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WO2020153503A1 - Inhibiteur de la prolifération du cancer ayant un inhibiteur d'expression d'arnnc dérivé du gène snhg12 en tant que principe actif - Google Patents

Inhibiteur de la prolifération du cancer ayant un inhibiteur d'expression d'arnnc dérivé du gène snhg12 en tant que principe actif Download PDF

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WO2020153503A1
WO2020153503A1 PCT/JP2020/002639 JP2020002639W WO2020153503A1 WO 2020153503 A1 WO2020153503 A1 WO 2020153503A1 JP 2020002639 W JP2020002639 W JP 2020002639W WO 2020153503 A1 WO2020153503 A1 WO 2020153503A1
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cancer
seq
snhg12
rna
expression
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Japanese (ja)
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政一 親泊
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Er Stress Research Institute Inc
University of Tokushima NUC
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Er Stress Research Institute Inc
University of Tokushima NUC
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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
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is a novel cancer growth inhibitor containing a compound that suppresses the expression of ncRNA derived from the SNHG12 gene, which is one of nucleolar small RNA (snoRNA), and further A therapeutic agent for cancer.
  • ncRNA nucleolar small RNA
  • ER stress is a cause of many diseases such as diabetes, neurodegenerative diseases, strokes, viral infections and heart diseases. From the results to date, chronic endoplasmic reticulum stress has been remarkably found in various cancer types such as black skin cancer, multiple myeloma, breast cancer, and hepatocellular carcinoma. Endoplasmic reticulum stress is characterized by three signal pathways triggered by three signal transducing factors (PERK, IREI, ATF6) localized in the endoplasmic reticulum membrane (Non-patent Document 1). BiP, which is a molecular chaperone, is bound to these factors and is normally inactive.
  • Non-patent Document 1 When ER stress occurs, BiP is detached from these factors, and then the three-dimensional structure of these factors is changed and activated, and signal information is transmitted through each signal pathway.
  • signal information based on PERK is known to promote the survival and growth of cancer.
  • Recent studies have revealed that signal information based on PERK is associated with the expression of lncRNA (long non-coding RNA, >200 bp).
  • MaltI of lncRNA is expressed by PERK signal information. It has been reported that this MalatI is an lncRNA that promotes cancer growth and metastasis (Non-patent Document 1).
  • the lncRNA which is expressed by receiving the signal information of PERK in cancer cells, promotes malignant transformation of cancer. Also, as an lncRNA that is considered to be expressed in cancer cells upon receiving PERK signal information, there is snhg12 (non-coding small nucleolar RNA host gene 12) derived from the SNHG12 gene. It is known that lncRNA snhg12 is prominently expressed in cancers such as breast cancer, osteosarcoma, and hepatocellular carcinoma. The upregulation of lncRNA is closely related to the size of cancer, and It is reported that the 5-year survival rate of patients with colorectal cancer is deteriorated as well as the stage is deteriorated (Non-patent document 2).
  • Non-patent Document 3 snhg12 regulates cell proliferation and metastasis by regulating the Notch signal pathway, and therefore it is reported that an increased expression of snhg12 can predict a poor prognosis of nasopharyngeal cancer. ..
  • Non-Patent Document 5 there are many reports on the mechanism of action of snhg12 (Non-Patent Document 5), and cancer treatment by suppressing the expression of snhg12 is hardly reported.
  • the object of the present invention is to provide a therapeutic agent for cancer having a new mechanism of action, which suppresses colonization and proliferation of cancer cells in vivo.
  • the present inventor has earnestly studied the research of lncRNA that is expressed in response to endoplasmic reticulum stress that occurs in cancer cells. Then, as shown in FIG. 1, it was found that the SNHG12 gene was highly expressed in various cancer cells. Furthermore, when the present inventor further focused on snhg12 among the lncRNAs derived from the SNHG12 gene, the inventors found that cancer patients with high expression of snhg12 had a low patient survival rate. As shown in FIGS. 2 to 5, in the case of cancer-bearing patients with pancreatic cancer, lung cancer, renal cancer, and glioma cancer, cancer patients with high expression of snhg12 are compared with cancer patients with low expression of snhg12.
