WO2011157294A1 - Compositions destinées à être utilisées dans le traitement ou la prévention de cancer, de cancer du sein, de cancer du poumon, de cancer de l'ovaire, de métastase, d'insuffisance cardiaque, de remodelage cardiaque, de myocardiopathie dilatée, de maladies auto-immunes ou de maladies ou de troubles apparentés - Google Patents

Compositions destinées à être utilisées dans le traitement ou la prévention de cancer, de cancer du sein, de cancer du poumon, de cancer de l'ovaire, de métastase, d'insuffisance cardiaque, de remodelage cardiaque, de myocardiopathie dilatée, de maladies auto-immunes ou de maladies ou de troubles apparentés Download PDF

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WO2011157294A1
WO2011157294A1 PCT/EP2010/058495 EP2010058495W WO2011157294A1 WO 2011157294 A1 WO2011157294 A1 WO 2011157294A1 EP 2010058495 W EP2010058495 W EP 2010058495W WO 2011157294 A1 WO2011157294 A1 WO 2011157294A1
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mir
dicer
polynucleotide
expression
cancer
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Stefano Piccolo
Graziano Martello
Silvio Bicciato
Michelangelo Cordenonsi
Sirio Dupont
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Universita' Degli Studi Di Padova
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • 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
    • C12N2310/113—Antisense targeting other non-coding nucleic acids, e.g. antagomirs
    • 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
    • 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
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA

Definitions

  • cancer cells use global downregulation of the miRNA network to induce epithelial plasticity and foster invasive and metastatic behaviors.
  • miR-103/107 targeting Dicer, was found to play a causal role in these events.
  • miR-103/107 are both, generated by and regulators of Dicer: this mutual feedback relationship allows to scale-down Dicer levels but is also intrinsically incompatible with complete depletion, maintaining sufficient Dicer for growth control and other cellular functions.
  • precursors of siRNAs may be long dsRNA molecules or shorter "hairpin loop" ssRNA molecules. Both types of these siRNA precursors may contain a stretch of base pairs without any mismatch.
  • the current model for maturation of mammalian miRNAs is nuclear cleavage of the primary rniRNA (pri-miRNA) which liberates a 60-70 nt stem loop intermediate, known as the mi RNA precursor or pre-miRNA.
  • the mature about 18-23 nt long mi R A is yielded from one arm of the stem loop precursor (B artel, Cell (2004), 116: 281-297; Lee. EMBO J (2002), 21: 4663-4670; Zeng and Cullen.
  • the polynucleotide which decreases or suppresses expression of Dicer to be inhibited in context of the present invention comprises or consists of the nucleotide sequence of any one of SEQ ID NO: 1 (mature miR- 103.1), SEQ ID NO: 2 (mature nr!R- 103.2), SEQ ID NO: 3 (mature miR-107), SEQ ID NO: 4 (seed sequence of SEQ ID NOs. 1 to 3), SEQ ID NO: 5 (seed sequence of miR-107), SEQ ID NO: 6 (consensus sequence of SEQ ID NOs.
  • the polynucleotide to be inhibited in context of the present invention may comprise or consist of a polynucleotide being at least 25%, 30%, 35%, 40%>, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to a polynucleotide comprising or consisting of the nucleotide sequence of any one of SEQ ID NO: 1 (mature miR- 103.1 ), SEQ ID NO: 2 (mature miR-103.2), SEQ ID NO: 3 (mature miR- 107), SEQ ID NO: 4 (seed sequence of SEQ ID NOs.
  • SEQ ID NO: 5 seed sequence of miR- 107
  • SEQ ID NO: 6 Consensus sequence of SEQ ID NOs. 1 to 3
  • SEQ ID NO: 7 pre-miR- 103.1
  • SEQ ID NO: 8 pre-miR-103.2
  • SEQ I D NO: 9 pre-miR-107
  • SEQ ID NO: 7 pre-miR- 103.1
  • SEQ ID NO: 8 pre-miR- 103.2
  • SEQ ID NO: 9 pre-miR-107 and comprise the nucleic acid sequence as shown in SEQ I D NO: 4 (seed sequence of SEQ I D NOs. 1 to 3) or SEQ ID NO: 5 (seed sequence of miR- 107) or any other seed sequence as shown in Table 1 herein.
