WO2022145949A2 - Composition comprenant un inhibiteur de tead4 pour la prévention ou le traitement du cancer colorectal - Google Patents

Composition comprenant un inhibiteur de tead4 pour la prévention ou le traitement du cancer colorectal Download PDF

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WO2022145949A2
WO2022145949A2 PCT/KR2021/020013 KR2021020013W WO2022145949A2 WO 2022145949 A2 WO2022145949 A2 WO 2022145949A2 KR 2021020013 W KR2021020013 W KR 2021020013W WO 2022145949 A2 WO2022145949 A2 WO 2022145949A2
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tead4
colorectal cancer
cells
elk1
inhibitor
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WO2022145949A3 (fr
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조광현
정창영
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Korea Advanced Institute of Science and Technology KAIST
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • 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
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a composition for preventing or treating colon cancer comprising a TEAD4 inhibitor.
  • GRN Gene Regulatory Network
  • Colorectal cancer has the third highest incidence and second highest mortality worldwide after lung cancer and breast cancer.
  • the 5-year survival rate of patients with early-stage colorectal cancer is close to 90%, but only a small number of patients are detected in the early stage. Therefore, a molecular understanding of the mechanism of colorectal cancer is necessary for early diagnosis and treatment of colorectal cancer.
  • Fearon and Vogelstein argued that colorectal cancer was caused by the accumulation of genetic and epigenetic mutations in cancer suppressor genes. Normal colonic epithelial cells develop into colorectal cancer through a chromosomal instability pathway known as the adenoma-carcinoma sequence. This process is accompanied by loss of APC and TP53 and overexpression of KRAS gene. Functional loss of APC, an antagonist of the Wnt pathway, is prioritized as the first process of cancer. The loss of APC function and its effects have been studied for many years, but the immediate changes following genetic changes have not been widely studied because it is difficult to observe.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating colorectal cancer comprising a TEAD4 (TEA Domain Transcription Factor 4) inhibitor.
  • TEAD4 TEAD4 (TEA Domain Transcription Factor 4) inhibitor.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating colon cancer, including a TEAD4 (TEA Domain Transcription Factor 4) inhibitor and an ELK1 (ETS Transcription Factor ELK1) inhibitor.
  • TEAD4 TEAD4
  • ELK1 ETS Transcription Factor ELK1
  • Another object of the present invention is to provide a reagent composition for regulating the differentiation of colon cancer cells into normal cells or normal-like cells, comprising a TEAD4 inhibitor and an ELK1 inhibitor, and a method for inhibiting proliferation or inducing normal differentiation of colorectal cancer cells comprising the composition will do
  • Another object of the present invention is to provide a method for screening a preparation for the treatment of colorectal cancer.
  • Another object of the present invention is to administer a TEAD4 (TEA Domain Transcription Factor 4) inhibitor to a subject in need thereof; It is to provide a method for preventing or treating colon cancer comprising a.
  • TEAD4 TAA Domain Transcription Factor 4
  • Another object of the present invention is to administer a TEAD4 (TEA Domain Transcription Factor 4) inhibitor and ELK1 (ETS Transcription Factor ELK1) inhibitor to a subject in need thereof; It is to provide a method for preventing or treating colon cancer comprising a.
  • TEAD4 TEAD4
  • ELK1 ETS Transcription Factor ELK1
  • the present invention provides a pharmaceutical composition for preventing or treating colon cancer, including a TEAD4 (TEA Domain Transcription Factor 4) inhibitor.
  • TEAD4 TEAD4 (TEA Domain Transcription Factor 4) inhibitor.
  • the TEAD4 inhibitor may be one or more selected from the group consisting of shRNA, siRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, antibody, or vector expressing the TEAD4 gene or protein.
  • the shRNA may include the nucleotide sequence shown in SEQ ID NO: 1 and SEQ ID NO: 2
  • the siRNA may include the nucleotide sequence shown in SEQ ID NO: 3 and SEQ ID NO: 4.
  • the colorectal cancer may be an adenoma at the stage of colorectal cancer development or an early colorectal cancer that progresses from an adenoma to an adenocarcinoma.
  • the early colorectal cancer may be an early cancer induced by the occurrence of adenomatous polyposis coli (APC) mutation.
  • APC adenomatous polyposis coli
  • the TEAD4 inhibitor may inhibit the transcriptional activity of MYC (MYC Proto-Oncogene) or E2F1 (E2F Transcription Factor 1) protein and increase the transcriptional activity of KLF4 (Kruppel-like factor 4) protein.
  • MYC MYC Proto-Oncogene
  • E2F1 E2F Transcription Factor 1
  • the TEAD4 inhibitor may inhibit the proliferation of early colon cancer epithelial cells.
  • the TEAD4 inhibitor may induce differentiation of early colon cancer epithelial cells into normal cells or normal-like cells.
  • the present invention provides a pharmaceutical composition for preventing or treating colon cancer, comprising a TEAD4 (TEA Domain Transcription Factor 4) inhibitor and an ELK1 (ETS Transcription Factor ELK1) inhibitor.
  • TEAD4 TEAD4
  • ELK1 ETS Transcription Factor ELK1
  • the TEAD4 inhibitor may include any one or more selected from the group consisting of siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, antibody or vector expressing the TEAD4 gene or protein; and the ELK1 inhibitor is an ELK1 inhibitor selected from the group consisting of siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, antibody, or vector expressing the ELK1 gene or protein.
