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WO2010016638A1 - Composition contenant de l'anti-micro arn pour le traitement ou la prévention des cancers solides - Google Patents

Composition contenant de l'anti-micro arn pour le traitement ou la prévention des cancers solides Download PDF

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Publication number
WO2010016638A1
WO2010016638A1 PCT/KR2008/005789 KR2008005789W WO2010016638A1 WO 2010016638 A1 WO2010016638 A1 WO 2010016638A1 KR 2008005789 W KR2008005789 W KR 2008005789W WO 2010016638 A1 WO2010016638 A1 WO 2010016638A1
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Prior art keywords
mir
cancer
microrna
treating
expression
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English (en)
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Duk-Soo Bae
Jeong-Won Lee
Young-Ae Park
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Samsung Life Public Welfare Foundation
Samsung Medical Center
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Samsung Life Public Welfare Foundation
Samsung Medical Center
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • 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

Definitions

  • composition for preventing or treating solid cancer preferably, cervical cancer, which contains an anti-microRNA complementarily binding to a specific microRNA the level of which increases specifically in cervical cancer, as well as an anti-cancer agent, for synergistic effect by the combined administration of the anti- microRNA and the anti-cancer agent.
  • alkylating agents are the most widely used type of anti- cancer agents.
  • alkyl-group By introducing an alkyl-group into a cancer cell, and thereby binding to the Guanine N-7 position and other critical regions on DNAs, they interfere with formation of base pairs and cross-links, thereby causing single- or double-strand breaks.
  • Cisplatin which is an alkylating agent type anti-cancer agent, is a platinum based heavy metal compound.
  • platinum is the central atom and is bonded to four ligands — two chlorine atoms and two amino groups — in cis position.
  • Cisplatin binds with two neighboring guanines on the DNA strands and forms interstrand crosslinks, thereby interfering with DNA synthesis.
  • cisplatin binds to the DNA double strands in the nucleus of a cancer cell. Interfering with DNA transcription, cisplatin suppress the growth and proliferation of the cancer cell, removing the cancer cell and exerting anti-cancer effect.
  • cisplatin is being used in priority order over other drugs, but problems are beginning to appear — such as development of tolerance to cisplatin in cancer cells.
  • MicroRNAs are a recently discovered class of small noncoding RNAs which regulate gene expression. Mature miRNAs are of 18 to 25 nucleotides in length and are processed from hairpin precursors. MircoRNAs complementarily binds to their target mRNAs and act as a post-transcriptional regulator. They are known to induce unstabilization, by inhibiting mRNA translation and thus down-regulating the gene expression, or by catalyzing the process of cleavage of the mRNA. Special cellular functions associated with miRNAs include cell proliferation, metabolism regulation, developmental time courses, apoptosis, hematosis, neurogenesis, human oncogenesis, DNA methylation, and chromatin modification.
  • miRNA gene expression is involved with oncogenesis and progress process of human cancers. Dinstinctive patterns of miRNA expressions are being reported in lung cancers, breast cancers, glioblastoma, hepatocellular carcinoma, thyroid papillary carcinoma, and recently, rectal cancers. Further, it is reported that miRNA expression signature is linked with clinical results of certain diseases. All this data suggest that miRNAs play a significant role in various types of human cancers.
  • the object is to identify specific miRNAs capable of improving anti-cancer effects of existing anti-cancer agents, and to provide a use thereof for preventing or preventing solid cancers.
  • an embodiment provides a composition for preventing or treating solid cancers, which comprises an anti-cancer agent and a specific miRNA which is identified to increase in its production level specifically in solid cancers, preferably in cervical cancer.
  • the present invention relates to a technology using microRNA for suppressing proliferation of cancer cells. More precisely, the inventors found that the level of a certain microRNA is increased in a cancer call, and the proliferation of the cancer cell is inhibited when an anti-microRNA oligonucleotide complementary to a primary microRNA (pri-microRNA) of the microRNA is introduced into the cancer cell. Based on such findings, the inventors also found that, when the anti- microRNA oligonucleotide is used combined with an existing anti-cancer agent, a synergetic effect can be obtained, to complete the present invention. In particular, an embodiment suggests a result for miRNA regulations in early invasive squamous cell carcinomas (ISCCs) and normal cervical epithelial tissue sets, using an analysis by real-time quantitative PCR array method having high sensitivity and efficiency.
  • ISCCs early invasive squamous cell carcinomas
  • normal cervical epithelial tissue sets using an analysis by real-time quantitative PCR array method having high sensitivity and efficiency.
  • miRNAs are different between in early invasive squamous cell carcinomas and in normal cervical epithelial tissue, and that miR-199a, among the miRNAs, was observed to specifically increase in its production in the epithelial tissues of cervical cancer, suggesting miR-199a as a target for cervical cancer treatment.
