WO2022053130A1 - Antago-mir-155 for treatment of v-src, c-src-tyrosine kinase-induced cancers - Google Patents
Antago-mir-155 for treatment of v-src, c-src-tyrosine kinase-induced cancers Download PDFInfo
- Publication number
- WO2022053130A1 WO2022053130A1 PCT/EP2020/075178 EP2020075178W WO2022053130A1 WO 2022053130 A1 WO2022053130 A1 WO 2022053130A1 EP 2020075178 W EP2020075178 W EP 2020075178W WO 2022053130 A1 WO2022053130 A1 WO 2022053130A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mir
- antago
- src
- molecule
- cells
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 75
- 108010069682 CSK Tyrosine-Protein Kinase Proteins 0.000 title claims abstract description 43
- 108010058765 Oncogene Protein pp60(v-src) Proteins 0.000 title claims abstract description 42
- 102000029330 CSK Tyrosine-Protein Kinase Human genes 0.000 title claims abstract 12
- 238000011282 treatment Methods 0.000 title description 56
- 108091033773 MiR-155 Proteins 0.000 claims abstract description 38
- 239000003814 drug Substances 0.000 claims abstract description 32
- 201000011510 cancer Diseases 0.000 claims abstract description 22
- 230000037361 pathway Effects 0.000 claims abstract description 19
- 230000009466 transformation Effects 0.000 claims abstract description 19
- 230000000694 effects Effects 0.000 claims abstract description 17
- 230000004913 activation Effects 0.000 claims abstract description 8
- 125000002091 cationic group Chemical group 0.000 claims abstract description 5
- 229920001577 copolymer Polymers 0.000 claims abstract description 4
- 230000014509 gene expression Effects 0.000 claims description 45
- 241000699670 Mus sp. Species 0.000 claims description 29
- 108090000623 proteins and genes Proteins 0.000 claims description 29
- 229940079593 drug Drugs 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 150000007523 nucleic acids Chemical class 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- 230000007423 decrease Effects 0.000 claims description 17
- 102000039446 nucleic acids Human genes 0.000 claims description 17
- 108020004707 nucleic acids Proteins 0.000 claims description 17
- 229920000642 polymer Polymers 0.000 claims description 12
- 239000000969 carrier Substances 0.000 claims description 11
- 239000002679 microRNA Substances 0.000 claims description 11
- 108091070501 miRNA Proteins 0.000 claims description 9
- 230000001225 therapeutic effect Effects 0.000 claims description 9
- 230000006698 induction Effects 0.000 claims description 8
- 150000002632 lipids Chemical class 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 230000033228 biological regulation Effects 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 230000008485 antagonism Effects 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000006870 function Effects 0.000 claims description 4
- 239000002105 nanoparticle Substances 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 108020004414 DNA Proteins 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000002502 liposome Substances 0.000 claims description 3
- 230000000638 stimulation Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 230000015556 catabolic process Effects 0.000 claims description 2
- 238000006731 degradation reaction Methods 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims 3
- 229920006317 cationic polymer Polymers 0.000 claims 2
- 239000003446 ligand Chemical group 0.000 claims 2
- 102000053602 DNA Human genes 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- 150000001299 aldehydes Chemical group 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- 239000007767 bonding agent Substances 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 238000012412 chemical coupling Methods 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 229920006158 high molecular weight polymer Polymers 0.000 claims 1
- 229920001477 hydrophilic polymer Polymers 0.000 claims 1
- 229920002521 macromolecule Polymers 0.000 claims 1
- 108020004999 messenger RNA Proteins 0.000 claims 1
- 239000002082 metal nanoparticle Substances 0.000 claims 1
- 239000000693 micelle Substances 0.000 claims 1
- 238000006116 polymerization reaction Methods 0.000 claims 1
- 229920002477 rna polymer Polymers 0.000 claims 1
- JNQYNXFGVRUFNP-JGVFFNPUSA-N 4-amino-1-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidin-2-one Chemical compound O=C1N=C(N)C(C)=CN1[C@@H]1O[C@H](CO)CC1 JNQYNXFGVRUFNP-JGVFFNPUSA-N 0.000 abstract description 75
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 abstract description 30
- -1 poly(N-vinylpyrrolidone) Polymers 0.000 abstract description 11
- 238000001727 in vivo Methods 0.000 abstract description 8
- 230000001640 apoptogenic effect Effects 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 230000001105 regulatory effect Effects 0.000 abstract description 4
- 230000003612 virological effect Effects 0.000 abstract description 4
- 229920002491 Diethylaminoethyl-dextran Polymers 0.000 abstract description 3