  • the shRNA targeting the TEAD4 gene or protein may include the nucleotide sequence shown in SEQ ID NO: 1 and SEQ ID NO: 2, and the siRNA may include the nucleotide sequence shown in SEQ ID NO: 3 and SEQ ID NO: 4.
  • the siRNA targeting the ELK1 gene or protein may include the nucleotide sequences shown in SEQ ID NO: 5 and SEQ ID NO: 6.
  • the colorectal cancer may be malignant colorectal cancer in which an adenoma-carcinoma sequence has progressed to acquire a genetic polymorphism.
  • the TEAD4 and ELK1 inhibitors may inhibit proliferation of malignant colorectal cancer epithelial cells and induce differentiation into normal cells or normal-like cells.
  • the present invention provides a reagent composition for regulating the differentiation of colon cancer cells into normal cells or normal-like cells, comprising a TEAD4 (TEA Domain Transcription Factor 4) inhibitor and an ELK1 (ETS Transcription Factor ELK1) inhibitor.
  • TEAD4 TEAD4
  • ELK1 ETS Transcription Factor ELK1
  • the shRNA targeting the TEAD4 gene includes the nucleotide sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2
  • the siRNA targeting the TEAD4 gene includes the nucleotide sequences shown in SEQ ID NO: 3 and SEQ ID NO: 4
  • the siRNA targeting the ELK1 gene or protein may include the nucleotide sequences shown in SEQ ID NO: 5 and SEQ ID NO: 6.
  • the present invention comprises the steps of treating the reagent composition to malignant colorectal cancer cells; It provides a method for inhibiting proliferation or inducing normal differentiation of colorectal cancer cells, including.
  • the present invention comprises the steps of (a) treating a candidate material to colorectal cancer cells; (b) measuring the expression level of TEAD4 in colorectal cancer cells treated with the candidate substance; and (c) selecting the candidate substance as a colorectal cancer treatment agent when the TEAD4 expression level is lower than that of the control group untreated with the candidate substance; It provides a screening method of a formulation for the treatment of colorectal cancer, including.
  • the colorectal cancer may be an early colorectal cancer induced by deletion of adenomatous polyposis coli (APC).
  • APC adenomatous polyposis coli
  • the present invention comprises the steps of (a) treating a candidate material to colorectal cancer cells; (b) measuring the expression level of TEAD4 and ELK1 in the candidate substance-treated colon cancer cells; and (c) selecting the candidate material as a colorectal cancer treatment agent when the TEAD4 and ELK1 expression levels are low compared to the control group untreated with the candidate material; It provides a screening method of a formulation for the treatment of colorectal cancer, including.
  • the colorectal cancer may be malignant colorectal cancer in which an adenoma-carcinoma sequence has progressed to acquire a genetic polymorphism.
  • the present invention comprises the steps of administering a TEAD4 (TEA Domain Transcription Factor 4) inhibitor to a subject in need thereof; It provides a method for preventing or treating colorectal cancer comprising a.
  • TEAD4 TAA Domain Transcription Factor 4
  • the present invention comprises the steps of administering a TEAD4 (TEA Domain Transcription Factor 4) inhibitor and an ETS Transcription Factor ELK1 (ELK1) inhibitor to a subject in need thereof; It provides a method for preventing or treating colorectal cancer comprising a.
  • TEAD4 TEA Domain Transcription Factor 4
  • ELK1 ETS Transcription Factor ELK1
  • the TEAD4 inhibitor of the present invention can treat early colorectal cancer by returning gene expression of early colorectal cancer to similar to that of normal colon tissue. It was confirmed that gene expression can be returned to similar to that of differentiated normal tissues. Unlike conventional anticancer drugs, this can be utilized as a treatment method for excluding normal cell death side effects that may occur during anticancer treatment and converting cancer cells into normal differentiated cells.
  • FIG. 1 is a diagram illustrating a colorectal cancer master regulator (MR) candidate group identified through the VIPER algorithm.
  • MR colorectal cancer master regulator
  • A The results of VIPER ARACNe indicate that the protein activity of 6 MRs is upregulated in CRC. Each vertical line in the second column represents a gene in the MR regulon. Genes were classified from most up-regulated to down-regulated using analysis rank-based analysis (aREA) in VIPER. Up-regulated MRs in cancer have a positive NES score, and normal up-regulated TFs have a negative NES score.
  • aREA analysis rank-based analysis
  • FIG. 2 is a diagram showing the results of comparing the gene expression of CRC MR candidate group.
  • A A diagram showing gene expression of MR at different stages of adenocarcinoma.
  • B A diagram showing the results of confirming the protein activity in GSE41657 using metaVIPER.
  • FIG. 3 is a diagram showing the gene expression profile in the HCEC cell line.
  • A 1CT cell line can mimic gene expression abnormal regulation.
  • B Shows that TEAD4 is negatively associated with APC expression levels.
  • FIG. 4 is a diagram showing the results of confirming that knockdown of TEAD4 inhibits cell proliferation.
  • B 1CT-A cell proliferation reduction by TEAD4 knockdown,
  • C in 1CT-A MYC expression reduction effect by stable knockdown of TEAD4,
  • D is a diagram showing that TEAD4 knockdown in 1CT-A significantly inhibits cell proliferation.