  • the present invention relates to a technology for treating and/or preventing cervical cancer which is of combined application of a miR-199a inhibitor and an anti-cancer agent.
  • An embodiment provides a dosage form (administration formulation) or unit dosage form for treating and/or preventing cervical cancer, which contains a miR- 199 inhibitor and an anti-cancer agent.
  • a miR-199 inhibitor and an anti-cancer agent may be provided respectively in separate formulations, or provided together in a single formulation.
  • compositions for treating and/or preventing cervical cancer which contains a miR-199 inhibitor and an anti-cancer agent as active ingredients.
  • a method of treating and/or preventing cervical cancer which comprises the step of administrating a miR-199 inhibitor and an anti-cancer agent to a patient in need thereof.
  • the method of treating and/or preventing cervical cancer can be characterized in that the miR-199 inhibitor and the anti-cancer agent can be provided respectively in separate formulations, or provided together in a single formulation.
  • a method of formulating a dosage form for treating and/or preventing cervical cancer containing a miR-199 inhibitor and an anti-cancer agent can be characterized in that a miR-199 inhibitor and an anti-cancer agent can be provided respectively in separate formulations, or provided together in a single formulation.
  • the above miR-199a may be originated from mammals, preferably from humans, and have nucleotide sequence of SEQ ID NO: 1 (5'- CCCAGUGUUCAGACUACCUGUUC-3'). Inhibition against miR-199a can be achieved by an anti-miR-199a which binds to miRNA-199a and inhibits its activity.
  • the miR-199a inhibitor may be a nucleotide complementary to at least 10, preferably at least 15 nucleotides, which are serially located within the nucleotide sequence of SEQ ID NO: 1. More preferably, the miR-199a inhibitor may be an oligonucleotide having the nucleotide sequence of SEQ ID NO: 2 (5'- GAACAGGUAGUCUGAACACUGGG-S').
  • the above anti-cancer agent may be an alkylating agent type anti-cancer agent, for example, cisplatin.
  • the alkylating agent is capable of introducing an alkyl-group (R-CH2) into a reacting compound and highly reactive. When contacting to a cell, it mostly reacts with the guanine N-7 position, distorts the DNA structure, and causes single- or double-strand breaks, thereby exhibiting anti-cancer and cytotoxic effects.
  • the anti-cancer agents classified to this group may include cisplatin, nitrogen mustard, chlorambucil, melphalan, cyclophosphamide, thiotepa, busulphan, DTIC (dacarbazine), procarbazine, and the like.
  • the anti-cancer agent may be one or more selected from the group consisting of cisplatin, nitrogen mustard, chlorambucil, melphalan, cyclophosphamide, thiotepa, busulphan, DTIC (dacarbazine), procarbazine, and the likes.
  • the anti-cancer agent may be cisplatin.
  • the dose of the miR-199a inhibitor may be within the range from 0.001 to 500 mg/kg, preferably, from 0.01 to 100 mg/kg, based on the content thereof in the formulation, but is not limited thereto. It can be adjusted according to patient's condition and seriousness of the disease. There are no special limitations with regard to a dose of the anti-cancer agent.
  • cisplatin for example, it can be applied within the range from 1 to 100 mg/m2(body surface area), preferably, 10 to 50 mg/ m2.
  • the administration of cisplatin may be generally conducted by one coure (meaing an administrative period unit of an anticancer agent including administering period of several consecutive days wherein the of anti-cancer agent is intravenously administered in a row, then followed by administration stopping period of several weeks) wherein the administration of cisplatin is continued in the amount of 15-20 mg/m2 once per a day for consecutive 5 days, and stopped for at least 2 weeks, and, depending on the patient's conditions, another coure wherein the administration of cisplatin is continued in the amount of 25-30 mg/m2 once per a day for consecutive 5 days, and stopped for at least one week; however it is not limited thereto, and it can be properly adjusted depending on the patient's conditions or the anti-cancer agent's efficacy.
  • the anti-microRNA molecules described herein may be produced by a conventional DNA synthesizer and directly used, or cloned into an expression vector.
  • the expression vector may be selected from the group consisting of a plasmid, a lentiviral vector, an adenoviral vector, and the likes, which are conventionally used for transcription and expression of mammalian cells and other types of target cells.
  • the genes encoding the anti-microRNA described herein may be prepared and inserted into the expression vectors in conventional manners.
  • the composition according to the present invention may contain an anti- microRNA molecule produced as described above or cloned into an expression vector, as an active ingredient.
  • the composition may contain the anti-microRNA molecule alone or along with pharmacologically acceptable carriers.
  • the pharmacologically acceptable carriers may include solvents, dispersive media, coating agents, anti-microbial agents and anti-bacterial agents, isotonic agents, absorption retarders, and the like, which are suitable to pharmaceutical administration. Supplementary active materials may be further included.
  • the anti-microRNA may be provided in a formulation suitable to a given administration route.