- 229920000578 graft copolymer Polymers 0.000 abstract description 3
- 239000012096 transfection reagent Substances 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
- 230000002001 anti-metastasis Effects 0.000 abstract 1
- 230000001028 anti-proliverative effect Effects 0.000 abstract 1
- 230000000295 complement effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 164
- 241001465754 Metazoa Species 0.000 description 44
- 238000000034 method Methods 0.000 description 37
- 210000004881 tumor cell Anatomy 0.000 description 35
- 102100031167 Tyrosine-protein kinase CSK Human genes 0.000 description 31
- 238000001890 transfection Methods 0.000 description 30
- 238000002474 experimental method Methods 0.000 description 23
- 231100000419 toxicity Toxicity 0.000 description 17
- 230000001988 toxicity Effects 0.000 description 17
- 230000001965 increasing effect Effects 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 13
- 230000004614 tumor growth Effects 0.000 description 13
- 239000013598 vector Substances 0.000 description 13
- 208000020816 lung neoplasm Diseases 0.000 description 11
- 102000009076 src-Family Kinases Human genes 0.000 description 11
- 108010087686 src-Family Kinases Proteins 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 241000700605 Viruses Species 0.000 description 10
- 230000002068 genetic effect Effects 0.000 description 10
- 239000001963 growth medium Substances 0.000 description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 9
- 241000714474 Rous sarcoma virus Species 0.000 description 9
- 101150001535 SRC gene Proteins 0.000 description 9
- 201000005202 lung cancer Diseases 0.000 description 9
- 101710126211 POU domain, class 5, transcription factor 1 Proteins 0.000 description 8
- 102100035423 POU domain, class 5, transcription factor 1 Human genes 0.000 description 8
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 8
- 210000004072 lung Anatomy 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 231100000331 toxic Toxicity 0.000 description 8
- 230000002588 toxic effect Effects 0.000 description 8
- 238000000134 MTT assay Methods 0.000 description 7
- 231100000002 MTT assay Toxicity 0.000 description 7
- 206010039491 Sarcoma Diseases 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 238000011081 inoculation Methods 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- 108010085238 Actins Proteins 0.000 description 6
- 108090000669 Annexin A4 Proteins 0.000 description 6
- 206010027476 Metastases Diseases 0.000 description 6
- 108091034117 Oligonucleotide Proteins 0.000 description 6
- 230000001413 cellular effect Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 230000004049 epigenetic modification Effects 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 230000001394 metastastic effect Effects 0.000 description 6
- 210000004940 nucleus Anatomy 0.000 description 6
- 102000004148 Annexin A4 Human genes 0.000 description 5
- 102100021631 B-cell lymphoma 6 protein Human genes 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 5
- 101000971234 Homo sapiens B-cell lymphoma 6 protein Proteins 0.000 description 5
- 206010061309 Neoplasm progression Diseases 0.000 description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 5
- 238000000540 analysis of variance Methods 0.000 description 5
- 230000036952 cancer formation Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 238000003125 immunofluorescent labeling Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000000877 morphologic effect Effects 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 108700026239 src Genes Proteins 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 230000005751 tumor progression Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 4
- 102100026548 Caspase-8 Human genes 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 4
- 238000012404 In vitro experiment Methods 0.000 description 4
- 108060006706 SRC Proteins 0.000 description 4
- 239000011543 agarose gel Substances 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 231100000517 death Toxicity 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000010195 expression analysis Methods 0.000 description 4
- 102000034287 fluorescent proteins Human genes 0.000 description 4
- 108091006047 fluorescent proteins Proteins 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000002427 irreversible effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 201000005249 lung adenocarcinoma Diseases 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 210000002307 prostate Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 3
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 3
- 108050006400 Cyclin Proteins 0.000 description 3
- 102000016736 Cyclin Human genes 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 102000001301 EGF receptor Human genes 0.000 description 3
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 3