  • FIG. 5 is a diagram showing the results of confirming that TEAD4 plays an important role in cell proliferation induced by APC deficiency.
  • 1CT-A cells are elongated and apoptosis is induced after TEAD4 knockdown
  • (b) shows the results of GSEA analysis using hallmark gene set
  • (c) showing a decrease in E2F1 after TEAD4 knockdown
  • (d) up-regulated genes involved in the cell cycle of the KEGG mechanism within the three mechanisms are significantly reduced after TEAD4 knockdown, and TEAD4 knockdown is widespread
  • It is a diagram showing that the body can be controlled.
  • FIG. 6 is a diagram showing that TEAD4 knockdown induces cell differentiation.
  • A Stemness scores
  • B HES1 and KLF4 mRNA expression level comparison results
  • C A diagram showing KLF4 gene and protein expression levels in adenoma and adenocarcinoma.
  • FIG. 7 is a view showing the results of confirming the effect of the TEAD4 and ELK1 knockdown combination in SW620.
  • (b) confirmation of differentiation marker KRT20 and stem cell marker ALDH1A1 change according to TEAD4 knockdown in SW620 and HT-29
  • (c) KLF4 and ELK1 expression relationship diagram
  • e a diagram showing the results of confirming the cell proliferation inhibitory effect according to ELK1 and TEAD4 knockdown.
  • FIG. 8 is a diagram showing the results of GENIE3 VIPER.
  • FIG. 9 is a diagram showing the results of confirming the expression change of TEAD4, MYC, KLF4, ELK1 after TEAD4 KD in malignant colorectal cancer.
  • TEAD4 plays an important role in the progression of early colorectal cancer, and when TEAD4 is knocked down, the gene expression of early colorectal cancer is returned to be similar to that of normal differentiated colonic epithelial cells. It was confirmed that colorectal cancer can be treated, and when ELK1 is knocked down together with TEAD4, it was confirmed that the gene expression of malignant colorectal cancer can be restored similar to that of normal differentiated colonic epithelial cells, and the present invention was completed.
  • the present invention provides a pharmaceutical composition for preventing or treating colon cancer comprising a TEAD4 inhibitor or a pharmaceutical composition for preventing or treating colon cancer comprising a TEAD4 inhibitor and an ELK1 inhibitor.
  • GRN was inferred from GEO colorectal cancer patient data in order to search for key regulators regulating colorectal cancer cancerization.
  • TEAD4 was selected as a target as a key regulator controlling the transcriptional regulators of the network, and it was confirmed that TEAD4 gene expression and transcriptional activity were increased in colorectal cancer.
  • TEAD4 knockdown (KD) in colorectal cancer could inhibit the proliferation of cancer cells and induce cancer cells to a normal differentiation state.
  • the TEAD4 inhibitor may be one or more selected from the group consisting of shRNA, siRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, antibody or vector expressing the TEAD4 gene or protein. have.
  • antisense nucleic acid refers to DNA or RNA or a derivative thereof containing a nucleic acid sequence complementary to a specific mRNA sequence, and binds to a complementary sequence in mRNA to inhibit the translation of mRNA into protein do
  • the antisense sequence refers to a DNA or RNA sequence that is complementary to the mRNA of the gene and capable of binding to the mRNA, and is involved in translation of the mRNA, translocation into the cytoplasm, maturation or all other overall biological functions. It may inhibit essential activity for
  • the antisense nucleic acid may be modified at the position of one or more bases, sugars or backbones to enhance efficacy.
  • the nucleic acid backbone can be modified with phosphorothioates, phosphotriesters, methyl phosphonates, short chain alkyls, cycloalkyls, short chain heteroatomics, heterocyclic intersugar linkages, and the like.
  • Antisense nucleic acids may also include one or more substituted sugar moieties.
  • Antisense nucleic acids may include modified bases.
  • Modified bases include hypoxanthine, 6-methyladenine, 5-methylpyrimidine (particularly 5-methylcytosine), 5-hydroxymethylcytosine (HMC), glycosyl HMC, gentobiosyl HMC, 2-aminoadenine, 2 -Thiouracil, 2-thiothymine, 5-bromouracil, 5-hydroxymethyluracil, 8-azaguanine, 7-deazaguanine, N6(6-aminohexyl)adenine, 2,6-diaminopurine, etc. There is this.
  • the antisense nucleic acid may be chemically bound to one or more moieties or conjugates that enhance the activity and cell adsorption of the antisense nucleic acid.
  • the antisense oligonucleotide may be synthesized in vitro by a conventional method and administered in vivo, or the antisense oligonucleotide may be synthesized in vivo.
  • siRNA refers to a nucleic acid molecule capable of mediating RNA interference or gene silencing. Since siRNA can inhibit the expression of a target gene, it is provided as an efficient gene knockdown method or gene therapy method.
  • the siRNA molecule of the present invention comprises a sense strand (according to one embodiment of the present invention, a sequence corresponding to the mRNA sequence of any one gene selected from among target genes TEAD4 and ELK1 inhibitors) and an antisense strand (complementary to the mRNA sequence) sequences) are positioned opposite to each other to form a double-stranded structure, and the siRNA molecule of the present invention may have a single-stranded structure having self-complementary sense and antisense strands.