  • a polynucleotide comprising the nucleic acid sequence of a sequence provided herein may also be a polynucleotide consisting of said nucleic acid sequence.
  • a test to determine hybridization between an miRNA and an mRNA may be a Luciferase Assay as also described in technical bulletins by Promega (C8021 (psiCHECK-2 Vector), El 960 (Dual-Luciferase® Reporter Assay System)).
  • reporter gene assays in which common reporter genes are used such as fluorescent proteins (e.g., GFP, eGFP, YFP, eYFP, BFP, or eBFP), or luminescent proteins (e.g., Renilla or firefly luciferase, or ⁇ -galactosidase encoded by the lacZ gene).
  • fluorescent proteins e.g., GFP, eGFP, YFP, eYFP, BFP, or eBFP
  • luminescent proteins e.g., Renilla or firefly luciferase, or ⁇ -galactosidase encoded by the lacZ gene.
  • degradation of mRNA or the level of the respective translation product can easily be examined by methods known in the art.
  • qPCR examples include qPCR, RT-PCR, qRT-PCR.
  • RT-qPCR Light Cycler®, TaqMan® Platform and Assays, Northern blot, dot blot, microarrays, next generation sequencing (VanGuilder, Biotechniques (2008), 44: 619-26; Elvidge, Pharmacogenomics (2006), 7: 123-134; Metzker, Nat Rev Genet (2010), 1 1 : 31-46).
  • the level of expressed Dicer in order to determine whether a polynucleotide decreases or suppresses expression of Dicer or a biologically active derivative thereof (e.g., by hybridizing to the mRNA of Dicer and thereby inducing degradation or preventing translation of Dicer mRNA), the level of expressed Dicer can be easily detected.
  • a polynucleotide is to be assessed as decreasing or suppressing expression of Dicer or a biologically active derivative thereof if the detected level of expressed Dicer in a test sample which was contacted with a polynucleotide to be tested is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80% lower than the Dicer expression level of a control sample which was not contacted 'with the polynucleotide.
  • a Western blot analysis can be performed for Dicer protein detection (Dupont, Cell (2009) 136: 123-135).
  • composition comprising an inhibitor of a polynucleotide or polynucleotides to be inhibited in context of the present invention may contain the inhibitor in an amount of about 1 ng/kg body weight to about 100 mg/kg body weight of the subject which is to be treated or in which cancer, particularly breast cancer, lung cancer, ovarian cancer, metastasis, heart failure, cardiac remodelling, dilated cardiomyopathy, autoimmune diseases, or diseases or disorders related thereto are to be prevented.
  • the composition comprises the inhibitor in an amount of about 1 ⁇ g/kg body weight to about 20 mg/kg body weight, more preferably 1 mg/kg body weight to about 10 mg/kg body weight.
  • compositions comprising such carriers can be formulated by well known conventional methods. These pharmaceutical compositions can be administered to the subject at a suitable dose, i.e. about 1 ng/kg body weight to about 100 mg/kg body weight of the subject which is to be treated or in which cancer, particularly breast cancer, lung cancer, ovarian cancer, metastasis, heart failure, cardiac remodelling, dilated cardiomyopathy, autoimmune diseases, or diseases or disorders related thereto are to be prevented.
  • a suitable dose i.e. about 1 ng/kg body weight to about 100 mg/kg body weight of the subject which is to be treated or in which cancer, particularly breast cancer, lung cancer, ovarian cancer, metastasis, heart failure, cardiac remodelling, dilated cardiomyopathy, autoimmune diseases, or diseases or disorders related thereto are to be prevented.
  • the composition comprising an inhibitor of a polynucleotide or polynucleotides to be inhibited in context of the present invention comprises the inhibitor in an amount of about 1 ⁇ g/kg body weight to about 20 mg/kg body weight, more preferably 1 mg/kg body weight to about 10 mg/kg body weight.
  • Administration of the composition may be effected or administered by different ways, e.g.
  • compositions described herein comprising an inhibitors of a polynucleotide or polynucleotides being capable of decreasing or suppressing expression of Dicer or a biologically derivative thereof as described herein may be used to treat or prevent cancer, particularly breast cancer, lung cancer, ovarian cancer, metastasis, heart failure, cardiac remodelling, dilated cardiomyopathy, autoimmune diseases, or diseases or disorders related thereto in a subject.