  • the present inventor considered that if the expression of snhg12 could be suppressed, the growth and metastasis of cancer cells could be suppressed, and examined the suppression of the expression of snhg12 using a nucleic acid.
  • Four sites (Region) of 776 base pairs of snhg12 were selected as a target, and a single-stranded or double-stranded nucleic acid that hybridizes to the site and suppresses RNA expression was prepared.
  • the base sequence of the DNA that is the source of snhg12 is shown in FIG.
  • the prepared nucleic acids siRNA and antisense DNA shown in the items of Examples
  • siRNA No. 22 corresponding DNA sequence is SEQ ID No. 22
  • the inventor has completed the present invention based on the above findings.
  • the gist of the present invention is as follows.
  • a cancer growth inhibitor which comprises a snhg12 expression inhibitor as an active ingredient.
  • the snhg12 expression inhibitor is a single-stranded or double-stranded nucleic acid, and has four sites of snhg12 (positions 127 to 147, 352 to 428, 458 to 480, 535 to 735) 1.
  • the cancer growth inhibitor according to (1) above which is one or more nucleic acids capable of hybridizing to any of the above.
  • nucleic acid is SEQ ID NO: 1 (tcgagagggtgggtgaatgt), SEQ ID NO: 3 (ccggcgtactactaaagcatat), SEQ ID NO: 22 (agggatagaaaacaatagata) sequence SEQ ID NO: 23 (agacaacagcatgcatagaatga), SEQ ID NO: 23 (acacaaccatcatgagaatgac), SEQ ID NO: 23 (agacaacagcatgacatagaatga), SEQ ID NO: 23 (acacaaccatcatagatagaga), SEQ ID NO: 23 (acacaaccatcatagatagaga) RNA consisting of an RNA sequence corresponding to SEQ ID NO: 32 (acagcatgctataatgcaaaa); complementary to the RNA sequence corresponding to SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31
  • the nucleic acid is an RNA consisting of an RNA sequence corresponding to SEQ ID NO: 22 or SEQ ID NO: 31 or an RNA consisting of an RNA sequence complementary to the RNA sequence corresponding to SEQ ID NO: 22 or SEQ ID NO: 31
  • the described cancer growth inhibitor is (6) The cancer growth inhibitor according to any of (1) to (5) above, wherein the cancer is a cancer cell that highly expresses snhg12.
  • a cancer therapeutic agent comprising the cancer growth inhibitor according to any one of (1) to (7) above as an active ingredient.
  • a method of suppressing cancer growth which comprises administering to a cancer patient an expression inhibitor of snhg12 that is effective in suppressing cancer growth.
  • a method for treating cancer which comprises administering an expression inhibitor of snhg12 effective for treating cancer to a cancer patient.
  • the cancer growth inhibitor and cancer therapeutic agent of the present invention suppress cancer cell growth in which snhg12 is highly expressed and treat cancer.
  • known means such as siRNA, shRNA, antisense, miRNA, aptamer, and decoy can be used.
  • As a site to which nucleic acid such as siRNA hybridizes four sites of snhg12 (positions 127 to 147, 352 to 428, 458 to 480, 535 to 735) can be used. Since the growth of renal cancer can be significantly suppressed by using a snhg12 expression inhibitor such as siRNA, the cancer growth inhibitor of the present invention is used for many cancers with high snhg12 expression including kidney cancer. It is effective as a therapeutic agent for
  • FIG. 9 is a diagram showing a protocol of a test method for suppressing proliferation of xenograft renal cancer cells using the siRNA (corresponding DNA sequence is SEQ ID NO: 22) used in FIG. 8. It is a figure showing the result of the growth suppression test of the cancer cell implemented by the protocol of FIG.
  • the "snhg12" of the present invention is an lncRNA (long noncoding RNA) derived from the SNHG12 gene, and its original DNA is composed of 776 base pairs shown in FIG.
  • the SNHG12 gene is a gene existing on chromosome 1p35.3 and having 6 exons. From this gene, a total of five ncRNAs of SNODR44, SNODR61, SNODR16A, and SNODR99 are expressed together with snhg12. The expression of the SNHG12 gene can be confirmed by the expression of a total of five ncRNAs of SNODR44, SNODR61, SNODR16A, and SNODR99 together with snhg12 of lncRNA.