  • siRNA is not limited to the complete pairing of double-stranded RNA parts that are paired with each other, but pairs are formed by mismatch (corresponding bases are not complementary), bulges (there is no base corresponding to one chain), etc.
  • the siRNA end structure can have either a blunt end or a cohesive end as long as it can suppress the expression of a target gene by the RNAi effect, and the cohesive end structure includes a 3'-end protrusion structure and a 5'-end structure. Both protrusion structures are possible.
  • the "shRNA” of the present invention is called small hairpin RNA or short hairpin RNA, and is used for the purpose of silencing genes by RNA interference.
  • a vector is used to introduce into the target cell. This shRNA hairpin structure is cleaved by other substances in the cell to become siRNA.
  • the shRNA included in the TEAD4 inhibitor may include the nucleotide sequence represented by SEQ ID NO: 1 and SEQ ID NO: 2
  • the siRNA may include the nucleotide sequence represented by SEQ ID NO: 3 and SEQ ID NO: 4, but is limited thereto not.
  • the colorectal cancer of the present invention may be an early stage colorectal cancer, and the early stage colorectal cancer is preferably an early stage colorectal cancer, specifically, APC (adenomatous polyposis coli) deficiency cancer.
  • APC adenomatous polyposis coli
  • the colorectal cancer for the prevention or treatment of the present invention is adenomatous polyposis coli (APC) mutation in normal colonic epithelial cells along the chromosomal instability pathway known as the adenoma-carcinoma sequence. It may be an adenoma in which gene expression is abnormally regulated, or an early colorectal cancer that progresses from adenoma to adenocarcinoma.
  • APC adenomatous polyposis coli
  • TEAD4 when TEAD4 was knocked down, it was confirmed through the transcript analysis result of 1CT-A, an APC-deficient cell, that the cell proliferation of 1CT-A was reduced in the same way as the MYC knockdown efficiency. Specifically, it was confirmed that the knockdown of TEAD4 reduced the MYC expression level and the expression of 43 genes including E2F1 involved in cell proliferation regulation. In addition, it was confirmed that it induces an increase in the transcriptional regulator KLF4 (Kruppel-like factor 4) that induces the final differentiation of colon cells.
  • KLF4 Keruppel-like factor 4
  • the TEAD4 inhibitor of the present invention may inhibit the proliferation of early colon cancer epithelial cells by inhibiting the transcriptional activity of MYC (MYC Proto-Oncogene) or E2F1 (E2F Transcription Factor 1) protein.
  • MYC MYC Proto-Oncogene
  • E2F1 E2F Transcription Factor 1
  • KLF4 Kruppel-like factor 4
  • TEAD4 of the present invention may be to regulate a major mechanism in the proliferation and differentiation of cells induced by APC deletion of early colonic epithelial cells, and by using this mechanism to inhibit or suppress TEAD4 gene or protein expression, colorectal cancer, preferably It can be used as a pharmaceutical composition for prevention or treatment of early colon cancer.
  • the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized in that it is targeted to humans.
  • the pharmaceutical composition is not limited thereto, but may be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods. .
  • the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, dyes, fragrances, etc. for oral administration, and in the case of injections, buffers, preservatives, pain-free agents
  • a topical agent, solubilizer, isotonic agent, stabilizer, etc. can be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. can be used.
  • the dosage form of the pharmaceutical composition according to the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • oral administration in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
  • the route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition according to the present invention may also be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition according to the present invention contains several factors including the activity of the specific active ingredient used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, disease severity, drug form, administration route and period, but may be appropriately selected by those skilled in the art.
  • an amount capable of obtaining the maximum effect with a minimum amount without side effects can be administered, more preferably from 1 to 10000 ⁇ g/weight kg/day, even more preferably from 10 to 1000 mg It can be administered repeatedly several times a day at an effective dose of /weight kg/day.
  • the above dosage does not limit the scope of the present invention in any way.
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer comprising a TEAD4 (TEA Domain Transcription Factor 4) inhibitor and an ELK1 (ETS Transcription Factor ELK1) inhibitor.
  • TEAD4 TEAD4
  • ELK1 ETS Transcription Factor ELK1
  • TEAD4 knockdown when the expression of cell proliferation and differentiation-related genes was confirmed in malignant colorectal cancer in which genetic mutations have accumulated, it was confirmed that TEAD4 knockdown can inhibit the proliferation of cancer cells, but is not sufficient to induce normal differentiation.
  • the TEAD4 inhibitor is a TEAD4 gene or protein targeting, siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, antibody, or any one or more selected from the group consisting of vectors expressing these TEAD4 inhibitors; and the ELK1 inhibitor is an ELK1 inhibitor selected from the group consisting of siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, antibody, or vector expressing the ELK1 gene or protein.
  • antiscent nucleic acid, shRNA and siRNA are the same as described above.
  • the shRNA targeting the TEAD4 gene may include the nucleotide sequence shown in SEQ ID NO: 1 and SEQ ID NO: 2
  • the siRNA targeting the TEAD4 gene may include the nucleotide sequence shown in SEQ ID NO: 3 and SEQ ID NO: 4
  • the present invention is not limited thereto.
  • the siRNA targeting the ELK1 gene may include the nucleotide sequences shown in SEQ ID NO: 5 and SEQ ID NO: 6, but is not limited thereto.
