WO2021105224A1 - Inhibiteur de protéine 6 de la sous-famille des kdm pour l'utilisation dans le traitement du cancer - Google Patents
Inhibiteur de protéine 6 de la sous-famille des kdm pour l'utilisation dans le traitement du cancer Download PDFInfo
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Definitions
- the present invention refers to the medical field. More specifically, the present invention refers to inhibitors of a KDM subfamily 6 protein selected from KDM6A and/or KDM6B for use in the treatment of patients suffering from cancer, wherein the patient's tumor or the patient's germ-line is characterized by the inactivation of a gene member of the SWI/SNF complex.
- SWI/SNF The mammalian SWI/SNF (mSWI/SNF) complex functions as a tumor suppressor in many human malignancies [ Hodges C, Kirkland JG, Crabtree GR (August 2016). "The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer". Cold Spring Harbor Perspectives in Medicine. 6 (8): a026930 ].
- SWI/SNF subunits were frequently absent in cancer cell lines. It was first identified in 1998 as a tumor suppressor in rhabdoid tumors, a rare pediatric malignancy. As DNA sequencing costs diminished, many tumors were sequenced for the first time around 2010.
- the present invention solves this problem by using inhibitors of a KDM (Histone lysine demethylase) subfamily 6 protein, preferably KDM6A and/or KDM6B , which are used to treat tumors characterized by the inactivation of a gene member of the SWI/SNF complex.
- KDM Histone lysine demethylase
- KDM6A and/or KDM6B KDM subfamily 6 enzymes
- KDM subfamily 6 enzymes specifically KDM6A and KDM6B , can be used as a valid therapeutic target to treat tumors characterized by the inactivation of a gene member of the SWI/SNF complex.
- the first embodiment of the present invention refers to inhibitors of a KDM subfamily 6 protein selected from KDM6A and/or KDM6B for use in the treatment of patients suffering from cancer, wherein the patient's tumor or the patient's germ-line is characterized by the inactivation of a gene member of the SWI/SNF complex.
- the present invention refers to a method for treating patients suffering from cancer, wherein the patient's tumor or the patient's germ-line is characterized by the inactivation of a gene member of the SWI/SNF complex, which comprises the administration of a therapeutically effective amount of an inhibitor of a KDM subfamily 6 protein selected from KDM 6 A and/or KDM6B.
- the second embodiment of the present invention refers to a pharmaceutical composition
- a pharmaceutical composition comprising an inhibitor of a KDM subfamily 6 protein selected from KDM6A and/or KDM6B and, optionally, pharmaceutically acceptable excipients or carriers, for use in the treatment of patients suffering from cancer, wherein the patient's tumor or the patient's germ-line is characterized by the inactivation of a gene member of the SWI/SNF complex.
- the third embodiment of the present invention refers to an in vitro method for identifying and producing candidate compounds useful in the treatment of patients suffering from cancer wherein the patient's tumor or the patient's germ-line is characterized by the inactivation of a gene member of the SWI/SNF complex, which comprises: a) Measuring the level of a KDM subfamily 6 proteins or transcripts selected from KDM6A and/or KDM6B in a biological sample isolated from the patient's tumor after the administration of the candidate compound; b) wherein if the levels of the proteins or transcripts determined in step a) is statistically lower than the level of proteins or transcripts determined before the administration of the candidate compound, this is indicative that the candidate compound is effective in the treatment of patients.
- the fourth embodiment of the present invention refers to an in vitro method for determining the efficacy or the response to a treatment of patients suffering from cancer wherein the patient's tumor or the patient's germ-line is characterized by the inactivation of a gene member of the SWI/SNF complex, which comprises: a) Measuring the level of a KDM subfamily 6 proteins or transcripts selected from KDM6A and/or KDM6B in a biological sample isolated from the patient's tumor after the administration of the therapy; b) wherein if the level of the proteins or transcripts determined in step a) is statistically lower than the levels of the proteins or transcripts determined before the administration of the therapy, this is indicative that the therapy is effective in the treatment of the patients.