  • Non-Patent Document 2 It is known that these ncRNAs are prominently expressed in cancers such as breast cancer, osteosarcoma, and hepatocellular carcinoma, and the upregulation of the expression of these ncRNAs is closely related to the size of cancer, and the stage of cancer It is reported that the 5-year survival rate of colorectal cancer patients is deteriorated along with the deterioration (Non-Patent Document 2).
  • the “expression inhibitor” of the present invention is not particularly limited as long as it is an agent that suppresses the expression of snhg12.
  • the expression inhibitor of snhg12 is a nucleic acid (single-stranded or double-stranded DNA, RNA, or a hybrid thereof), and siRNA or shRNA having an RNA interference action on snhg12 or antisense (DNA, RNA) , MiRNA, decoy, aptamer and the like.
  • the number of bases of the nucleic acid compound such as antisense or siRNA to be used may be 14 to 45, and an appropriate number of bases can be used depending on the kind of the nucleic acid compound.
  • the antisense base number is 14 to 30, the siRNA base number is 19 to 25, the miRNA base number is 19 to 25, the decoy base number is 16 to 24, and the aptamer base number is 26 to 45. Individuals are preferred.
  • a nucleic acid such as siRNA can be hybridized to the target region.
  • Examples of the DNA site corresponding to the target site of snhg12 include the four sites shown in FIG. 6 (Regions 1 to 4). Region 1 is a site at positions 127 to 147, and Region 2 is a site at positions 352 to 428. Region 3 is a site at positions 458 to 480, and Region 4 is a site at positions 535 to 735.
  • the nucleic acid that hybridizes to snhg12 is 30 or less, preferably 14 to 30 and more preferably 15 to 15 that hybridizes to any of the RNA sites corresponding to the four sites (Region 1 to 4) shown in FIG. Mention may be made of nucleic acids consisting of 25, even more preferably 18 to 21 bases.
  • RNA comprising an RNA sequence corresponding to a DNA sequence comprising 30 or less, preferably 25 or less, more preferably 23 or less bases containing any of the base sequences of SEQ ID NOs: 1 to 32,
  • RNA having an RNA sequence corresponding to any of the nucleotide sequences of SEQ ID NOs: 1 to 32 can be mentioned.
  • RNA particularly RNA having an RNA sequence corresponding to a DNA sequence having a nucleotide sequence complementary to any of SEQ ID NOS: 1 to 32 can be mentioned.
  • a DNA comprising 30 or less, preferably 25 or less, more preferably 23 or less bases containing any of the nucleotide sequences of SEQ ID NOS: 1 to 32, particularly, any of the nucleotide sequences of SEQ ID NOS: 1 to 32
  • the DNA consisting of
  • a DNA comprising 30 or less, preferably 25 or less, more preferably 23 or less bases containing a base sequence complementary to any of SEQ ID NOS: 1 to 32, particularly SEQ ID NOS: 1 to 32 DNA having a base sequence complementary to any of the above can be mentioned.
  • preferable nucleic acids include those having an expression suppression rate of snhg12 of 50% or more, as shown in FIG. 7, and the nucleotide sequences of SEQ ID NOs: 1, 3, 22, 23, 30, 31, or 32.
  • RNA consisting of an RNA sequence corresponding to the sequence particularly an RNA consisting of an RNA sequence corresponding to a DNA sequence consisting of a nucleotide sequence complementary to SEQ ID NO: 1, 3, 22, 23, 30, 31, or 32 can be mentioned. ..
  • a DNA having a nucleotide sequence of 3, 22, 23, 30, 31, or 32 can be mentioned.
  • DNA having a nucleotide sequence complementary to SEQ ID NO: 1, 3, 22, 23, 30, 31, or 32 can be mentioned.
  • the nucleic acids may be used alone or in combination of two or more kinds.
  • the expression inhibitor when it is an RNA molecule, it may be designed so that it can be produced in vivo.
  • the DNA encoding the RNA molecule may be inserted into an expression vector for mammalian cells.
  • an expression vector include viral vectors such as retrovirus, lentivirus, adenovirus, adeno-associated virus, herpes virus, Sendai virus, and animal cell expression plasmids.