  • Colon cancer develops into carcinoma due to the accumulation of genetic and epigenetic mutations in cancer suppressor genes in early adenoma, and normal colonic epithelial cells have chromosomes known as adenoma-carcinoma sequence. It is known that the chromosomal instability pathway acquires additional mutations along the pathway to progress to malignant colorectal cancer.
  • the colorectal cancer has an adenoma-carcinoma sequence and acquires genetic polymorphism through chromosomal instability induced in the process of abnormal growth and division to have adaptability in the selective pressure of cancer treatment. It can be a malignant colorectal cancer with several types of mutations.
  • TEAD4 knockdown can inhibit cell proliferation in malignant colorectal cancer, but is insufficient to induce normal differentiation. It was confirmed that the expression of goblet cells was significantly increased, and the expression of MUC2 (Mucin 2) and TFF3 (Trefoil Factor 3), which are functional markers of goblet cells, and KRT20 (Keratin 20), a normal differentiation marker, also increased. .
  • the TEAD4 inhibitor inhibits the transcriptional activity of MYC (MYC Proto-Oncogene) or E2F1 (E2F Transcription Factor 1) protein when co-treated with an ELK1 inhibitor, KLF4 (Kruppel-like factor 4), MUC2 (Mucin 2) , may be to increase the transcriptional activity of TFF3 (Trefoil Factor 3) or KRT20 (Keratin 20) protein.
  • the TEAD4 and ELK1 inhibitors may inhibit proliferation of malignant colorectal cancer epithelial cells and induce differentiation into normal cells or normal-like cells.
  • the gene expression of malignant colorectal cancer can be returned to normal for treatment, so it can be usefully used as a pharmaceutical composition for preventing or treating malignant colorectal cancer.
  • the pharmaceutical composition is the same as described above.
  • the present invention relates to a reagent composition for regulating the differentiation of colon cancer cells into normal cells or normal-like cells, comprising a TEAD4 (TEA Domain Transcription Factor 4) inhibitor and an ELK1 (E2F Transcription Factor 1) inhibitor.
  • TEAD4 TEAD4
  • ELK1 E2F Transcription Factor 1
  • the TEAD4 inhibitor may include any one or more selected from the group consisting of shRNA, siRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, antibody, or vector expressing the TEAD4 gene or protein
  • the ELK1 inhibitor may include any one or more from the group consisting of siRNA, shRNA, miRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, antibody or vector expressing the ELK1 gene or protein.
  • the shRNA targeting the TEAD4 gene includes the nucleotide sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2
  • the siRNA targeting the TEAD4 gene includes the nucleotide sequences shown in SEQ ID NO: 3 and SEQ ID NO: 4
  • the siRNA targeting the ELK1 gene or protein may include the nucleotide sequences shown in SEQ ID NO: 5 and SEQ ID NO: 6.
  • the TDAD4 inhibitor and ELK1 inhibitor are the same as described above.
  • the proliferation of malignant colorectal cancer cells can be inhibited and normal differentiation into normal cells or normal-like cells can be induced.
  • the present invention comprises the steps of: (a) treating a candidate material to colon cancer cells; (b) measuring the expression level of TEAD4 in colorectal cancer cells treated with the candidate substance; and (c) selecting the candidate substance as a colorectal cancer treatment agent when the TEAD4 expression level is lower than that of the control group untreated with the candidate substance; It relates to a screening method of a formulation for the treatment of colorectal cancer, including.
  • the colorectal cancer may be an early colorectal cancer induced by an adenomatous polyposis coli (APC) mutation.
  • APC adenomatous polyposis coli
  • the present invention comprises the steps of: (a) treating a candidate material to colon cancer cells; (b) measuring the expression level of TEAD4 and ELK1 in the candidate substance-treated colon cancer cells; and (c) selecting the candidate material as a colorectal cancer treatment agent when the TEAD4 and ELK1 expression levels are low compared to the control group untreated with the candidate material; It relates to a screening method of a formulation for the treatment of colorectal cancer, including.
  • the colorectal cancer may be malignant colorectal cancer in which an adenoma-carcinoma sequence has progressed to acquire a genetic polymorphism.
  • a candidate substance to be analyzed can be contacted with cancer cells containing the gene or protein first.
  • the candidate substance refers to an unknown substance used in screening to test whether it affects the expression level of the gene, the amount of the protein, or the activity of the protein.
  • the candidate substance may include, but is not limited to, a chemical substance, antisense oligonucleotide, antisense-RNA, siRNA, shRNA, miRNA, an antibody specific for the protein, or a natural product extract.
  • siRNA, shRNA, miRNA or antibody specific for TEAD4 or ELK1 may be included.
  • the expression level of the gene, the amount of the protein, or the activity of the protein can be measured in the cell treated with the candidate substance, and when it is measured that the expression level of the gene, the amount of the protein, or the activity of the protein is reduced as a result of the measurement, the It can be determined that the candidate substance can be used as an agent capable of treating or preventing cancer.
  • the method for measuring the expression level of the gene or the amount of the protein may be performed including a known process for isolating mRNA or protein from a biological sample using a known technique.
  • the "biological sample” refers to a sample collected from a living body in which the expression level of the gene or the level of protein according to the occurrence or progression of cancer is different from that of a normal control, and the sample includes, for example, tissues, cells, Blood, serum, plasma, saliva and urine may be included, but are not limited thereto.
