixation, storage, freezing, etc.) prior to determining the cell densities.
  • fixation e.g., fixation, storage, freezing, etc.
  • the tumor tissue sample is fixed in formalin and embedded in a rigid fixative, such as paraffin (wax) or epoxy, which is placed in a mould and later hardened to produce a block which is readily cut.
  • TMA tissue microarrays
  • TMA consists of paraffin blocks in which up to 1000 separate tissue cores are assembled in array fashion to allow multiplex histological analysis. This technology allows rapid visualization of molecular targets in tissue specimens at a time, either at the DNA, RNA or protein level. TMA technology is described in W02004000992, US8068988, Olli et al 2001 Human Molecular Genetics, Tzankov et al 2005, Elsevier; Kononen et al 1198; Nature Medicine.
  • SGMSF has its general meaning in the art and refers to the gene encoding the sphingomyelin synthase 1 (SMS1).
  • NCBI gene ID for SGMS1 is Gene ID: 259230.
  • An exemplary human nucleic acid sequence is represented by the NCBI reference sequence NM 147156.3.
  • An exemplary human amino acid sequence for is represented by the NCBI reference sequence NP_671512.1.
  • the expression level of SGMS1 in the tumor tissue sample is determined by immunohistochemistry.
  • the determination is performed by contacting the tumor tissue sample with a binding partner (e.g. an antibody) specific for SMS1.
  • Immunohistochemistry typically includes the following steps i) fixing the tumor tissue sample with formalin, ii) embedding said tumor tissue sample in paraffin, iii) cutting said tumor tissue sample into sections for staining, iv) incubating said sections with the binding partner specific for SMS1, v) rinsing said sections, vi) incubating said section with a secondary antibody typically biotinylated and vii) revealing the antigen-antibody complex typically with avidin- biotin-peroxidase complex.
  • the tumor tissue sample is firstly incubated with the binding partners having for SMS1.
  • the labeled antibodies that are bound to SMAase2 are revealed by the appropriate technique, depending of the kind of label is borne by the labeled antibody, e.g. radioactive, fluorescent or enzyme label.
  • exemplary labels include radioactive isotopes, fluorophores, ligands, chemiluminescent agents, enzymes, and combinations thereof.
  • Non-limiting examples of labels that can be conjugated to primary and/or secondary affinity ligands include fluorescent dyes or metals (e.g. fluorescein, rhodamine, phycoerythrin, fluorescamine), chromophoric dyes (e.g.
  • the method of the present invention may use a secondary antibody coupled to an amplification system (to intensify staining signal) and enzymatic molecules.
  • a secondary antibody coupled to an amplification system (to intensify staining signal) and enzymatic molecules.
  • Such coupled secondary antibodies are commercially available, e.g. from Dako, EnVision system.
  • Counterstaining may be used, e.g. Hematoxylin & Eosin, DAPI, Hoechst.
  • Other staining methods 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 expression level of SGMS1 is determined by determining the quantity of mRNA encoding for SGMS1.
  • Methods for determining the quantity of mRNA are well known in the art.
  • the nucleic acid contained in the samples e.g., cell or tissue prepared from the subject
  • the extracted mRNA is then detected by hybridization (e. g., Northern blot analysis, in situ hybridization) and/or amplification (e.g., RT-PCR).
  • nucleic acid probes include one or more labels, for example to permit detection of a target nucleic acid molecule using the disclosed probes.
  • a nucleic acid probe includes a label (e.g., a detectable label).
  • A“detectable label” is a molecule or material that can be used to produce a detectable signal that indicates the presence or concentration of the probe (particularly the bound or hybridized probe) in a sample.
  • a labeled nucleic acid molecule provides an indicator of the presence or concentration of a target nucleic acid sequence (e.g., genomic target nucleic acid sequence) (to which the labeled uniquely specific nucleic acid molecule is bound or hybridized) in a sample.
  • a label associated with one or more nucleic acid molecules can be detected either directly or indirectly.