  • the composition may be administered through any conventional oral or non- oral administration route, for example, intravenous, intraperitoneal, intramuscular, subcutaneous, percutaneous (local) or rectal administration, or administration through inhalation or mucous membrane, but not be limited thereto.
  • Administration regimes can follow conventional medical or pharmacological methods, safety and efficacy of which are proven.
  • Toxicity and treatment efficacy of the composition of the present invention can be assessed by the standard pharmacological process applied in cell cultures and experiment animals, which measures LD50 (the lethal dose of a drug for 50% of the population) and ED50 (the minimum effective dose for 50% of the population).
  • a therapeutic index is defined as the ratio between the toxicity and the efficacy, that is, LD50:ED50.
  • a high therapeutic index is preferable to a low one, and it is necessary to design a delivery system to target a site affected by the therapeutic agent, in order to minimize injuries to uninfected cells and reduce side effects.
  • a suitable dosage of the composition according to the present invention comprising anti-microRNA depends on the expression and activity of pri- microRNAs to be regulated.
  • the physician a veterinarian or a researcher
  • a dose specific to a patient is determined with many factors taken into account — such as the activity of substance to be applied, the patient's age, weight, general health condition, and infection with a venereal disease and eating habit, administration frequency and times, administration routes, excretion rates, other drugs administered along with, and extent of expression and activity to be controlled.
  • composition according to the present invention can be administered to mammals, preferably to humans, while dosages can be adjusted according to a subject's age and seriousness of the disease.
  • a dose can be within the range of from 0.001 to 500 mg/kg, preferably, from 0.01 to 100 mg/kg, of the effective ingredient per kg of body weight.
  • Administration of the composition according to the present invention can be conducted by any manner of administration as commonly used. For example, oral or rectal administration, or intravenous, intramuscular, subcutaneous or intrauterine injection can be applied.
  • composition according to the present invention may be prepared for oral administration in such forms as powders, granules, tablets, capsules, suspensions, emulsions, syrup, and aerosols; or for non-oral administration in such forms as transdermal patches, suppositories, or injections.
  • Tissue-specific pattern of miRNA expression has recently been reported and is viewed to reflect an aspect of embryologic development. According to a few reports, over- or under-expression of certain miRNAs is specifically observed in specific tumor types. The present inventors discovered that overexpression of specific miRNAs — rather than their underexpression — is predominantly found in ISCC (invasive squamous cell carcinoma) cases, compared to normal cervical epithelium (cervical epithelium) tissues. Overexpression of miRNAs in cervical cancer has not been reported. The results obtained by the present inventors can be explained by tissue-specificity of miRNA expression, as shown through large-scale profiling studies using a variety of tissue types of tumors.
  • ISCC invasive squamous cell carcinoma
  • Intron miRNAs Most of the human miRNAs are expressed from the introns of protein- coding genes, and approximately 1/3 of them are located within the introns of annotated mRNAs. Those intron mRNAs, generally having the same direction with the pre-mRNAs, can be regulated by the promoter that controls the mRNA precursors. Until now, more than 90 of intron miRNAs have been identified by biological informatic approaches, but for most of them, their functions remain not disclosed. Intron miRNAs generally have an identical manner of expression with their host gene's mRNAs. The present inventors found by biological informatics analysis that DNM2 intron 16 is the host gene of miR-199a intron 16 and that miRNAs of DNM2 is expressed along with the intron mRNAs (See Fig. 1).
  • miR-199a inhibits cell growth and promotes chemotherapeutic reactions (in vitro), thus presenting that miR-199a can be a potential target of cervical cancer treatment.
  • MicroRNAs as described above can be used for cancer treatment, and an application for diagnosis of cancer cell proliferation is possible by measuring the extent of microRNA expression.
  • Fig. 1 shows a result of real-time quantitative PCR analysis for DNM2 intron 16, the host gene of miR-199, and indicates that mRNA level is significantly higher in ISCC (P ⁇ 0.0001).
  • Figs. 2 A to 2E show the suppression of cell growth by anti-miR-199a oligonucleotides in cervical squamous cell carcinoma.
  • Fig. 2A shows the relative expressions of miR-199a in cervical squamous cell carcinoma tissues and normal cervical squamous epithelial cells, as measured by TaqMan real-time PCR (p 0.0001).
  • Fig. 1 shows a result of real-time quantitative PCR analysis for DNM2 intron 16, the host gene of miR-199, and indicates that mRNA level is significantly higher in ISCC (P ⁇ 0.0001).
  • Figs. 2 A to 2E show the suppression of cell growth by anti-miR-199a oligonucleotides in cervical squamous cell carcinoma.
  • FIG. 2B shows the suppression of the miR-199a expression by anti-miR- 199 in squamous cells in the cervix (ME- 180 and SiHa).