  • Measurement of the expression level of the gene is preferably to measure the level of mRNA, and as a method for measuring the level of mRNA, reverse transcription polymerase chain reaction (RT-PCR), real-time reverse transcription polymerase chain reaction, RNase protection assay, Northern blots and DNA chips, but are not limited thereto.
  • RT-PCR reverse transcription polymerase chain reaction
  • RNase protection assay RNase protection assay
  • Northern blots DNA chips
  • an antibody may be used to measure the protein level.
  • the marker protein in the biological sample and an antibody specific therefor form a binding substance, that is, an antigen-antibody complex, and the amount of the antigen-antibody complex formed is determined by the detection label ( It can be quantitatively measured through the magnitude of the signal of the detection label).
  • the detection label may be selected from the group consisting of an enzyme, a fluorescent substance, a ligand, a luminescent substance, a microparticle, a redox molecule, and a radioisotope, but is not limited thereto.
  • Analysis methods for measuring protein levels include Western blot, ELISA, radioimmunoassay, radioimmunodiffusion, Oukteroni immunodiffusion, rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, FACS, protein chips, and the like, but are not limited thereto.
  • the present invention comprises the steps of administering a TEAD4 (TEA Domain Transcription Factor 4) inhibitor to an individual in need thereof; It provides a method for preventing or treating colorectal cancer comprising a.
  • TEAD4 TAA Domain Transcription Factor 4
  • the individual is expected to develop colorectal cancer; affected individuals; or an individual who has been determined to be cured; may be, but is not limited thereto.
  • the colorectal cancer may be an adenoma in which adenomatous polyposis coli (APC) mutation occurs in normal colonic epithelial cells and abnormally regulated gene expression, or an early colorectal cancer that progresses from adenoma to adenocarcinoma.
  • APC adenomatous polyposis coli
  • TEAD4 TEAD4 (TEA Domain Transcription Factor 4) inhibitor
  • the present invention comprises the steps of administering a TEAD4 (TEA Domain Transcription Factor 4) inhibitor and an ETS Transcription Factor ELK1 (ELK1) inhibitor to an individual in need thereof; It provides a method for preventing or treating colorectal cancer comprising a.
  • TEAD4 TEAD4
  • ETS Transcription Factor ELK1 ELK1
  • the individual is expected to develop colorectal cancer; affected individuals; or an individual who has been determined to be cured; may be, but is not limited thereto.
  • the colorectal cancer may be a malignant colorectal cancer possessing several types of mutations that allow the adenoma-carcinoma sequence to progress to acquire genetic polymorphism and to have adaptability in the selection pressure of cancer treatment.
  • TEAD4 TEAD4
  • ELK1 ETS Transcription Factor ELK1
  • Redundant content is omitted in consideration of the complexity of the present specification, and terms not defined otherwise in the present specification have the meanings commonly used in the technical field to which the present invention pertains.
  • Wild type 1CT and adenomatous polyposis coli (APC, Adenomatous polyposis coli)-deleted 1CT-A human colonic epithelial cell HCEC-1CT were used for cell experiments.
  • Human colorectal cancer cells (HT-29, SW48, SW620) were cultured in DMEM supplemented with 10% FBS and antibiotics. All cells were incubated in an
  • HCEC and CRC cell lines were infected with virus supernatant containing polybrene (4 ⁇ g/ml; Sigma) and during the incubation period, infected HCECs with puromycin (500 ng/ml; Sigma) and CRC with puromycin (1 ⁇ g/ml; Sigma) ) was selected.
  • HEK 293T cells were transfected using shRNA (shTEAD4; SHCLNG-NM_003213, Sigma) targeting TEAD4.
  • RNAiMAX Thermo Fisher Scientific
  • siRNA BIONEER Corporation, Daejeon, Korea
  • siRNAs used are as follows.
  • Infected cells were seeded into 96-well plates (5 x 10 3 cells/well) to measure cell growth and recorded every 3 h using IncuCyte ZOOM (Essen Bioscience), and cell confluence using IncuCyte ZOOM 2016A software. was analyzed.
  • Total RNA Extraction Kit (iNtRON Biotechnology, Gyeonggi, South Korea) was used to extract total RNA from cells. Total RNA was treated with RNase-free DNase I (Thermo Fisher Scientific) to prevent genomic DNA contamination. DNA was synthesized from total RNA using DiaStar RT kit (Solgent, Daejeon, Korea) and PCR system (Veriti 96-well Thermal Cycler; Applied Biosystems, Waltham, MA, United States), and quantitative real-time polymerase chain reaction (qRT) -PCR) was performed with the QuantStudio 5 real-time PCR system (Applied Biosystems) using the primers shown in Table 1.
  • DiaStar RT kit Solgent, Daejeon, Korea
  • PCR system Very 96-well Thermal Cycler; Applied Biosystems, Waltham, MA, United States
  • qRT quantitative real-time polymerase chain reaction
  • RNA sequencing experiments were performed using a commercial microarray service of Ebiogen, Inc. (Seoul, Korea). Total RNA was extracted from target cells according to the method described above, and the extracted mRNA was amplified and converted into complementary DNA (cDNA) for cDNA microarray (Ebiogen).