  • a label can be detected by any known or yet to be discovered mechanism including absorption, emission and/ or scattering of a photon (including radio frequency, microwave frequency, infrared frequency, visible frequency and ultra-violet frequency photons).
  • Detectable labels include colored, fluorescent, phosphorescent and luminescent molecules and materials, catalysts (such as enzymes) that convert one substance into another substance to provide a detectable difference (such as by converting a colorless substance into a colored substance or vice versa, or by producing a precipitate or increasing sample turbidity), haptens that can be detected by antibody binding interactions, and paramagnetic and magnetic molecules or materials.
  • Probes made using the disclosed methods can be used for nucleic acid detection, such as ISH procedures (for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)) or comparative genomic hybridization (CGH). Numerous procedures for FISH, CISH, and SISH are known in the art.
  • the nCounter® Analysis system is used to detect intrinsic gene expression.
  • the basis of the nCounter® Analysis system is the unique code assigned to each nucleic acid target to be assayed (International Patent Application Publication No. WO 08/124847, U.S. Patent No. 8,415,102 and Geiss et ak Nature Biotechnology. 2008. 26(3): 317-325; the contents of which are each incorporated herein by reference in their entireties).
  • Expression level of a gene may be expressed as absolute level or normalized level.
  • levels are normalized by correcting the absolute level of a gene by comparing its expression to the expression of a gene that is not a relevant for determining the cancer stage of the subject, e.g., a housekeeping gene that is constitutively expressed.
  • Suitable genes for normalization include housekeeping genes such as the actin gene ACTB, ribosomal 18S gene, GUSB, PGK1 and TFRC. This normalization allows the comparison of the level in one sample, e.g., a subject sample, to another sample, or between samples from different sources.
  • the predetermined reference value is a threshold value or a cut off value.
  • a “threshold value” or “cut-off value” can be determined experimentally, empirically, or theoretically.
  • a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skilled in the art. For example, retrospective measurement of expression level of the gene in properly banked historical subject samples may be used in establishing the predetermined reference value. The threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative).
  • the optimal sensitivity and specificity can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • the optimal sensitivity and specificity can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • receiver operator characteristic curve which is also known as receiver operation characteristic curve. It is mainly used for clinical biochemical diagnostic tests.
  • ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1 -specificity). It reveals the relationship between sensitivity and specificity with the image composition method.
  • a series of different cut-off values are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of diagnosis.
  • AUC area under the curve
  • the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values.
  • the AUC value of the ROC curve is between 1.0 and 0.5. When AUC>0.5, the diagnostic result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.9, the accuracy is moderate.
  • the predetermined reference value is determined by carrying out a method comprising the steps of a) providing a collection of samples; b) providing, for each ample provided at step a), information relating to the actual clinical outcome for the corresponding subject (i.e.
  • the expression level of the gene has been assessed for 100 samples of 100 subjects.
  • the 100 samples are ranked according to the expression level of the gene.
  • Sample 1 has the highest level and sample 100 has the lowest level.
  • a first grouping provides two subsets: on one side sample Nr 1 and on the other side the 99 other samples.
  • the next grouping provides on one side samples 1 and 2 and on the other side the 98 remaining samples etc., until the last grouping: on one side samples 1 to 99 and on the other side sample Nr 100.
  • Kaplan Meier curves are prepared for each of the 99 groups of two subsets. Also for each of the 99 groups, the p value between both subsets was calculated.
  • the predetermined reference value is then selected such as the discrimination based on the criterion of the minimum p value is the strongest.
  • the expression level of the gene corresponding to the boundary between both subsets for which the p value is minimum is considered as the predetermined reference value.
  • the predetermined reference value is not necessarily the median value of expression levels of the gene.
  • the predetermined reference value thus allows discrimination between a poor and a good prognosis for a subject.
  • high statistical significance values e.g. low P values
  • a range of values is provided. Therefore, a minimal statistical significance value (minimal threshold of significance, e.g.
  • a range of quantification values includes a "cut-off value as described above.
  • the outcome can be determined by comparing the expression level of the gene with the range of values which are identified.