  • the nucleic acid may be chemically modified to improve stability.
  • a nucleic acid containing a nucleic acid analog such as phosphorothioate, morpholinophosphorodiamidate, boranophosphate, LNA (Locked Nucleic Acid), 2'-O-methylated nucleic acid, 2'-O- Methoxyethylated nucleic acid and the like can be mentioned.
  • the “cancer growth inhibitor” of the present invention is an agent capable of suppressing cancer growth, and can be achieved by using an agent suppressing the expression of snhg12 as an active ingredient. ..
  • the “cancer therapeutic agent” of the present invention refers to a therapeutic agent that suppresses cancer growth to induce apoptosis of cancer cells or kill cancer cells that have stopped growing due to the immune reaction of the living body. Say that.
  • cancer cells to be growth-suppressed or treated 33 types of cancer cells having high expression of the SNHG12 gene (thymoma, diffuse large B-cell lymphoma, including 17 types of cancer cells described in FIG. 1, Cervical cancer, testicular cancer, bladder urothelial cancer, bladder cancer, acute myelogenous leukemia, mesothelioma, pancreatic cancer, intraocular melanoma, endometrial cancer, endometrial cancer sarcoma, sarcoma , Lung cancer, bile duct cancer, colon cancer, glioblastoma multiforme, squamous cell lung cancer, ovarian cancer, esophageal cancer, papillary renal cancer, renal cancer, gastric cancer, head and neck cancer, skin Cancer, thyroid cancer, prostate cancer, breast cancer, glioma cancer, paraganglioma, adenoid abscess cancer, liver cancer, chromophobe renal cell carcinoma).
  • Preferable examples include pancreatic cancer, lung cancer, renal cancer and glioma cancer.
  • the cancer growth inhibitor and cancer therapeutic agent of the present invention are not only used for the treatment of cancer-bearing patients, but are also administered for the purpose of preventing recurrence or metastasis after excision of cancer from cancer-bearing patients. Alternatively, it can also be used as a prognosis improving agent or a cancer metastasis preventive agent in patients after cancer resection.
  • the growth inhibitor and therapeutic agent of the present invention are used as follows.
  • the administration route is not particularly limited as long as it can deliver the growth inhibitory agent and therapeutic agent of the present invention to cancer in vivo, but, for example, intravascular (intraarterial or intravenous), intramuscular, subcutaneous, topical (particularly , Intratumor), lymphatic vessels or lymph nodes, intrathecal, rectal, transmucosal, transdermal, nasal cavity, intrapulmonary, intrauterine and the like.
  • intravascular intraarterial or intravenous
  • intramuscular intramuscular
  • subcutaneous particularly , Intratumor
  • lymphatic vessels or lymph nodes intrathecal
  • intrathecal rectal
  • transmucosal transdermal
  • nasal cavity intrapulmonary
  • intrauterine intrapulmonary
  • the administration method varies depending on the dosage form, but injection (bolus injection, drip injection) is preferred.
  • the dose of the cancer growth inhibitor may be an amount effective for inhibiting the growth of cancer, and the cancer therapeutic agent may be an amount effective for the treatment of cancer. It can be appropriately set by those skilled in the art within a range capable of suppressing the expression and/or inhibiting the function of the target molecule according to the type of active ingredient to be used, the degree of symptom of the patient, sex of the patient, age and the like.
  • the amount of the expression inhibitor of snhg12 that is effective in suppressing the growth of cancer or treating cancer varies depending on the various conditions described above, but is, for example, 0.00001 mg to 100 g, especially 0.0001 mg to 10 g, and especially It can be 0.001 mg to 1 g, 0.01 mg to 100 mg, and especially 0.1 mg to 10 mg.
  • the expression inhibitor of snhg12 is modified RNA, this dose is the amount converted to RNA. Further, when not administered daily or when the administration frequency changes over time, the daily dose is calculated from the total dose.
  • the frequency or schedule of administration varies depending on the above-mentioned various conditions. 4, 5, 6, 7 days, etc.) several times a week (eg, 2, 3, 4 times a week, etc.), weekly, every few weeks (ie 2, 3, 4 weeks etc.) May be Further, the administration frequency may change over time depending on the symptoms.