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 102000001332 SRC Human genes 0.000 description 3
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 3
- 101100311214 Xenopus laevis stat3.1 gene Proteins 0.000 description 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 3
- 208000009956 adenocarcinoma Diseases 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 231100000504 carcinogenesis Toxicity 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 230000001973 epigenetic effect Effects 0.000 description 3
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 3
- 229960005542 ethidium bromide Drugs 0.000 description 3
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 3
- 230000005017 genetic modification Effects 0.000 description 3
- 230000006882 induction of apoptosis Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000003278 mimic effect Effects 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 230000004660 morphological change Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000008672 reprogramming Effects 0.000 description 3
- 238000003757 reverse transcription PCR Methods 0.000 description 3
- 238000004626 scanning electron microscopy Methods 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000007492 two-way ANOVA Methods 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 2
- 101100298998 Caenorhabditis elegans pbs-3 gene Proteins 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 108090000538 Caspase-8 Proteins 0.000 description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 102100023387 Endoribonuclease Dicer Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 2
- 101000907904 Homo sapiens Endoribonuclease Dicer Proteins 0.000 description 2
- 101001027081 Homo sapiens Killer cell immunoglobulin-like receptor 2DL1 Proteins 0.000 description 2
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 2
- 101000687905 Homo sapiens Transcription factor SOX-2 Proteins 0.000 description 2
- 101000904499 Homo sapiens Transcription regulator protein BACH2 Proteins 0.000 description 2
- 108091027558 IsomiR Proteins 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 2
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 2
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 2
- 108010018650 MEF2 Transcription Factors Proteins 0.000 description 2
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 2
- 108700011259 MicroRNAs Proteins 0.000 description 2
- 102000001759 Notch1 Receptor Human genes 0.000 description 2
- 108010029755 Notch1 Receptor Proteins 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 101150099493 STAT3 gene Proteins 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 102100024270 Transcription factor SOX-2 Human genes 0.000 description 2
- 102100023998 Transcription regulator protein BACH2 Human genes 0.000 description 2
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 2
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000009400 cancer invasion Effects 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000010307 cell transformation Effects 0.000 description 2
- 230000007541 cellular toxicity Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 210000005266 circulating tumour cell Anatomy 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 230000008826 genomic mutation Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 238000007885 magnetic separation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 238000002493 microarray Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 108091027963 non-coding RNA Proteins 0.000 description 2
- 102000042567 non-coding RNA Human genes 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 2
- 238000010837 poor prognosis Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012340 reverse transcriptase PCR Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000012128 staining reagent Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- ROICYBLUWUMJFF-RDTXWAMCSA-N (6aR,9R)-N,7-dimethyl-N-propan-2-yl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound CN(C(=O)[C@H]1CN(C)[C@@H]2CC3=CNC4=CC=CC(C2=C1)=C34)C(C)C ROICYBLUWUMJFF-RDTXWAMCSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- 206010001197 Adenocarcinoma of the cervix Diseases 0.000 description 1
- 208000034246 Adenocarcinoma of the cervix uteri Diseases 0.000 description 1
- 102100034612 Annexin A4 Human genes 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 108091012583 BCL2 Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 102000005403 Casein Kinases Human genes 0.000 description 1
- 108010031425 Casein Kinases Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 241000283153 Cetacea Species 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 108010043471 Core Binding Factor Alpha 2 Subunit Proteins 0.000 description 1
- 101100239628 Danio rerio myca gene Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102100031690 Erythroid transcription factor Human genes 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 101150073536 FET3 gene Proteins 0.000 description 1