  • a given compound can be assessed as an inhibitor to be employed in context of the present invention if it is able to prevent hybridization of a polynucleotide to be inhibited in context of the present invention with the mRNA (e.g., the 3'UTR thereof) of Dicer or a biologically derivative thereof.
  • a polynucleotide to be inhibited in context of the present invention is capable of decreasing or suppressing the expression of Dicer or a biologically derivative thereof such as it amounts to an expression level of 50% compared to the normal expression level (i.e. without said polynucleotide), and the expression level increases by applying an inhibitor as described herein such that the expression level of Dicer or a biologically derivative thereof increases to an amount of 75% compared to the normal expression level (i.e. without said polynucleotide), the effect of said polynucleotide is reversed by the inhibitor by 50%.
  • the hybridization of said nucleic acid to be employed as an inhibitor in context of the present invention to a polynucleotide to be inhibited in context of the present invention may be over the entire length of said polynucleotide to be inhibited or only over a part of the sequence of said polynucleotide to be inhibited, e.g., over at least 25%, at least 35%, at least 45%, at least 55%, at least 65%, at least 75%, at least 85% or at least 95% of the sequence of said polynucleotide to be inhibited, one embodiment of the present invention, the inhibitor to be employed in context of the present invention may be an antisense oligonucleotide which is complementarv to a polynucleotide to be inhibited in context of the present invention.
  • the present invention relates to a composition
  • a composition comprising a nucleic acid molecule which hybridizes under stringent conditions with the polynucleotide consisting of the nucleic acid sequence shown in SEQ ID NO: 4, thereby preventing hybridization of said polynucleotide with the mRNA of Dicer, for use in treating or preventing breast cancer or metastasis in a human subject.
  • the present invention relates to a composition
  • a composition comprising a nucleic acid molecule which hybridizes under stringent conditions with the polynucleotide consisting of the nucleic acid sequence shown in SEQ ID NO: 6, thereby preventing hybridization of said polynucleotide with the mRNA of Dicer, for use in treating or preventing breast cancer or metastasis in a human subject.
  • nucleic acid molecule which hybridizes under stringent conditions with the polynucleotide consisting of the nucleic acid sequence shown in any one of SEQ ID NOs: 1 to 9 is an miRCURY LNA microRNA inhibitor.
  • the inhibitor (i. e. in case of a nucleic acid inhibitor) of the polynucleotide to be inhibited in context of the present invention may be cloned into a vector.
  • vector as used herein particularly refers to plasmids, cosmids, viruses, bacteriophages and other vectors commonly used in genetic engineering.
  • these vectors are suitable for the transformation of cells, like fungal cells, cells of microorganisms such as yeast or prokaryotic cells.
  • such vectors are suitable for stable transformation of bacterial cells, for example to transcribe the polynucleotide of the present invention.
  • a nucleic acid inhibitor in case of a nucleic acid inhibitor of a polynucleotide to be inhibited in context of the present invention has been cloned may be miR-Vec, a retroviral expression vector (Voorhoeve, Cell (2006), 124: 1 169-1 181).
  • the present invention also relates to a compound binding to a polynucleotide described herein, i.e. to a polynucleotide which is capable of decreasing or suppressing expression of Dicer or a biologically derivative thereof as described herein, for use in diagnosing or predicting the progression of diseases or disorders such as cancer, breast cancer, lung cancer, ovarian cancer, metastasis, heart failure, cardiac remodelling, dilated cardiomyopathy, autoimmune diseases, or diseases or disorders related thereto in a subject.
  • diseases or disorders such as cancer, breast cancer, lung cancer, ovarian cancer, metastasis, heart failure, cardiac remodelling, dilated cardiomyopathy, autoimmune diseases, or diseases or disorders related thereto in a subject.
  • G Expression of a miR-103/107-insensitive Dicer cDNA rescues mature miRNA expression, here exemplified by mi R- 1 5a.
  • the effects of miR-107 on mature miR-15a levels were compared in parental and MDA-MB-231 cells stably expressing a miR- 103/107-insensitive form of Dicer (+Dicer).
  • miR- 1 5a expression was measured by qRT-PCR and normalized to snRNA-U6b loading control. Relative values are shown as mean and SD.