  • the administration period can be, for example, until the cancer is cured or ameliorated.
  • the antiproliferative agent and therapeutic agent of the present invention may be used alone, or may be used in combination with one or more other agents having an antitumor effect and/or radiation therapy.
  • the antiproliferative agent and therapeutic agent of the present invention are formulated by adding pharmaceutically acceptable carriers and additives depending on the formulation form.
  • a solid preparation it can be prepared using an excipient, a binder, a disintegrating agent, a lubricant and the like.
  • a liquid preparation it can be prepared using physiological saline, a buffer solution or the like.
  • a preferable dosage form is an injection.
  • the nucleic acid molecule is formulated together with a nucleic acid introduction auxiliary agent so that the nucleic acid molecule is easily transferred into cancer cells.
  • a nucleic acid introduction auxiliary agent such as lipofectamine, oligofectamine, RNAifect, liposome, polyamine, DEAE dextran, calcium phosphate, dendrimer and the like.
  • the present invention provides a method for suppressing cancer growth, which comprises administering to a cancer patient an expression inhibitor of snhg12 in an amount effective for suppressing cancer growth.
  • the present invention also provides a method for treating cancer, which comprises administering to a cancer patient a snhg12 expression inhibitor in an amount effective for treating cancer.
  • Cancer treatment is to induce apoptosis of cancer cells by suppressing the growth of cancer, or kill cancer cells whose growth has stopped by an immune reaction of the living body.
  • Example 1 Measurement of SNHG12 gene expression level in cancer-bearing patients
  • Materials/reagents Published data of cancer genomes, epigenomes, transcriptomes, mutation information, etc. in various tissues collected by the National Cancer Institute's Cancer Genome Atlas Project by the National Cancer Institute
  • Method RNA expression data (RPKM value: Reads per kilobase of exon per million mapped reads) of the SNHG12 gene analyzed by RNA-seq in the public data was obtained, and SNHG1 was expressed from the expression level of all genes. The relative value (AU) of the 2RNA expression level was calculated by the normalization method, and the SNHG12 gene expression level for each patient was expressed as log2.
  • Results As shown in FIG. 1, it was revealed that many cancers highly expressed.
  • Example 2 Difference in survival rate between cancer-bearing patients with high expression and low expression of lncRNA snhg12 a) Materials/reagents: Published data of cancer genomes, epigenomes, transcriptomes, mutation information, etc. in various tissues collected by the Cancer Genome Atlas Project by the National Cancer Institute of the United States National Cancer Institute b) Method: The expression level of snhg12 in cancer-bearing patients and the number of survival days after the start of treatment were collected from the published data. The median value of the expression level of snhg12 was calculated, and those above the median value were classified as high and those below were classified as low.
  • Example 3 Snhg12 Expression Suppression Evaluation Test Using siRNA (1) Material/Reagent/Evaluated Cell Line: Human Renal Cancer Cell Line 786O mock ⁇ SiRNA: Thirty types of siRNAs and two types of antisense DNAs that hybridize to the four sites shown in FIG. 6 of the original DNA of snhg12 were prepared.
  • the base sequence of the DNA that becomes the source of the region to which each siRNA hybridizes is the base sequence of SEQ ID NOs: 1 to 30 in Tables 1 to 4, and the base sequence of the DNA that becomes the source of the region to which each antisense DNA hybridizes is It is the base sequence of SEQ ID NOs: 31 and 32 in Table 4.
  • Each RNA consists of an RNA sequence corresponding to each DNA sequence of SEQ ID NOs: 1-30.
  • siRNA consisting of RNA sequences corresponding to the DNA sequences of SEQ ID NOs: 1 to 30 or a nucleotide sequence complementary to the DNA sequences of SEQ ID NOs: 31 and 32
  • RNA was extracted and the expression level of snhg12 was analyzed by RT-qPCR.
  • results As shown in FIG. 8, it was revealed that the expression of snhg12 from the renal cancer cell line was suppressed by the siRNA used.
  • the expression suppression rate of 50% or more of snhg12 by siRNA or antisense DNA in the renal cancer 7860 strain can be summarized as shown in, for example, FIGS. 7 to 8 and Table 5.