  • Fig. 2C shows the cell growth inhibited by anti-miR-199a.
  • Figs. 2D and 2E show the cell growth inhibited with increasing amounts of cisplatin when cisplatin is administered along with anti- miR-199a (Columns, the average value of three independent experiments; bars , SE (*, p ⁇ 0.05; **, p ⁇ 0.01)).
  • FIG. 3 shows the inhibition of cell growth in the three kinds of cervical squamous epithelial cells (Caski, ME- 180, and SiHa) by the combined administration of the oligonucleotide of anti-miR-199a and cisplatin, an anti-cancer agent, in which it is confirmed that increase in cell growth effect by the combined administration of the oligonucleotide of anti-miR-199a and cisplatin, as shown in Figs 2D and 2E (ME-180 and SiHa), identically applies to different cervical squamous epithelial cells (Caski).
  • Example 1 Tissue specimens
  • Fresh cervical biopsies (5-8 mm3) were obtained before undertaking any surgical procedures.
  • Dispase II (2.4 units/mL; Roche) was used to obtain the normal epithelial tissues alone from the entire cervical tissues including the stroma. These biopsies were washed in sterile PBS for a few minutes and incubated for 1 hour in dispase II at 37°C, with the stromal side down. The epithelial sheets were then gently removed from the stromal layers and then washed twice in sterile PBS before extracting the total RNA.
  • RNA extraction and reverse transcription Total RNA was extracted from the ISCC and normal epithelial tissues using an easy-spin (genomic DNA-free) Total RNA Extraction Kit (iNtRON Biotechnology). The concentration was quantified using the NanoDrop ND- 1000 Spectrophotometer (Nano-Drop Technologies). cDNA was synthesized from total RNA using stem-loop reverse transcription primers (provided from ABI) according to the TaqMan MicroRNA Assay protocol (PE Applied Biosystems; ref. 38).
  • Rea-ltime PCR for miRNA expression profiling was done using a 7900HT Sequence Detection system (Applied Biosystems).
  • the expression levels of the 157 human mature miRNAs were measured using the Human Panel Early Access Kit (PN 4365381; Applied Biosystems).
  • Relative quantification of miRNA expression was calculated by the 2- ⁇ CT method (Livak KJ, SchmittgenTD. Analysis of relative gene expression data using real-time quantitative PCR and the 2- ⁇ CT method. Methods 2001;25:402-8). The relative expression values were multiplied by 106 in order to simplify the presentation of the data.
  • DNM2 as an overlapping transcript of miR-199
  • GAPDH glyceraldehyde-3- phosphate dehydrogenase
  • DNM2 Hs00191900, Applied Biosystems; NM_001005362, exon boundary 13-14, probe 5 I -CATCCCCAATCAGGTGATCCGCAGG-3 I , SEQ ID NO: 8), and
  • Example 5 Cell lines and transfection of anti-miR-199a
  • SiHa cells were grown at 37 ° C in 5% CO2 in MEM supplemented with 10% fetal bovine serum, penicillin (100 units/mL), and streptomycin (100 Ag/mL).
  • ME-180 cells were maintained in McCoy's 5A and
  • RNA- spin total extraction Kit (Intron Biotech).
  • Example 6 Cell viability determined by [3-(4,5-dimethylthiazol-2-yl * )-2,5- diphenyl-tetrazoliumbromide] assay Cervical cancer cells (SiHa and ME-180) were plated in a 96-well plate at
  • MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide] assay.
  • MTT solution 1 niL of 10 mg/niL MTT in PBS added to 9 mL of serum-free medium
  • the cells were incubated for 3 h in the dark.
  • the formazan grain was then dissolved in DMSO (Sigma), and absorbance was read at 570 run using an ELISA plate reader (Bio-Rad).
  • the transfected cells were treated with 1.5 and 3 ⁇ g/mL of cisplatin for 2 days.
  • SPSS software version 10.0, SPSS Inc.
  • the Mann- Whitney U test was used to evaluate the significance between the gene expression of tumor and nonmalignant tissue samples.
  • unsupervised hierarchical clustering was done on the PCR data to investigate the relationships among genes and among samples. Each miRNA raw data CT were median-centered for all samples before clustering.
  • Hierarchical average-linkage clustering was done by means of the GeneSpring GX software (version 7.3.1, Agilent Technologies), using log-transformed, median-centered gene expression values and the Pearson correlation as similarity metrics.
  • Fig. 1 shows the results of Real-time quantitative PCR analysis of the mRNA level of DNM2 intron 16, which is the host gene of miR-199a, wherein the number of X axis means random serial number of the samples.
  • DNM2 mRNA was identified as an overlapping transcript of miR-199-s, miR-199a*, and miR-199a. It was found that the nucleotide sequence at DNM2 intron 16 was complementary to the sequences of miR-199a* and miR-199a (see Table 2). Because intronic miRNAs are coordinately expressed with their host gene's mRNA, the mRNA level of DNM2 in the same tissues was evaluated using real-time quantitative PCR. It was found that the mRNA level was significantly increased in the ISCCs compared with the normal tissues (P ⁇ 0.0001; Fig. 1). Therefore, these findings suggest that miR-199a* and miR-199a are intronic miRNAs from the host mRNA, DNM2 intron 16.
  • miR-199a which is one of the most up-regulated ISCCs was selected (Fig. 2A).
  • the TaqMan real-time PCR revealed that anti-miR-199a significantly reduced the expression of miR-199a in cervical cancer cells, suggesting that anti-miR-199a is efficiently introduced into the cells and acts to knock down miR-199a (Fig. 2B).
  • this inhibitor reduced cell growth (Fig. 2C).
  • anti-miR-199a -mediated cell growth inhibition was increased in cisplatin-treated cells in a dose-dependent fashion (Fig. 2D and 2E).