- the fifth embodiment of the present invention refers to an in vitro method for selecting patients suffering from cancer for a treatment with an inhibitor of a KDM subfamily 6 protein selected from KDM6A and/or KDM6B , which comprises: a) identification of the inactivation of a gene member of the SWI/SNF complex in a DNA sample derived from the patient's tumor or the patient's germ-line; b) wherein if it is identified that a gene member of the SWI/SNF complex is inactivated, this is indicative that the patient can be selected for a treatment with an inhibitor of a KDM subfamily 6 of proteins selected from KDM 6 > A and/or KDM6B.
- the patient's tumor or the patient's germ-line is characterized by the inactivation of any of the following genes coding for proteins which are members of the SWI/SNF complex: SMARCA4, ARID1A, ARID1B, SMARCB1, SMARCC1, SMARCC2, SMARCD1, SMARCD2, SMARCD3, SMARCE1, PBRM1, ARID2 and/or SMARCAD1.
- the patient 's tumor is further characterized by a higher value of the ratio [trimethylation at lysine 27 of histone H3 (H3K27me3) / acetylation at the 27-lysine residue of the histone H3 (H3K27ac)], as compared with those patients whose tumors do not have mutations at the SWI/SNF-related genes.
- the patient's tumor or the patient's germ-line is characterized by the inactivation of any of the following genes MGA, MAX, ATF7IP, KDM6A and/or KDM6B.
- the patient to be treated is suffering from any type of cancer characterized by the inactivation of a gene member of the SWI/SNF complex, preferably: lung cancer, ovarian cancer, rhabdomyosarcomas, breast cancer or prostate cancer.
- Non-small-cell lung carcinoma NSCLC
- ovarian cancer ovarian small cell carcinoma
- SWI/SNF complex a gene member of the SWI/SNF complex
- lung cancer ovarian cancer
- rhabdomyosarcomas breast cancer or prostate cancer
- the inhibitor is a chemical molecule selected from the group comprising: GSK-J4/GSK-J1, IOX1 or metformin; or a biological molecule is selected from the group comprising: anti-KDM6A and/or anti-KDM6B antibodies or RNA interferences.
- GSK-J4/GSK-J1, IOX1 or metformin or a biological molecule is selected from the group comprising: anti-KDM6A and/or anti-KDM6B antibodies or RNA interferences.
- KDM subfamily 6 proteins KDM6A and/or KDM6B as therapeutically targets for the treatment of cancer characterized by the inactivation of a gene member of the SWI/SNF complex, irrespective of the inhibitor which is finally used.
- the following reference reveals a group of inhibitors which could be used in the present invention [Inhibition of demethylases by GSK-J1/J4. Heinemann B, Nielsen JM, Hudlebusch HR, Lees MJ, Larsen DV, Boesen T, Labelle M, Gerlach LO, Birk P, Helin K. Nature.
- the sample which is obtained from the patient comprises tumor DNA and can be selected from: liquid biopsies, primary tumors, small biopsies from lymph nodes and metastasis, pleural effusions and/or ascites.
- the present invention studied the functional relation between the mutational status of SMARCA4 and histone H3 methylation pattern regulation. We verified the link between SMARCA4 inactivation and KDM6A and KDM6B expression levels. Connected to the less amount of KDMs in SMARCA4 mutant cells, it has been very interesting to concentrate on the difference between the ratio H3K27Ac/H3K27me3 in the SMARCA4-Mut and SMARCA4-WT, in fact in primary tumor samples levels of trimethylation are so much higher than those of acetylation, resulting in a transcriptional repressed context.
- the Suberoylanilide Hydroxamic Acid also known, as Vorinostat catalyzes the removal of the acetyl moiety from the lysine residues of histones, leading to an open state of the chromatin and enhancing gene transcription.
- SAHA action measured as acetylation increasing and the novo gene transcription
- GSK-J4 inhibits chemically the “eraser” capability of KDMs.