  • a cut-off value thus consists of a range of quantification values, e.g. centered on the quantification value for which the highest statistical significance value is found (e.g. generally the minimum p value which is found).
  • a suitable (exemplary) range may be from 4-6.
  • a subject may be assessed by comparing values obtained by measuring the expression level of the gene, where values higher than 5 reveal a good prognosis and values less than 5 reveal a poor prognosis.
  • a subject may be assessed by comparing values obtained by measuring the expression level of the gene and comparing the values on a scale, where values above the range of 4-6 indicate a good prognosis and values below the range of 4-6 indicate a poor prognosis, with values falling within the range of 4-6 indicating an intermediate occurrence (or prognosis).
  • a further object of the present invention relates to a method of treating melanoma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an agent capable of restoring the intratumoral sphingomyelin/glucosylceramide homeostasis.
  • the therapeutic method of the present invention is particularly suitable for the treatment of patients characterized as having a poor prognosis by the diagnostic method as above described.
  • a further object of the present invention relates to a method of treating melanoma in a patient in need thereof comprising i) determining the expression level of SGMS1 in a tumor sample obtained from the patient ii) comparing the expression level determined at step i) with a predetermined reference value and iii) administering to the patient a therapeutically effective amount of an agent capable of restoring the intratumoral sphingomyelin/glucosylceramide homeostasis when the level determined at step i) is lower than the predetermined reference value.
  • an agent capable of restoring the intratumoral sphingomyelin/glucosylceramide homeostasis consists in a SMS1 polypeptide or a polynucleotide encoding for a SMS1 polypeptide.
  • the polynucleotide encoding for SMS1 is delivered 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.
  • the vector transports the polynucleotide 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 polynucleotide sequence of interest.
  • Viral vectors are a preferred type of vector and include, but are not limited to polynucleotide 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
  • Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo.
  • Standard protocols for producing replication-deficient retroviruses including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles
  • KRIEGLER A Laboratory Manual
  • MURRY Method of Recombinant retroviruses by the packaging cell line
  • Methods in Molecular Biology vol.7, Humana Press, Inc., Cliffton, N.J., 1991.
  • 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 hematopoietic 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.
  • Other vectors include plasmid vectors. Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g., SANBROOK et ah, "Molecular Cloning: A Laboratory Manual," Second Edition, Cold Spring Harbor Laboratory Press, 1989. In the last few years, plasmid vectors have been used as DNA vaccines for delivering antigen-encoding genes to cells in vivo.
  • Plasmids may be delivered by a variety of parenteral, mucosal and topical routes.
  • the DNA plasmid can be injected by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally. It may also be administered into the epidermis or a mucosal surface using a gene-gun.
  • 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 mi croencapsul ati on .
  • the agent capable of restoring the intratumoral sphingomyelin/glucosylceramide homeostasis is an inhibitor of glucosylceramide synthase.
  • the term“glucosylceramide synthase” or“GCS” has its general meaning in the art and refers to a pivotal enzyme which catalyzes the conversion of ceramide to glucosylceramide.
  • GCS is a transmembrane, type III integral protein localized in the cis/medial Golgi.
  • the term“inhibitor of glucosylceramide synthase” refers to any compound capable of inhibiting the activity or expression of GCS. The term thus encompasses pharmacological inhibitors (e.g. small organic molecules) but also inhibitor of expression such as siRNA or antisense oligonucleotides.
  • GCS inhibitors have been disclosed, for example, in U.S. Patent Nos. 5,302,609; 5,472,969; 5.525,616; 5,916,911; 5,945,442; 5,952,370; 6,030,995; 6,051,598; 6,255,336; 6,569,889; 6,610,703; 6,660,794; 6,855,830; 6,916,802; 7,253,185; 7,196,205; and 7,615,573. Additional GCS inhibitors and treatments are disclosed in WO 2008/150486; WO 2009/1 17150; WO 2013059119, WO 2010/014554; and WO 2012129084.