  • cDNA complementary DNA
  • ARACNe Accurate Cellular Networks
  • GEO gene expression omnibus
  • GENIE3 (GENe Network Inference with Ensemble of trees) uses a random forest algorithm for GRN3 reconstruction. GENIE3 can infer feedback loops that are important for understanding biological networks. Another GRN was reconstructed from the same GEO-integrated cancer data set using the GENIE3 algorithm implemented in the GENIE3 package of R4.
  • VPER Virtual Inference of Protein-activity by Enriched Regulon analysis
  • MR colorectal cancer-specific master regulator
  • APC KRAS using ARACNe and GENIE3 GRN and expressing differently between GEO-cancer-related data sets and GEO-normal data sets (
  • the NES score was calculated by inputting a list of 4891 genes including TP53.
  • a colorectal cancer-specific GRN was constructed from colorectal cancer patient data using the ARACNe algorithm.
  • MR candidates for colorectal cancer were selected through the VIPER algorithm.
  • VIPER infers the activity of the transcriptional regulator by calculating the NES for each regulon composed of a set of transcriptional regulators and target genes.
  • Six MR candidates (SOX4, CBFB, MSX1, NR1H4, ETV4, TEAD4) upregulated in colorectal cancer were identified with VIPER results deduced from the ARACNe network ( p -value ⁇ 0.05).
  • the ARACNe algorithm provides statistical significance for the edge of genes in GRN, but has a limitation in that it cannot reflect the feedback loop due to the characteristic of the algorithm that removes indirect links. Therefore, to verify the MR candidates identified in the GRN inferred using the ARACNe algorithm, a GRN that can include a feedback loop was constructed using the GENIE3 algorithm.
  • GRN GENIE3 GRN constructed using the same data only provides weights for edges and does not provide statistical significance, so there is a limitation in that there is no scale that can determine the size of the network.
  • the edge of GRN GENIE3 was cut based on the smallest weight of GRN ARACNe and the size of the network was determined.
  • up-regulated MR candidates were inferred in 11 colorectal cancers ( p -value ⁇ 0.05).
  • GEO's GSE41657 data were analyzed and confirmed.
  • the data consisted of 12 normal mucosa, 21 low-grade adenomas (mild hyperplasia), 30 high-grade adenomas (severe hyperplasia) and 25 adenocarcinomas. has been
  • the activity of the transcriptional regulators of the GSE41657 data was inferred through the metaVIPER algorithm that infers the activity of the transcriptional regulators from gene expression data derived from orphan tissue in which a network does not exist ( FIG. 2B ).
  • the metaVIPER results show that the transcriptional activity of MR candidates increases as colorectal cancer progresses. This result proved that MR candidates are abnormally regulated as cancer progresses.
  • MSX1 and TEAD4 were significantly different from normal epithelial tissue in mRNA expression, but MSX1 had the lowest level of transcriptional regulator activity and TEAD4 had the greatest change in activity.
  • APC mutation is considered an important event in early cancer.
  • Inactivation of APC induces the activation of the Wnt signaling pathway and changes the activity of transcription factors to change the state of the cell to malignant.
  • the activation of the Wnt signaling pathway increases the transcriptional activity of ⁇ -catenin/TCF, which induces transcription of MYC, a major factor in cancer.
  • HCEC-1CT was produced through immortalization of normal tissues by expressing Cdk4 and hTERT.
  • 1CT cell line is a cell line specialized for colonic epithelial cell research because it can differentiate into stem cell markers and cells of various lineages.
  • various genetic variants such as 1CT-A (APC deficient version) and 1CT-RPA (APC deficiency, ectopic expression of KRAS, harbors TP53 version) exist in the HCEC cell line, when comparing gene expression, the effect of the mutation It reflects well (FIG. 3A).
  • TEAD4 was most differentially expressed in 1CT-A compared to 1CT as shown in Table 4.
  • APC deletion or activation of the Wnt signaling pathway induces nuclear translocation of YAP/TAZ, a coactivator of the TEAD transcriptional regulatory group.
  • the activated YAP/TAZ/TEAD transcriptional regulatory complex increases the expression of genes involved in cell proliferation, such as CYR61 and CTGF.
  • a recent study showed that the YAP/TAZ/TEAD transcriptional regulatory complex could be involved in more than 50% of genes belonging to the Wnt signaling pathway in APC-depleted epithelial cells.
  • Increased expression of TEAD4 and migration to the nucleus may induce colonic epithelial cell carcinoma and induce epithelial mesenchymal transition (EMT).
  • EMT epithelial mesenchymal transition
  • TEAD4 plays a major role in the carcinogenesis of APC-deleted cells.
  • TEAD4 knockdown using siRNA and shRNA was performed in 1CT-A cell line. Since MYC expression is increased in 1CT-A and it is known that TEAD4 induces MYC expression through the hippo pathway, a knockdown experiment using siRNA was performed using siTEAD4 and siMYC. The knockdown efficiency of siRNA was measured 72 hours after transfection using qRT-PCR (FIG. 4A).
  • siTEAD4 treatment significantly reduced the expression of the target gene TEAD4, and significantly reduced the expression of MYC in the 1CT-A cell line treated with siTEAD4 ( p -value ⁇ 0.004, p -value ⁇ 0.02).
  • TEAD4 knockdown was measured using IncuCyte Zoom.