- SMARCA4-WT cells were able to increase KDM6A under the action of GSK-J4, probably as a compensatory mechanism, the SMARCA4-Mut were not only incapable of up-regulate KDM6A, but the levels of KDM6A decreased in a GSK-J4 dose-dependent manner. We hypothesized that this impaired compensation was the ultimate cause of death in SMARCA4-Mut cells. This failure could be indicative of the activity of another methyltransferase that, through its enzymatic activity could inhibit the expression of KDM6A, probably by methylating its promoter.
- This methyltransferase could be EZH2 since the addition to GSK-J4 to the EZH2 inhibitor, GSK-126, prevented the down-regulation of KDM6A levels, being comparable to those of control cells, which remained constant regardless of the administration of increasing doses of GSK-J4.
- Caspases are cysteine proteases that induce crucial morphological and biochemical changes during apoptosis while PARP belongs to Poly (ADP-ribose) polymerase (PARP), a family of proteins involved in several cellular processes such as DNA repair, genomic stability and programmed cell death.
- PARP Poly (ADP-ribose) polymerase
- SCCOHT has been recently re classified as a rhabdoid-type of cancer with genetic inactivation of SMARCA4. Near 100% of SCCOHT carry this genetic event, with few mutations in other oncogenes or tumor suppressor genes. Given this background, we investigated the effectiveness of GSK-J4 treatment on SCCOHT in primary cell cultures. In agreement to what it was observed in other SMARCA4-mutant cancer cells, SCCOHT cells were highly sensitive to this KDM6-inhbitor.
- “Pharmaceutically acceptable excipient or carrier” refers to an excipient that may optionally be included in the compositions of the invention and that causes no significant adverse toxicological effects to the patient.
- terapéuticaally effective dose or amount an amount that, when administered as described herein, brings about a positive therapeutic response in a subject having cancer.
- the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, mode of administration, and the like.
- An appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation, based upon the information provided herein.
- reference value refers to the values used a “control”.
- a “reference value” can be a threshold value or a cut-off value. Typically, a “threshold value” or “cut-off value” can be determined experimentally, empirically, or theoretically.
- a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skilled in the art. The threshold value must be determined to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative). Preferably, the person skilled in the art may compare the biomarker levels (or scores) obtained according to the method of the invention with a defined threshold value.
- the optimal sensitivity and specificity can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
- ROC Receiver Operating Characteristic
- the full name of ROC curve is receiver operator characteristic curve, which is also known as receiver operation characteristic curve. It is mainly used for clinical biochemical diagnostic tests.
- ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1-specificity). It reveals the relationship between sensitivity and specificity with the image composition method.
- a series of different cut-off values are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of diagnosis.
- AUC area under the curve
- the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values.
- the AUC value of the ROC curve is between 1.0 and 0.5. When AUC>0.5, the diagnostic result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.9, the accuracy is good.
- FIG. 1 Colony formation assay in lung cancer cell lines (SCLC and NSCLC) including 3 MYC-amplified (SWI/SNF proficient) cell lines: H460 H446 and DMS-273 compared with 3 SMARCA4-deficient cell lines: DMS114, H23, H841
- SCLC and NSCLC 3 MYC-amplified (SWI/SNF proficient) cell lines: H460 H446 and DMS-273 compared with 3 SMARCA4-deficient cell lines: DMS114, H23, H841
- the plates were seeded with 5,000 cells from each cell line, and were treated with ImM of SAHA for 5 days. Cells were stained with crystal violet solution (0.5% Crystal Violet in 25 % of methanol). Distribution and mean of the IC50 for SAHA in the indicated group of cells.
- a- TUBULIN, protein-loading control (c) Western blot depicting the levels of H3K27me3, H3K27Ac and EZH2 in the indicated cells after 4 days of treatment with SAHA (ImM) GSK-126 (ImM) or combination of both b-ACTIN, protein-loading control (d) Cell viability of the indicated cell lines measured using MTT assays, after treatment with increasing concentrations of GSK-126 for five days. Lines show the number of viable cells relative to the total number at 0 h.
- FIG. 1 Phase contrast images of the co-culture of H1299-SMARCA4-Wt (green) or H1299-SMARCA4-Mut (red) cells, after treatment with SAHA (ImM) for 3 days. Left panel untreated cells (FBS, fetal bovine serum) included as a control. Right panel cells after induction of Wt.