  • FIG. 7 The miR-200 family members are inhibited by miR-103/107 to promote mesenchymal traits.
  • Figure 1 1 Effects of miR-103/107 or Dicer manipulations on migration, proliferation, dicer levels and cell cycle distribution
  • pri-miR- 103/107 expression promotes migration of non-metastatic 168FARN breast cancer cells.
  • Stable cell lines expressing shGFP, pri-miR- 103 or pri-miR- 107 from retroviral expression vectors were compared in transwell migration assays. The graph shows the absolute quantitations of ceils migrated through the filter.
  • siDicer corresponds to lane 4 (6 nM). Note the increased motility promoted by miR- 107 and siDicer. as well as the loss of epithelial morphology.
  • Figure 12 Effects of AntagomiR-103/107 administration and correlations between the genetic status of Dicer, pri-miR-103/107 levels and metastasis free survival
  • AntagomiR-103/1 07 administration in the fat-pad of wild-type mice has no effects on mammary gland structure and morphology.
  • Top panels representative whole mount eosin stainings of delipidated fat-pads explanted from mice treated with AntagomiR- 103/107 of AntagomiR-MUT. No defects are apparent in the overall morphology of the gland, nor in the number of the Terminal End Buds (not shown).
  • Bottom panels representative histological H&E-stained sections of the same tissues, showing no obvious differences in the differentiation of ductal cells.
  • the "Dicer+/-” group of patients displays a copy number compatible with heterozigosity at the Dicer locus, while the “Dicer+/+” has wild-type gene copy number.
  • the log-rank test p values reflect the significance of the association between Dicer heterozygosity and metastatic relapse.
  • FIG. 1 C Panels show immunoblotting of MDA-MB-231 cells transfected with miR- 107 as in Figure 1 C.
  • Lam in B serves as loading control.
  • miR-107 overexpression causes downregulation of mature miR- 15/ 16, of the miR- 17-92 cluster and of the let-7 family (see Figure 3F and Table 2), but their direct established targets (BCL2, c-Myc and K-Ras, respectively), are not upregulated.
  • Table 2 Expression of mature miRNAs in MDA-MB-23 1 transfected with miR- 107-MUT or miR-107, as quantitated by using Taqman Human miRNA microarray (see Supplemental Experimental Procedures for details). Results are given as the difference between the Cycle thresholds of a given miRNA and the snRNA-U6 (Delta Ct). Relative quantitation was
  • Example 1 Biological assays in mammalian cells
  • the sequences of the siRNA were: 5'-UCC AGA GCU GCU UCA AGC ATT-3 ' and 5'-UGC UUG AAG CAG CUC UGG ATT-3 '.
  • miR- 107 5' -AGC AGC AUU GUA CAG GGC UAU CA-3' and S'-AUA GCC CUG UAC AAU GCU GCC UU-3';
  • miR-107-MUT 5'-AUA GCC CUG UAC AuU cCg GaC UU-3' and 5'-AuC cGg AaU GUA CAG GGC UAU CA-3'; miR-200b: 5'-AUC AUU ACC AGG CAG UAU UAG A-3' and 5'-UAA UAC UGC CUG GUA AUG AUG A-3 '.
  • Example 2 Experimental models of metastasis and Antagomi -treatment
  • AntagomiRs were designed as described in Krutzfeldt, Nature (2005), 438: 685-689, and purchased from Fidelity System. Sequences were as follows:
  • U20S, HCT1 16chr3 cells were cultured in DM EM 10%FCS, MDA-MB231 and SUM149 cells in DMEM/F 12 10% PCS. HepG2 in MEM 10%FCS supplemented with NEA. 67NR, 168FARN, 4T07 and 4T1 mouse mammary tumor cells were cultured as previously described (Aslakson, Cancer Res (1992), 52: 1399- 1405). DNA transfections were performed with Transit-LTl reagent (MirusBio); for siRNA transfections, Lipofectamine-RNAiMax (Invitrogen) were used in all cell lines.
  • the sequences of the siRNA were: 5'-UCC AGA GCU GCU UCA AGC ATT- 3 ' and 5'-UGC UUG AAG CAG CUC UGG ATT-3'.
  • pri-miRs were cloned in the miR-Vec expression vector (Voohoeve, loc cit). miRNA expression was confirmed by qPCR. Control shGFP was as previously described (Adorno, Cell (2009), 137: 87-98).