  • said inhibitor of glucosylceramide synthase may be eliglustat tartrate (N-(( I R,2R)- 1 -(2,3 - dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)- 1 -hydroxy-3 -(pyrrolidin- 1 -yl)propan-2- yl)octanamide, also known as Genz-1 12638) as described in Cox TM. Curr Opin Investing Drugs 2010 Oct; 11(10): 1 169-81 or peterschmitt MJ. Et al. Clin Pharmacol. 2010 Oct 25.
  • D-threo-l-phenyl-2- decanoylamino-3-morpholino-l-propanol PDMP
  • derivatives thereof as described in Abe A. et al. Curr Drug Metab. 2001 Sep;2(3):331-8 such as D-threo- 3', 4'-ethylenedioxy-l- phenyl-2-palmitoylamino-3- pyrrolidino-l-propanol and D-threo-4'- hydroxy-l-phenyl-2- palmitoylamino-3- pyrrolidino-l-propanol.
  • PDMP D-threo-l-phenyl-2- decanoylamino-3-morpholino-l-propanol
  • piperidine derivatives as described in WO02/055498 and 3,4,5-piperidinetriol, 2- (hydroxymethyl)-l-[(4- (pentyloxy)phenyl)methyl]-, (2S,3S,4R,5S) such as decribed in US2007/0259918.
  • the inhibitor of GlcCer synthesis is selected from the group consisting of l-(3 7 ,4 7 -ethyl enedioxy)phenyl-2-nonanoylamino-3 -pyrrolidino-l- propanol; l-(3 7 ,4 7 -ethylenedioxy)phenyl-2-octanoylamino-3-pyrrolidino-l-propanol; D- threo-(lR,2R)-phenyl-2-decanoylamino-3-morpholino-l-propanol (PDMP) and analogs thereof including D-PDMP; PPMP (DL-threo-l-Phenyl-2-palmitoylamino-3-morpholino-l- propanol), D-threo-EtDO-P4; ((lR,2R)-nonanoic acid[2-(2 / ,3 7 -dihydro-
  • the deoxynojiromycin-based GlcCer inhibitor is N-(5 7 -adamantane- 1 ' -yl- methoxy)-pentyl-l-deoxynojirimycin (AMP-DNM), or N-butyl-deoxynojirimycin (miglustat).
  • a “therapeutically effective amount” is meant a sufficient amount of the agent capable of restoring the intratumoral sphingomyelin/glucosylceramide homeostasis 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 agent capable of restoring the intratumoral sphingomyelin/glucosylceramide homeostasis 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.
  • SMS1 is frequently downregulated in cancer tissues.
  • A cDNA samples isolated from normal (N) and tumor (T) tissues from the same patient were compared. Hybridization with a SGMS1 probe was carried out first (left panel); the same array was stripped and hybridized with a probe to ubiquitin (Ub) (right panel).
  • B The ratios T/N and N/T between standardized samples for each pair was calculated and the data expressed as a fold increase (T/N) (left panel) or fold decrease (N/T) (right panel) of SMS1 expression in tumor vs normal tissues are depicted.
  • D SMS1 expression was analysed in various cancer type cohorts from cbioportal. Missense and frameshift mutations are depicted.
  • Cancer Profiling array II (#631777) including patient-derived cDNA tumor and non-tumor samples was purchased from BD Biosciences Clontech. Human samples were collected in accordance with all applicable laws and regulations in an ethical manner. Membrane was successively hybridized according to the manufacturer’s instructions with SMS1 and ubiquitin 32P-labeled probes generated using a random nonamer primer labeling procedure (# RPN1604, Amersham Biosciences). The membrane was exposed to an intensifying screen that was developed using Phosphorlmager and Image Quant software.
  • SGMS1, SGMS2 and UGCG expression and mutations in human melanoma was evaluated from Oncomine database (Riker et al, 2008, Talantov et al., 2005, Haqq et al., 2005) and the cancer genome atlas (TCGA) melanoma (Cancer Genome Atlas, 2015).