- SAHA SAHA
- SMARCA4 green or Mutant SMARCA4 (red)
- SMARCA4 with doxycycline (lng/m ⁇ ) and SAHA treatment (ImM) for 3 days a- TUBULIN, as protein-loading control (d) Heatmap showing peak intensity and peak distribution from TSS (transcription start site) at gene promoters obtained from a ChlP- seq of H3K27Ac, SMARCA4, EZH2 and H3K27me3 in H1299-SMARCA4-Wt and H1299-SMARCA4-Mut cells, after induction of SMARCA4 with doxycycline (lng/pl) and SAHA treatment (ImM) for 3 days.
- TSS transcription start site
- Figure 3 Assessment of cell viability measured using MTT assays, after treatment with increasing concentrations of GSK-J4 for five days, in a panel of five SMARCA4 deficient or six MYC-amplified (SWI/SNF proficient) cell lines. Inset, box plot with the logIC50 values of the different cell panels (SMARCA4-deficient vs MYC-amplified) after GSK-J4 treatment (b) Colony formation assay in the MYC amplified cell line model H460 (SWESNF proficient) and DMS114 SMARCA4-deficient cell line model, under different treatments with SAHA (lpM), GSK-J4 (lpM) or GSK-126 (lpM), for five days.
- Figure 4 (a) Kaplan-Meier curves showing overall survival (OS) probability for GSK- J4 treatment compared with that for the vehicle control group.
- Lung cancer cell lines where orthotopically implanted in lung parenchyma in each case and the number of mice in each group (n) are indicated.
- DMS273 SWI/SNF proficient
- cell line center and right panel
- DMS114 and H841 SWI/SNF deficient
- Panels on the bottom show the mean ⁇ SD survival time for the different groups of cell lines
- FIG. 5 (a) Mutational analyses of SMARCA4 deleterious mutations in SCCOHT primary tumors OVA250 and OVA259. (b) Western blot depicting the protein expression levels of KDM6B (JMJD3), KDM6A( UTX), SMARCA4 , and a- TUBULIN as protein-loading control in a SWI/SNF deficient SCCOHT primary culture OVA250 and the SWI/SNF proficient cell line OVCAR-8 under different treatments with SAHA (ImM), GSK-J4 (ImM) or combination (c) Western-blot depicting the protein expression levels of H3K27me3, H3K27Ac and a- TUBULIN as protein-loading control in a SWI/SNF deficient SCCOHT primary culture OVA250 and the SWI/SNF proficient cell line OVCAR8 under different treatments with SAHA (ImM), GSK-J4 (ImM) or combination (d) Colony formation assay in the cell line model OVC
- FIG. 6 (a) Western blot depicting the protein expression levels of H3K27me3, H3K27ac and a- TUBULIN as protein-loading control in a panel of SMARCA4 deficient (DMS114), MYC amplified (DMS273), KDM6B/JMJD3 deficient (SNU5, U266B1), KDM6A/UTX deficient (H520, KM12 and KYSE180) and in a panel of SWI/SNF deficient cell lines (SW1573, A204, H727 and T47D) under treatment with SAHA (lpM).
- Example 1 Material and methods Example 1.1. Cell culture. Most cell lines were obtained from the American Type Culture Collection (ATCC, Rockville, MD), grown under recommended conditions and maintained at 37oC in a humidified atmosphere of 5% C0 2 /95% air. All cell lines were routinely evaluated for mycoplasma contamination. The cells lines were authenticated by genotyping for TP53 and other known mutations. Genomic DNA and total RNA were extracted by standard protocols. The study was approved by the relevant institutional review boards and ethics committees.
- Example 1.2 Determination of IC50 of each drug (SAHA or GSK-J4).
- SAHA or GSK-J4 a drug that was administered to a patient.
- IC50 IC50 of each drug (SAHA or GSK-J4).
- cells were treated with each drug alone for 96 h.
- Estimates of IC50 were derived from the dose response curves.
- Example 1.3 Antibodies and western-blots.