  • human Dicer cDNA (gift from P. Provost) was subcloned in pRRLsin . ppts . hCMV . gfppre (gift from L. Naldini). For Dicer knockdown in SUM- 149 cells, pLKO.
  • the full-lenght 4,2 Kb human Dicer 3 'UTR was PGR amplified from MDA-MB-231 cells, cloned into a CMV-luciferase expression plasmid (Martello, loc cit) and sequence-verified. All predicted miR-103/107 seed-pairing sites were mutated by changing them to unique restriction sites (see list of primers). Cells were transfected with Dicer 3' UTR reporters using Transit-LTl (MirusBio) and harvested after 48 hours.
  • Luciferase reporters 25ng/cm2 were cotransfected with CMV -beta-gal (40ng/cm2) to normalize for transfection efficiency by CPRG (Roche) colorimetic assay. Each sample was transfected in triplicate. Each experiment was repeated at least twice.
  • Tissues for histological examination were fixed in 4% buffered formalin, dehydrated and embedded in paraffin by standard methods.
  • serial sections of the lungs were cut at a distance of 70 mm from each other, were first stained with Hematoxylin and Eosin (H&E) and then processed for human cytokeratin expression (see below).
  • H&E Hematoxylin and Eosin
  • serial sections of the lungs were cut at a distance of 70 mm from each other and stained with H&E.
  • Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue using an indirect immunoperoxidase technique (Bond Polymer Refine Detection; Vision BioSystems, UK). Sections mounted on silanized slides will be dewaxed in xylene, dehydrated in ethanol, boiled in 0.01 M citrate buffer (pH 6.0) for 20 min. in a microwave oven and then incubated with 3% hydrogen peroxide for 5 min. After washing with PBS, they were be incubated in 10% normal BSA for 5 min, followed by incubation for 45 min.
  • Example 9 Antibodies and Western Blotting ⁇ -LaminB (C20) and ⁇ -Dicer (SC-30226) were obtained from SantaCruz; a-beta-catenin was obtained from Sigma. To monitor endogenous gene responses, cells were harvested by sonication in Ub-lysis buffer as in described (Dupont, Cell (2009), 136: 123-135). Proteins were loaded according to Bradford quantification, ran in commercial 4-12% or 10% Nupage MOPS acrylamide gels (Invitrogen) and transferred onto PVDF membranes (ImmobilonP) by wet electrophoretic transfer.
  • blots were blocked one hour at RT with 0,5% non-fat dry milk (BioRad) in PBSw (0,05% Tween) and incubated over night, at 4 °C with primary antibodies. Secondary antibodies were incubated 50 min at RT. Washes after antibody incubations were done on an orbital shaker, three times 10 min, with IX PBS 0,05% Tween20. Blots were developed with Pico or Dura SuperSignal West chemiluminescent reagents (Pierce).
  • Poly(A) + -RNA was retrotranscribed with M-MLV Reverse Transcriptase (Invitrogen) and oligo-d(T) primers following total RNA purification with Trizol (Invitrogen).
  • Real-time PGR messengerRNAs were performed on a RotorGene 3000 (Corbett) using the FastStart SYBR Green Master Mix (Roche). The primers are listed m the table below.
  • Detection of the mature form of miRNAs was performed using the Taqman microRNA assay kit (Applied Biosystem) according to the manufacturer's instructions. U6 small nuclear RNA was used as an internal control.
  • Detection of 70 nt precursors miRNA was performed using the methods and primers described in Schmittegen, Nucleic Acid Res (2004), 32: e43.
  • the case series consisted of 69 women with primary resectable invasive estrogen receptor- positive breast cancer, histologically node-negative, and with no radiologic or clinical evidence of distant metastasis, a synchronous bilateral tumor, or a concomitant second primary tumor. These cases, with a minimum potential of 10 years of follow-up (i.e. the time elapsed from the date of surgery to the date of the last updating of the patient records), underwent surgery at the Istituto Nazionale Tumori (INT) of Milan during the period from January 1990 to December 1998. Patients were treated with mastectomy or quadrantectomy plus radiotherapy, and ail of them underwent axillary node dissection (median number of examined nodes, 18).
  • INT Istituto Nazionale Tumori
  • This assay is an adaptation of the proven DASL (cDNA-mediated Annealing, Selection, Extension, and Ligation) assay.