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Abstract

L'invention porte sur une technologie de prévention ou traitement d'un cancer solide, de préférence un cancer du col de l'utérus, qui est caractérisé en ce qu'on obtient un effet anti-cancer synergique par l'administration combinée d'un agent anti-cancer et d'un anti-micro ARN lié de façon complémentaire à un micro-ARN spécifique qui augmente dans sa production spécifiquement dans un cancer solide, de préférence, un cancer du col de l'utérus.
PCT/KR2008/005789 2008-08-05 2008-10-01 Composition contenant de l'anti-micro arn pour le traitement ou la prévention des cancers solides Ceased WO2010016638A1 (fr)

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KR1020080076484A KR101042052B1 (ko) 2008-08-05 2008-08-05 항-ｍｉｃｒｏＲＮＡ를 포함하는 고형암 예방 또는 치료용조성물
KR10-2008-0076484 2008-08-05

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US9006201B2 (en) 2010-07-08 2015-04-14 Takeda Pharmaceutical Company Limited Prophylactic or therapeutic agent for diabetes

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KR102371833B1 (ko) * 2020-09-14 2022-03-08 서울대학교산학협력단 GDF11 유전자의 발현을 조절하는 microRNA 및 이를 함유하는 조성물

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EP2314688B1 (fr) * 2004-11-12 2014-07-16 Asuragen, Inc. Procédés et compositions impliquant l'ARNmi et des molécules inhibitrices de l'ARNmi

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MALLARDO, M. ET AL.: "Non-Protein Coding RNA Biomarkers and Differential Expression in Cancers: A Review.", J. EXPERIMENTAL CLINICAL CANCER RESEARCH., vol. 27, 16 July 2008 (2008-07-16), pages 19 - 30 *
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US9006201B2 (en) 2010-07-08 2015-04-14 Takeda Pharmaceutical Company Limited Prophylactic or therapeutic agent for diabetes

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