- 102100034553 Fanconi anemia group J protein Human genes 0.000 description 1
- 102100027581 Forkhead box protein P3 Human genes 0.000 description 1
- 208000031448 Genomic Instability Diseases 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101100493653 Homo sapiens BACH2 gene Proteins 0.000 description 1
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 description 1
- 101001066268 Homo sapiens Erythroid transcription factor Proteins 0.000 description 1
- 101000848171 Homo sapiens Fanconi anemia group J protein Proteins 0.000 description 1
- 101000861452 Homo sapiens Forkhead box protein P3 Proteins 0.000 description 1
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 1
- 101000852964 Homo sapiens Interleukin-27 subunit beta Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000894871 Homo sapiens Transcription regulator protein BACH1 Proteins 0.000 description 1
- 102100036712 Interleukin-27 subunit beta Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102100037363 Killer cell immunoglobulin-like receptor 2DL1 Human genes 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 102100039229 Myocyte-specific enhancer factor 2C Human genes 0.000 description 1
- 102100039212 Myocyte-specific enhancer factor 2D Human genes 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 102000016979 Other receptors Human genes 0.000 description 1
- 239000012807 PCR reagent Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 102000008022 Proto-Oncogene Proteins c-met Human genes 0.000 description 1
- 108010089836 Proto-Oncogene Proteins c-met Proteins 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 description 1
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 108700027336 Suppressor of Cytokine Signaling 1 Proteins 0.000 description 1
- 102100024779 Suppressor of cytokine signaling 1 Human genes 0.000 description 1
- 101150057615 Syn gene Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 101710101493 Viral myc transforming protein Proteins 0.000 description 1
- 101100326560 Xenopus laevis cdh2-a gene Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 238000011256 aggressive treatment Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940083476 bosulif Drugs 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229940056434 caprelsa Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 201000006662 cervical adenocarcinoma Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 230000008711 chromosomal rearrangement Effects 0.000 description 1
- 210000001726 chromosome structure Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- UMGXUWVIJIQANV-UHFFFAOYSA-M didecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC UMGXUWVIJIQANV-UHFFFAOYSA-M 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000008472 epithelial growth Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000054078 gamma Catenin Human genes 0.000 description 1
- 108010084448 gamma Catenin Proteins 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 229940049235 iclusig Drugs 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000006525 intracellular process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 101150111214 lin-28 gene Proteins 0.000 description 1
- 101150108076 lin28a gene Proteins 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000002122 magnetic nanoparticle Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 231100000324 minimal toxicity Toxicity 0.000 description 1
- 230000006740 morphological transformation Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 230000006654 negative regulation of apoptotic process Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 231100000028 nontoxic concentration Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000005937 nuclear translocation Effects 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 210000004976 peripheral blood cell Anatomy 0.000 description 1
- 238000002135 phase contrast microscopy Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000962 poly(amidoamine) Polymers 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 239000012474 protein marker Substances 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 210000001243 pseudopodia Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229940068117 sprycel Drugs 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
- C12N2310/141—MicroRNAs, miRNAs
Definitions
- This invention relates to a therapeutic use of antago-miR-155 molecule an equivalent such as a source of an antago- miR with capability to inhibit/suppress/block of miR-155, as active compound for preventing, treating, reverting, curing and/or delaying v-src, c-src -tyrosine kinase-induced cancers (breast cancer, lung cancer, prostate cancer, colorectal cancer) or a disease or a condition, associated with v-src, c-src -tyrosine kinase pathway and induces transformation of cancer cells into non-cancerous cell form.