  • 800 ng of total RNA were retrotranscribed, annealed with a miRNA-specific oligonucleotide pool consistsing of a universal PCR priming site at the 5' end, an address sequence complementary to a capture sequence on the BeadArray and a microRNA-specific sequence at the 3' end.
  • the probes were hybridized on miRNA expression profiiing_v2 BeadChips, containing 1,146 sequences for detecting 95% of miRNAs described in the miRBase database (vl4.0).
  • Raw data were normalized using the Robust Spline Normalization algorithm implemented in the lumi R package. Probes with a detection p-value ⁇ 0.01 in less than 10% of samples were filtered out.
  • miR-103 and miR-107 are intronic microRNA, their primary transcripts could be mapped on Affymetrix arrays (Baskerville, RNA (2005), 11 : 241-247; Lee. Pancreatology (2009), 9: 293-301 ; Wang, J Neurosci (2008), 28: 1213-1223).
  • Affymetrix arrays Baskerville, RNA (2005), 11 : 241-247; Lee. Pancreatology (2009), 9: 293-301 ; Wang, J Neurosci (2008), 28: 1213-1223.
  • ⁇ is the score of Pri-miR-103/107 genes in each sample i, ju p and ⁇ ⁇ are the estimated mean and standard deviation of P ; , over the entire dataset,
  • Tumors were then classified as "miR-103/107 High” if the score was equal to or above a threshold and as “miR-103/107 Low” if the score was below the threshold, i.e. the score S F for each sample i was compared with the selected threshold to classify any sample as "miR- 103/107 High” or "miR-103/107 Low”. This classification was applied to log2 expression values obtained using RMA on datasets described in the table above.
  • Dicer Low Dicer Low
  • ⁇ and j D1CER and & mtkR are the estimated mean and standard deviation of Dicer calculated over the entire dataset (Adorno, loc cit).
  • the data-driven procedure described above was adopted to select the threshold providing the best separation between survival curves. Briefly, multiple quantiles of go i cER va j ues were evaluated considering quantiles corresponding to probabilities from 0.5 to 0.2, thus selecting the threshold for low expression among lower quantiles, excluding very extreme values. The quantile giving the best separation, i.e.
  • Retroviral transduction of either pri-miR-103 or pri-miR-107 expression vectors caused further inhibition of the wild-type 3' UTR reporter ( Figure IB, compare lane 5 with lanes 6 and 7), but not of the corresponding seed-mutant reporter.
  • Dicer protein was specifically downregulated (about 50-60% reduction) by expressing pri-miR-103 or pri-miR-107 ( Figure 1C, left panel and Figure 8A).
  • pri-miR-103 or pri-miR-107 Figure 1C, left panel and Figure 8A.
  • Figure 1C, left panel and Figure 8A To exclude any potentially confounding effect from the viral expression system - or from flanking sequences of the pri-miR constructs - cells - cells were also transiently transfected with the mature form of miR-107 or, as control, a mutant miR-107 that contained three mismatches in the seed-binding sequence (miR-107-MUT).
  • Dicer protein levels were downregulated by mature miR-107, but not miR-107-MUT ( Figure 1 C, right panel and Figure 8B).
  • miR103/107 affect Dicer levels acting on its 3'UTR, as lentiviral expression of Dicer lacking the 3'UTR was insensitive to miR-107 ( Figure 8C).
  • miR-103/107 restrict miRNA processing at the level of Dicer, then the levels of miR- 103/107 should directly correlate with the abundance of Dicer substrate, i.e. the 70 nt precursor miRNAs (pre-miRNAs). Indeed, pre-miRNAs, but not pri -miRNAs, accumulate in miR-107 expressing MDA-MB-231 cells ( Figure 8H).
  • miR-103/107 lead to inhibition of miRNA biogenesis through Dicer downregulation.