  • Examples of preferred DNA sequences that are targets of nucleic acids used for suppressing the expression of snhg12 include SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32. You can As a particularly preferred target DNA of nucleic acid, there are SEQ ID NO:22 and SEQ ID NO:31.
  • Example 4 Growth suppression test of xenograft renal cell carcinoma by suppressing expression of snhg12
  • Materials/reagents/human kidney cancer cell line for xenotransplantation 786O mock -SiRNA consisting of the RNA sequence corresponding to SEQ ID NO: 22 (agggtagaaacaacagcatg) (2) Method 5 ⁇ 10 6 human renal cancer cell lines (786O mock) were subcutaneously injected into nude mice (male, 4 weeks old).
  • the siRNA of SEQ ID NO: 22 (1 nM) was administered according to the schedule shown in FIG. Further, as a control, a human renal cancer cell line was similarly administered to the body side on the opposite side, and EGFP siRNA (1 nM) was administered.
  • the diameter of the transplanted kidney cells was measured on the day of administration of siRNA, and on the 5th, 10th, 17th, 25th, and 32nd days thereafter.
  • (3) Results As shown in FIG. 10, when siRNA consisting of the RNA sequence corresponding to SEQ ID NO: 22 was administered, engraftment and proliferation of renal cancer was significantly suppressed. On the other hand, when EGFP siRNA was administered as a control, transplanted kidney cancer was proliferated. As described above, when siRNA consisting of the RNA sequence corresponding to SEQ ID NO: 22 was administered, the expression of snhg12 was suppressed, and the engraftment/proliferation of renal cancer cells in nude mice could be significantly suppressed. This indicates that in cancer cells that highly express snhg12, the growth of cancer cells can be suppressed by suppressing the expression of snhg12. That is, it is shown that cancer treatment is possible by using a snhg12 expression inhibitor.
  • the cancer growth inhibitor and cancer therapeutic agent of the present invention can suppress cancer cell growth effectively and suppress cancer cells by suppressing the expression of snhg12 in cancer cells highly expressing snhg12. .
  • the cancer growth inhibitor of the present invention can be used as a single agent, and can be used in combination with an immunostimulatory cancer therapeutic agent to enhance its effect.

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Abstract

Grâce à la présente invention, il a été découvert que dans des cellules cancéreuses ayant une expression de snhg12 élevée, un réactif, qui inhibe l'expression de snhg12, inhibe significativement la prise de greffe ou la prolifération des cellules cancéreuses. Par conséquent, l'inhibiteur de prolifération de cellules cancéreuses de la présente invention est efficace en tant qu'agent de traitement du cancer, et peut avoir une efficacité améliorée lorsqu'il est utilisé en combinaison avec un agent immunothérapeutique pour le cancer.
PCT/JP2020/002639 2019-01-25 2020-01-24 Inhibiteur de la prolifération du cancer ayant un inhibiteur d'expression d'arnnc dérivé du gène snhg12 en tant que principe actif Ceased WO2020153503A1 (fr)

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
INOUE, TAKAO: "Development trends of nucleic acid drugs targeting RNA", JOURNAL CLINICAL AND EXPERIMENTAL MEDICINE(IGAKU NO AYUMI, vol. 267, no. 8, 2018, pages 591 - 597 *
SUN, Y. ET AL.: "Long noncoding RNA SNHG12 facilitates the tumorigenesis of glioma through miR-101-3p/F0XP1 axis.", GENE, vol. 676, 2018, pages 315 - 321 *
WANG, O. ET AL.: "C-MYC-induced upregulation of IncRNA SNHG12 regulates cell proliferation, apoptosis and migration in triple-negative breast cancer.", AM J TRANSL RES, vol. 9, no. 2, 2017, pages 533 - 545, XP055726998 *
WANG, X. ET AL.: "Knockdown of long noncoding RNA small nucleolar RNA host gene 12 inhibits cell growth and induces apoptosis by upregulating miR- 138 in nonsmall cell lung cancer.", DNA AND CELL BIOLOGY, vol. 36, no. 11, 2017, pages 892 - 900, XP055726997 *

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