- antago-miR-155 molecule an equivalent such as a source of an antago- miR with capability to inhibit/suppress/block of miR-155, as active compound for preventing, treating, reverting, curing and/or delaying v-src, c-src -ty
- This invention was supported, in whole or in part, by an funds of SID ALEX GROUP, s.r.o.
- MicroRNAs are a class of small, non-coding RNAs with lengths 30-31 bps, which control gene expression by hybridizing to and triggering either translational repression.
- Small non-coding RNAs sncRNAs
- sncRNAs Small non-coding RNAs
- tumor cells genes can be regulated by epigenetic modifications and underlying genomic mutations that due to reversible and irreversible changes of cellular genome, which can result in the activation of oncogenes and the inhibition of tumor-suppressor genes.
- Tumorigenesis is a complex process that is driven by active and passive mutations.
- the resultant tumors generally comprise heterogeneous tissues with tumor cell characteristics (Nishikawa S. et al., 2012).
- miR-155 was identified as metastatic sncRNA in lung cancer. Increased levels of miR-155 correlated with increased cancer invasion and migration and, correlated with poor prognosis in patients with lung cancer. Moreover, it was shown that miR-155 promoted tumor formation in the lung when cells were injected directly in the bloodstream (Volinia et al, 2006; Wang et al, 2015). MiR-155 also inhibits apoptosis in lung cancer cells by inhibiting Apaf-1 expression (Zang et al, 2012). Among the microRNAs that have been linked to cancer, it is the most commonly overexpressed miRNA in malignancies of the breast, lung, liver, colon, and rectum, and prostate.
- BCL6 down- regulates BCL6, which modulates the STAT-dependent IL-4 responses of B-cells and increases their function.
- the reduction of BCL6 is due to the up-regulation of inhibitors of differentiation such as IL -6, cMYC, Cyclin DI, and Mipla/Ccl3, all of which promote cell survival and proliferation.
- MiR-155 also upregulates the Mxdl/Madl transcription factors that mediate cellular proliferation, differentiation, and apoptosis through the regulation BCL6.
- miR-155 leads to the resistance of cell death and enables replicative immortality.
- HDAC4 is also a target for BCL6. HDAC alters chromosome structure and affects the access of transcription factors to DNA.
- BCL6 acts with MEF2C and MEF2D.
- MiR-155 activates metastatic processes in breast cancer cells by activating Rho. It also represses SHIP, which is a negative regulator of myeloid cell proliferation and survival. MiR-155 suppresses BACH1 and SOCS-1 and induces G-2 arrest through the CD40 ligand (CD 154) and further represses of BCL2.
- MiR 155 also targets casein kinase (CKla) which enhances beta-catenin signaling and cyclin DI expression, thereby promoting tumor growth (Due et al, 2016; Wan et al, 2016; Huffaker. and O’Connell, 2015). All of these genetic and morphological changes are due to cell death or a cell’s irreversible transformation. As the result, structural modification of cancer tissues occurs.
- Viruses are one of the main causes for induction, development and progression of majority of cancers. Such as colorectal cancer, prostate cancer, lung cancer, skin and liver cancers, etc. These cancers are first-placed causes of cancer-related deaths in United States and throughout the world, affecting more than 163.5 per 100,000 men and women per year (based on 2011-2015 causes of deaths).
- Rous sarcoma virus is carcinogenic retrovirus.
- the tumor -inducing gene of RSV and RSV-induced tumors is the viral src oncogene (v-src) (Sudol, 2011).
- the v-src oncogene is a truncated and active form of the wildtype proto-oncogene c-src.
- the src gene codes a non-receptor protein tyrosine kinase that is a member of the Src family kinases (SFKs). SFKs are involved in processes of tumor progression, invasion, and metastasis.