  • siRNA transfection was performed by planting cells in a 96-well plate and culturing for 12 hours. Reduction of TEAD4 significantly reduced 1CT-A cell proliferation with the same efficiency as MYC ( p -value ⁇ 0.0001, FIG. 4B).
  • TEAD4 knockdown can inhibit cell proliferation through reduction of MYC in 1CT-A cells in which APC is inactivated. Through this, it was confirmed that TEAD4 can induce abnormal cell proliferation in cells undergoing cancer in the initial state in which APC is deleted, and suppression of TEAD4 expression can inhibit such cell proliferation.
  • the GSEA analysis results of normal 1CT-A and 1CT are shown in Table 5, and the GSEA analysis results of 1CT-A control (1CT-A_shScr) and TEAD4 knockdown 1CT-A (1CT-A_shTEAD4) are shown in Table 6.
  • the top three pathways appeared as E2F_targets, G2M_checkpoint, and MYC_TARGETS_V1 directly linked to cell proliferation.
  • 1CT-A was activated compared to 1CT (FDR ⁇ 0.01, NES >3.0, Fig. 5b left).
  • Table 6 when TEAD4 was inhibited in 1CT-A, the top three pathways were most decreased (FDR ⁇ 0.01, NES ⁇ - 2.5, FIG. 5b right).
  • the Enrichr package of the R program was utilized to analyze the gene set within the top three pathways. Functional annotation of 247 genes upstream of the gene set (Fold-Change>0.5, FDR ⁇ 0.05) was performed through the KEGG pathway. As a result, among the 247 genes, the change of genes related to the cell cycle (43/124, FDR ⁇ 0.05) and the change of genes related to DNA replication (18/36, FDR ⁇ 0.05) were the most significant.
  • E2F1 and E2F2 of the E2F family which regulate cell proliferation through induction to the G1/S phase.
  • TEAD4 was knocked down
  • Figure 5d the expression of 43 genes involved in cell proliferation as well as E2F1 This was reduced.
  • TEAD4 plays an important role in colon cancer epithelial cells caused by APC deletion and is a significant regulator.
  • TEAD4 plays a very important role in the cell proliferation of colorectal cancer by inducing a decrease in the signaling pathway increased in cancer cells through TEAD4 knockdown.
  • TEAD4 knockdown can also affect the differentiation of 1CT-A.
  • the stem cell ability score of 1CT, 1CT-A control (1CT-A_shScr) and TEAD4 knockdown 1CT-A (1CT-A_shTEAD4) using the R program was calculated.
  • 1CT-A which showed a higher stem cell ability score compared to 1CT, significantly decreased the stem cell ability score through TEAD4 knockdown. Therefore, it was confirmed that TEAD4 may have an effect on the stem cell ability of early colorectal cancer.
  • KLF4 is a major regulator involved in cell differentiation, cell proliferation, and apoptosis, and it is known that a decrease in KLF4 expression correlates with a decrease in differentiated normal cells.
  • colonic cancer could be restored to normal by normalizing gene expression at the genome level through TEAD4 knockdown in colonic epithelial cells in which APC deletion occurred, suppressing cancer cell proliferation and inducing differentiation into normal cells.
  • Example 7 Derivation of target ELK1 in combination with malignant colorectal cancer
  • TEAD4 knockdown was confirmed in malignant colorectal cancer in which gene mutations were accumulated.
  • TEAD4 was inhibited in four colorectal cancer cell lines (HCT-116, HT-29, LS180, SW620), it was possible to induce a decrease in the expression of MYC, but the change in the expression of KLF4 did not occur except for HT-29 and SW620 (Fig. 7a). ).
  • KRT20 did not change in both cell lines and the expression of ALDH1A1, a stem cell marker, also did not change, so it was confirmed that TEAD4 knockdown can inhibit cell proliferation in malignant colorectal cancer, but is insufficient to induce differentiation.
  • ELK1 could strongly influence the expression of KLF4 on GRN, so the relationship between ELK1 and KLF4 was investigated.
  • ELK1 is a transcription factor known as an oncogene with the potential to cause cancer. ELK1 forms a polycomb-mediated complex in human embryonic stem cells to inhibit the expression of KLF4, which induces cell differentiation, and induces pluripotency. ) is known to maintain It was confirmed that the expression of ELK1 did not change after TEAD4 knockdown in malignant colorectal cancer, unlike early colorectal cancer (FIG. 9).

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Abstract

La présente invention concerne une composition pour prévenir ou traiter le cancer colorectal. L'inhibiteur de TEAD4 de la présente invention peut ramener l'expression génique du cancer colorectal dans un stade précoce à un motif d'expression génique similaire à celui dans des cellules colorectales normales différenciées pour traiter le cancer colorectal à un stade précoce, et lorsqu'il est utilisé en combinaison avec un inhibiteur d'ELK1, l'inhibiteur de TEAD4 peut ramener l'expression génique du cancer colorectal malin à un motif d'expression génique similaire à celui dans des cellules colorectales normales, ce qui permet de trouver des applications avantageuses dans le domaine prophylactique et thérapeutique du cancer colorectal.
PCT/KR2021/020013 2020-12-28 2021-12-28 Composition comprenant un inhibiteur de tead4 pour la prévention ou le traitement du cancer colorectal Ceased WO2022145949A2 (fr)

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