  • TCGA genomic and clinical data were downloaded from the UCSC cancer genome browser project (https://genomecancer.ucsc.edu). The analysis population consisted of 342 patients with distant metastasis for whom RNAseq and clinical data overlap.
  • SGMS1 methylation analysis The correlation between SGMS1 expression and methylation status of SGMS1 CpGs in metastatic patient samples was analysed using the TCGA melanoma RNA-seq and DNA methylation Illumina datasets. For each analysed CpG, the rho values, indicating the Spearman’s rank correlation coefficients between the CpG methylation and the SGMS1 expression, are reported. The organization of the SGMS1 locus is depicted in Figure 2A as previously described (Vladychenskaya et al., 2004).
  • Melanoma cell lines Human melanoma cell lines (M249, SKMEL28, A375, WM9, WM35, WM115, WM266, WM793, WM1346, C0L0829, G361) were from ATCC or Wistar institute.
  • SMS and GCS activities 1x106 melanoma cells were incubated with 2.5 mM C6-NBD-ceramide (Sigma) solubilized in ethanol and SMS and GCS activities were measured as previously described (Lafont et al., 2010, Bilal et al., 2017a).
  • sphingolipids were analysed from 1.106 melanoma cells by liquid chromatography/mass spectrometry (LC/MS) as previously described (Bilal et al, 2017b).
  • qRT-PCR analysis Total RNA was reverse-transcribed using 1 pg of input RNA and random primers (Superscript II, Invitrogen). qRT-PCR reactions were performed in duplicate on StepOne apparatus (Applied Biosystems) using SYBR Green (QuantiTect, Qiagen) as fluorescent detection dye. Results were quantified and mRNA expression for each target gene (UGCG, SGMS1 or SGMS2) was determined by normalization to reference genes (b-actin and GAPDH) using the ACt method. Primers for UGCG and reference genes were from Qiagen. Primers for SGMS1 and SGMS2 were from Sigma (Lafont et al., 2010).
  • SMS1 downregulation in melanoma is associated with SL metabolism reprogramming
  • melanoma expressed SGMS2 at rather low levels, while expressing UGCG at high levels (not shown).
  • the expression of UGCG was significantly higher than that of SGMS1 and SGMS2 (not shown).
  • melanoma cells exhibited low SGMS1 and SGMS2 expression, while they expressed UGCG at higher levels (not shown).
  • SMS1 downregulation in human melanoma is associated with a worse prognosis.
  • SGMS1 mutation and methylation status in the public databases of melanoma. Whereas SGMS2 and UGCG were mutated with low frequency, SGMS1 exhibited a higher mutation rate in the coding sequence (not shown). Most of the mutations were missense mutations and some of them affected residues in the catalytic domain (not shown). In the TCGA melanoma cohort, 7.7% of the 287 sequenced samples were mutated (16 missense mutations, 2 nonsense mutations and 4 deep deletions). One of the nonsense mutations (W309*) was also found in one specimen from another melanoma cohort (not shown). The other nonsense mutation (R387*) was also found in colorectal carcinoma, sarcoma and uterus carcinoma (not shown).
  • Eliglustat a selective GCS inhibitor, which is used in the clinic for the treatment of Gaucher's disease. Whereas Eliglustat reduced GlcCer levels, it concomitantly enhanced SM and ceramide content (not shown). Miglustat, another GCS inhibitor used for Gaucher disease therapy, also modified SL content (not shown).
  • BILAL F., PERES, M., LE FAOUDER, P., DUPUY, A., BERTRAND-MICHEL, T, ANDRIEU-ABADIE, N., LEVADE, T., BADRAN, B., DAHER, A. & SEGUI, B. 2017b. Liquid Chromatography-High Resolution Mass Spectrometry Method to Study Sphingolipid Metabolism Changes in Response to CD95L. Methods Mol Biol, 1557, 213-217.
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  • the cBio cancer genomics portal an open platform for exploring multidimensional cancer genomics data. Cancer Discov, 2, 401- 4.