- Src kinase activity and protein levels are elevated in several cancers, including those of the colon, prostate, lung and breast (Rothschild and Gautschi, 2012; Gargalionis et al, 2014; Varkaris et al, 2014; Zhang et al, 2013).
- Oncogenic activity of the Src gene is connected with the activation of the src protein kinase after interactions with other receptor tyrosine kinases: epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), colony-stimulating factor-1 receptor (CSF-1R), HER2/neu, HER1, hepatocyte growth factor receptor (c-Met), and vascular epithelial growth factor (VEGF).
- EGFR epidermal growth factor receptor
- PDGFR platelet-derived growth factor receptor
- FGFR fibroblast growth factor receptor
- CSF-1R colony-stimulating factor-1 receptor
- HER2/neu HER2/neu
- VEGF vascular epithelial growth factor
- Src-tyrosine kinase is associated with the regulation of adhesion factors such as, a-, ⁇ -. and y-catenins; cadherin; and plakoglobin (JUP).
- Src-tyrosine kinase activates the anti-apoptotic factor Bcl-xL by inducing Stat3 expression.
- Stat3 activation leads to the transcriptional regulation of cyclin DI and c-Myc. The expression of these genes results in the stimulation of proliferative processes (Irby and Yeatman, 2000; Giglione et al, 2001).
- Src-tyrosine kinase inhibitors have been synthesized. Of these, the most heavily clinically investigated are the dual inhibitors of Src and Bcr-Abl protein kinases (Fernandez et al, 2019). In 2006, 100 years after Rous’s discovery, one such inhibitor, SPRYCEL (dasatinib), gained U.S. Food and Drug Administration (FDA) approval for the complex therapy of patients with chronic myelogenous leukemia (W02017144109A1).
- SPRYCEL dasatinib
- FDA U.S. Food and Drug Administration
- Src inhibitors with initial US approval are ICLUSIG (ponatinib) (US8114874), CAPRELSA (vandetanib) (US7173038), BOSULIF (bosutinib) (US7417148).
- ICLUSIG ponatinib
- CAPRELSA vandetanib
- BOSULIF bisutinib
- Other inhibitors of src-tyrosine kinases are still in different phases of preclinical and clinical investigations. However, none of the investigated src-tyrosine kinase inhibitors has shown appreciable activity in the monotherapy of patients with solid tumors (Puls et al, 2011). All proposed drugs are very toxic and have hepatotoxicity, cardiotoxicity, misbalance of blood cells count, changes of the hemostasis and immune activity.
- the main hallmarks of cancer are: genetic and epigenetic modifications, changes in the cell cycle with inhibition of apoptosis, metastatic activity of cancer cells, unlimited proliferation and division, and regulation of the tumor microenvironment.
- genes can be regulated by epigenetic modifications and underlying genomic mutations that due to reversible and irreversible changes of cellular genome, which can result in the activation of oncogenes and the inhibition of tumor-suppressor genes.
- Tumorigenesis is a complex process that is driven by active and passive mutations. (Nishikawa et al, 2012). Genetic and epigenetic modifications are enabling characteristics that generates random mutations including chromosomal rearrangements. Rare genetic changes can occur that orchestrate hallmark capabilities of cancer growth and progression.
- antago-miR-155 molecule or source thereof as identified herein.
- the invention is provided an antago-miR-155 molecule, an equivalent or a source thereof or a composition comprising said miRNA molecule antago-miR-155, said equivalent or said source thereof, preferably for use as a medicament for preventing, treating, reverting, curing and/or delaying v-src, c-src-tyrosine kinase-induced cancers (breast cancer, lung cancer, prostate cancer, colorectal cancer) or a disease or a condition, associated with v-src, c-src-tyrosine kinase pathway.
- the term “antago-miR- 155 (a-miR-155, antago-miRNA-155, a-miRNA-155) of present invention is molecule or an equivalent, or a mimic, or an isomiR with capability to inhibit/suppress/block of miR-155.