- the following primary antibodies were used for western-blots: polyclonal anti-C-MYC, N- 262 (1:500; Santa Cruz Biotechnology);anti-TUBULIN, T6199 mouse (1/10000, Sigma Aldrich, St.
- Protein concentrations were determined using a Bio-Rad DC Protein Assay kit (Life Science Research, Hercules, CA). Equal amounts of lysates (20 pg) were separated by SDS-PAGE and transferred to a Nitrocellulose membrane that was blocked with 5% nonfat dry milk. Membranes were incubated with the primary antibody overnight at 4°C, then washed before incubation with species-appropriate horseradish peroxidase (HRP)-conjugated secondary antibodies for 1 h at room temperature.
- HRP horseradish peroxidase
- Example 1.4 Cell Treatments and shRNAs.
- Chemicals were obtained from the following sources: SAHA, suberoyl+anilide+hydroxamic acid (Cayman Chemical company, Ann Arbour, MI); GSK-J4 (Shelleckchem, Houston, TX, USA); GSK-126 (Cayman Chemical Company, Ann Arbour, MI, USA) shRNAs against SMARCA4 were purchased from SIGMA-MISSION (LentiExpressTM Technology, Sigma- Aldrich, St.
- Non target (NT) shRNA (Sigma MISSION shRNA non-mammalian control SHC002) was used as a control.
- the lentiviruses were generated within the 293 T packaging cells.
- Example 1.5 Cell viability assays (MTTs).
- MTT Cell viability assays
- cell lines were incubated in 96-well plates. Prior to harvest, cells were treated for 24-72 h with the indicated concentrations of each compound or combinations.
- Example 1.6 Orthotopic xenograft models. Athymic mice male nu/nu aged 4-5 weeks were maintained in a sterile environment. All animal specimens used for the experiments with lung cancer were male and with ovarian cancer were females. None of the mice samples were excluded before analysis. All animal experiments were approved by the local Ethical Committee (no. AAALAC-3880) and performed in accordance with guidelines stated in The International Guiding Principles for Biomedical Research involving Animals, developed by the Council for International Organizations of Medical Sciences (CIOMS). Ovarian primary tumours were directly orthotopically implanted from patients into the mice ovary. The different lung cancer cells (2x106) were first grown subcutaneously and then implanted orthotopically into the lung.
- mice were randomized for treatments. Animals were treated by intraperitoneal injection with GSK-J4 (50 mg/kg/day), vehicle only. Each treatment was administrated daily, for four weeks. In the case or mice implanted with orthotopic lung tumors, animals were sacrificed when they displayed serious respiratory difficulty, which was subsequently confirmed to be associated with lung tumor burden. In the case of ovarian cancer implanted animals were sacrificed after finalization of the 4 weeks of treatments.
- the tumor specimens were fixed and embedded in paraffin stained with hematoxilin and eosin (H&E), using standard protocols, and examined by light microscopy in a blinded fashion.
- H&E hematoxilin and eosin
- immunohistochemical staining four pm thick sections from the tumors were transferred to silanized glass slides. After deparaffinization and quenching endogenous peroxidase, the slides were boiled in citrate buffer for 15 minutes. After antibody incubation, immunodetection was performed with the secondary anti-rabbit conjugated HRP (Dako) with diaminobenzidine chromogen as the substrate (Invitrogen). Sections were counterstained with hematoxylin and evaluated in the Leica DM1000 microscope.
- Example 1.7 Statistical analysis. Data were analysed using a chi-square test or a two- tailed Student’s unpaired- samples t test. Group differences were presented as means and standard deviations. Differences were considered statistically significant for any value of p ⁇ 0.05. Kaplan-Meier estimates of the survival distribution for each group were computed. Survival analysis was performed in Graphpad Prism with comparison of survival curves by log-rank (Mantle Cox) test. In order to test the equality of the survival distributions for different groups, the statistics log rank, was calculated. We considered significant any test with a p-value smaller than 5% (that is, the compared groups have significant different survival distributions).