  • Example 16 Inverse correlation between miR-103/107 and Dicer levels in cancer ceil lines
  • Example 17 Clinical association of miR-103/107 expression to breast cancer metastasis and poor-prognosis
  • Mature miR-103/107 levels were measured in a collection of breast cancer patients treated in our Institution with annotated clinical history. Patients were divided in two groups, with respectively high or low levels of miR-103/107 (Figure 2C, see Examples 13 and 14). Remarkably, when tested using the Kaplan-Meier survival analysis, the "miR-103/107 High " group displayed a significant higher probability to develop metastasis when compared to the "Low” group ( Figure 2D). In line with the biochemical characterization of Dicer as target of miR-103/107, the "high” group tumors showed reduced level of Dicer protein when compared to the "Low” group, as assayed by immunohistochemisty (Figure 2E-H).
  • miR-103 and miR- 107 are intronic miRNAs contained in three PANK (Pantothenate kinase) loci of the human genome (i.e. , PANK1 , 2 and 3 corresponding to pri-miR-107, pri-miR- 103- 2 and pri-miR- 103-1, respectively).
  • PANK Purothenate kinase loci of the human genome
  • Example 18 miR-103/107 downregulatc Dicer to promote cell migration and invasion in vitro
  • miR-103/107 Induction of migratory capacity by miR-103/107 relies on attenuation of Dicer. First, it is phenocopied in shDicer SUM 149 cells (reducing Dicer to about 40% its normal levels). Second, it is rescued by coexpression of a miR-insensitive Dicer transgene that restores Dicer protein to level near-to-endogenous ( Figure 3 A, lanes 4 and 5, see immunoblots in Figure 11C). Similar results were obtained in wound-healing assays with another, more aggressive cell line, MDA-MB-231 cells ( Figures 3C and 3D). Thus, miR-103/107 empowers cell motility through Dicer inhibition.
  • Dicer overexpressing 4T1 cell clones were selected from a lentivirally infected cell population ( Figure 13C).
  • Dicer-4T1 derived tumors were deprived of metastatic capacity when compared to lesions from mock-infected cells ( Figures 5G-I).
  • the data reveals a functional pathway in aggressive tumors, whereby endogenous miR-103/107 is instrumental to attenuate Dicer levels below a threshold for metastasis protection.
  • Example 21 miR-103/107 promote Epithelial-to-Mesenchymal-Transition (EMT)
  • E- Cadherin and ZO-1 in NMuMg cells, a well-established model system for the study of EMT (Miettinen, J Cell Biol (1994), 127: 2021-2036). Immunofluorescence showed that these proteins were strongly downregulated in cells expressing miR- 107 ( Figure 6B). EMT was also validated by gene expression analysis: in the presence of miR- 107, expression of E- Cadherin mRNA was downregulated whereas the mesenchymal markers vimentin, IC AM- 1 and fibronectin mRNAs were significantly increased ( Figures 6C-F).
  • epithelial plasticity and required for maintenance of mesenchymal gene expression.
  • Example 22 miR-103/107 control mesenchymal traits by regulating the expression of the miR-200 family of miRNAs.
  • the miR-200 targets ZEBl and ZEB2 were monitored. These genes were found to be downregulated (Figure 7F) in AntagorniR- 103/107 treated cells to about 50%, mimicking the effect of mature miR-200 overexpression (see Figure 71). In agreement, it was found in context of the present invention that overexpression of miR-107 downregulates miR-200 and upregulates ZEBl and ZEB2 mRNA levels ( Figure 7G and 7H).

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Abstract

La présente invention concerne des compositions comprenant un inhibiteur d'un polynucléotide, ledit polynucléotide à inhiber étant capable de réduire ou de supprimer l'expression de Dicer ou d'un de ses dérivés biologiquement actifs, destinées à être utilisées dans le traitement ou la prévention de cancer, de métastase, d'insuffisance cardiaque, de remodelage cardiaque, de myocardiopathie dilatée, de maladies auto-immunes ou de maladies ou de troubles apparentés. En outre, l'invention concerne également des procédés de traitement ou de prévention de cancer, de métastase, d'insuffisance cardiaque, de remodelage cardiaque, de myocardiopathie dilatée, de maladies auto-immunes ou de maladies ou de troubles apparentés.
PCT/EP2010/058495 2010-06-16 2010-06-16 Compositions destinées à être utilisées dans le traitement ou la prévention de cancer, de cancer du sein, de cancer du poumon, de cancer de l'ovaire, de métastase, d'insuffisance cardiaque, de remodelage cardiaque, de myocardiopathie dilatée, de maladies auto-immunes ou de maladies ou de troubles apparentés WO2011157294A1 (fr)

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