  • COLIE S., VAN VELDHOVEN, P. P., KEDJOUAR, B., BEDIA, C., ALBINET, V., SORLI, S. C., GARCIA, V., DJAVAHERI-MERGNY, M., BAUVY, C., CODOGNO, P., LEVADE, T. & ANDRIEU-ABADIE, N. 2009. Disruption of sphingosine 1-phosphate lyase confers resistance to chemotherapy and promotes oncogenesis through Bcl-2/Bcl-xL upregulation. Cancer Res, 69, 9346-53.
  • HANNUN Y. A. & OBEID, L. M. 2002.
  • HAQQ C., NOSRATI, M., SUDILOVSKY, D., CROTHERS, J., KHODABAKHSH, D., PULLIAM, B. L., FEDERMAN, S., MILLER, J. R., 3RD, ALLEN, R. E., SINGER, M. F, LEONG, S. P., LJUNG, B. M., SAGEBIEL, R. W. & KASHANI-SABET, M. 2005.
  • the gene expression signatures of melanoma progression Proc Natl Acad Sci USA, 102, 6092-7.
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  • Complex formation of sphingomyelin synthase 1 with glucosylceramide synthase increases sphingomyelin and decreases glucosylceramide levels. J Biol Chem, 293, 17505-17522.
  • HODIS E., WATSON, I. R., KRYUKOV, G. V., AROLD, S. T., IMIELINSKI, M., THEURILLAT, J. P., NICKERSON, E., AUCLAIR, D., LI, L., PLACE, C., DICARA, D., RAMOS, A. H., LAWRENCE, M. S., CIBULSKIS, K., SIVACHENKO, A., VOET, D., SAKSENA, G, STRANSKY, N., ONOFRIO, R.
  • LAFONT E., MILHAS, D., CARPENTIER, S., GARCIA, V., JIN, Z. X., UMEHARA, H., OKAZAKI, T., SCHULZE-OSTHOFF, K., LEVADE, T., BENOIST, H. & SEGUI, B. 2010.
  • Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death. Cell Death Differ, 17, 642-54.
  • RIKER A. T, ENKEMANN, S. A., FODSTAD, O., LIU, S., REN, S., MORRIS, C., XI, Y., HOWELL, P., METGE, B., SAMANT, R. S., SHEVDE, L. A., LI, W., ESCHRICH,
  • Neoplasma SUN, Y. L., ZHOU, G. Y., LI, K. N., GAO, P., ZHANG, Q. H., ZHEN, J. H., BAI, Y. H. & ZHANG, X. F. 2006. Suppression of glucosylceramide synthase by RNA interference reverses multidrug resistance in human breast cancer cells. Neoplasma, 53, 1-8.
  • VELDMAN R. J., MITA, A., CUVILLIER, O., GARCIA, V., KLAPPE, K., MEDIN, J. A., CAMPBELL, J. D., CARPENTER, S., KOK, J. W. & LEVADE, T. 2003.
  • the absence of functional glucosylceramide synthase does not sensitize melanoma cells for anticancer drugs. FASEB J, 17, 1144-6.

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Abstract

L'invention concerne des altérations du métabolisme des sphingolipides (SL) affichées par le mélanome, qui contribuent vraisemblablement à la progression du mélanome. Dans des cellules non cancéreuses, un céramide synthétisé de novo est principalement converti en sphingomyéline (SM) et, dans une moindre mesure, en glucosylcéramide (GlcCer). Les inventeurs ont démontré que les deux synthases SM 1 (SMS1) et 2 (SMS2) étaient exprimées à de faibles niveaux dans le mélanome humain et qu'une faible expression de SMS1 était associée à un pronostic moins favorable. Ainsi, la présente invention concerne une méthode de prédiction de la survie d'un patient atteint d'un mélanome comprenant la détermination du niveau d'expression de SGMS1 (par exemple au niveau de l'ARN ou par immunocytochimie) dans un échantillon de tumeur obtenu chez le patient.
PCT/EP2020/058682 2019-03-28 2020-03-27 Méthodes de prédiction de la survie de patients atteints de mélanome WO2020193746A1 (fr)

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