- Example 2.1 Genetic inactivation of SMARCA4 promote an aberrant accumulation of H3K27me3 levels in response to HD AC inhibitors (SAHA), linked to defects in the expression levels of specific Lysine demethylases (KDMs) in SMARCA4-deficient cells.
- SAHA HD AC inhibitors
- KDMs specific Lysine demethylases
- SMARCA4-mutant lung cancer cells do not inhibit proliferation in the presence to the pan HD AC (Histone deacetylase) inhibitor suberanilohydroxamic acid (SAHA), when compared with a group of lung cancer cells carrying genetic activation of MYC (MYC-amplification) (and SWI/SNF-proficient) lung cancer cell lines ( Figure la). This happened despite SAHA triggered an increase in H3K27Ac levels in both groups of cancer cell lines, which is the expected effect after the treatment with a global histone deacetylase inhibition.
- SAHA Histone deacetylase
- Example 2.2 SMARCA4 and EZH2 antithetically regulate KDM expression.
- H1299-SMARCA4-Wt green cells
- H1299-SMARCA4-mutant did not suffer any morphological change.
- the changes in cell morphology were only observed in the H1299-SMARCA4-Wt after induction of SMARCA4 expression with doxocyclin ( Figure 2a).
- the H1299-SMARCA4-Mut also shown a decrease in global H3K27Ac and effect that was opposed in the H1299-SMARCA4-Wt that increased H3K27ac upon exposure to SAHA (Figure 2b). These observations evidence defects, in the SMARCA4-deficient cancer cells, that prevent an appropriate balance between the H3K27ac and H3K27me3 marks following the administration of SAHA, which may underlie the refractoriness to SAHA.
- RT-q-PCR to test the effects of inducing SMARCA4 in the expression levels of several KDMs and KMTs in response to SAHA.
- Example 2.3 GSK-J4 is preferentially toxic in SMARCA4-mutant cells and reverts SAHA effect in MYC-amplified cell lines
- Example 2.5 Inhibition of KDM6A in SMARCA4-deficient lung cancer increases survival in vivo.
- Example 2.6 Inhibition of KDM6A in SMARCA4-deficient cancer cells promotes cell death in SCCOHT in vivo.
- SCCOHT hypercalcemic type
- mice bearing SCCOHT tumors treated with GSK-J4 were significantly smaller in size as compared to the matched controls ( Figure 5f).
- haematoxylin and eosin staining evidenced large tumor regions with necrosis in the SCCOHT tumors treated with GSK- J4, as compared to the other groups of tumors ( Figure 5g).
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne un inhibiteur de protéine 6 de la sous-famille des KDM pour l'utilisation dans le traitement du cancer. La présente invention concerne des inhibiteurs d'une protéine 6 de la sous-famille des KDM sélectionnée parmi KDM6A et/ou KDM6B pour l'utilisation dans le traitement de patients souffrant de cancer, la tumeur du patient ou la lignée germinale du patient étant caractérisée par l'inactivation d'un gène membre du complexe SWI/SNF.
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PCT/EP2020/083386 WO2021105224A1 (fr) | 2019-11-26 | 2020-11-25 | Inhibiteur de protéine 6 de la sous-famille des kdm pour l'utilisation dans le traitement du cancer |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114522233A (zh) * | 2021-11-30 | 2022-05-24 | 首都医科大学附属北京口腔医院 | Kdm6b的多肽序列及对间充质干细胞功能的调控应用 |
WO2023072215A1 (fr) * | 2021-10-27 | 2023-05-04 | 蚌埠医学院第一附属医院 | Utilisations de la cible du cancer du poumon non à petites cellules arid1a et son inhibiteur dans la préparation d'un médicament pour le traitement du cancer du poumon |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023072215A1 (fr) * | 2021-10-27 | 2023-05-04 | 蚌埠医学院第一附属医院 | Utilisations de la cible du cancer du poumon non à petites cellules arid1a et son inhibiteur dans la préparation d'un médicament pour le traitement du cancer du poumon |
CN114522233A (zh) * | 2021-11-30 | 2022-05-24 | 首都医科大学附属北京口腔医院 | Kdm6b的多肽序列及对间充质干细胞功能的调控应用 |
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