- the present invention disclosure nucleic acid sequence to target the miR-155 to inhibit v-src, c-src-tyrosine kinase pathways in virus-induced cancers.
- an antago-miR-155 molecule or an equivalent, or a mimic, or an isomiR thereof may be a synthetic or natural, or recombinant.
- Antagonism for miR-155 may be for immature, or part of a mature, or mature miR-155.
- An antago-miR-155 molecule or an equivalent, or a mimic thereof may be a single stranded or double stranded RNA molecule.
- an antago-miR-155 of a miR-155 molecule is from 8 to 30 nucleotides in length, preferably 10 to 31 nucleotides in length, preferably 12 to 28 nucleotides in length, more preferably said molecule has a length of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 nucleotides or more.
- a source of an antago-miR-155 of a miR-155 molecule or a source of an equivalent of an antago-miR with capability to inhibit/suppress/block of a miRNA molecule may be any molecule, which is able to induce the production of said antago-miR-155.
- nucleic acid molecule antago-miR-155 molecule or source thereof as active component with the carrier and use it as a medicament for suppression of miR-155, result in preventing, treating, reverting, curing and/or delaying v-src, c-src-tyrosine kinase or a disease or a condition associated with v-src, c-src- tyrosine kinase pathway, thereby realize the treatment of v-src, c-src-tyrosine kinase-induced cancers.
- antago- miRNA molecule or a source of an equivalent of an antago-miR with capability to inhibit/suppress/block of a miR- 155 may be made by any known technique, such as for example, enzymatic or chemical synthesis, or biological production. Though antago-miR according to the invention could be produced using recombinant methods. Nucleic acid synthesis is performed according to standard methods. (U.S. Patent Nos 4704362A, 5221619A).
- An activity of a given antago-miR-155 molecule or an equivalent or a source thereof or a corresponding source thereof all as defined herein is preferably the ability to exhibit a detectable anti-v-src, c-src-tyrosine kinase activity and/or induce a decrease of v-src, c-src- tyrosine kinase pathways.
- an anti-v-src, c-src- tyrosine kinase activity may comprise or comprises at least one of the following: reduction or decrease of v-src or c- src-tyrosine kinase pathways protein activity, induction of apoptosis, decrease of proliferation, decrease of metastatic activity, death of cancer cells or theirs transformation into non-cancerous form.
- Exhibiting such a detectable anti-v-src, c-src-tyrosine kinase pathway proteins activity and/or inducing such a reduction or decrease of v-src, c-src-tyrosine kinase-induced cancerogenesis is crucial in the present invention in order to be able to prevent, delay, cure and/or treat v-src, c-src-tyrosine kinase-induced cancers and/or any disease or condition associated with v-src, c-src-tyrosine kinase pathways.
- preventing, treating, reverting, curing and/or delaying v-src, c-src-tyrosine kinase- induced cancerogenesis or a disease, or condition associated with v-src, c-src-tyrosine kinase-induced cancerogenesis may be replaced by achieving an anti-tumor effect.
- an anti-tumor effect is preferably assessed or detected after at least one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months or more in a treated subject.
- An anti-tumor effect is preferably identified in a subject as: an inhibition of proliferation of tumor cells, a decrease of proliferation markers in cancer cells, and/or an induction or increased induction of tumor cells death, an increase of markers of apoptotic activity, and/or a delay in occurrence of metastases and/or of tumor cell migration and inhibition of markers of metastatic activity and/or an inhibition or prevention or delay of the increase of a tumor weight, and/or a prolongation of patient survival of at least one month, several months or more (compared to those not treated or treated with a control or compared with the subject at the onset of the treatment), and/or an improvement of the quality of life and observed pain relief.
- a patient may survive and/or may be considered as being disease free. Alternatively, the disease or condition may have been stopped or delayed.
- An improvement of quality of life and observed pain relief may mean that a patient may need less pain relief drugs than at the onset of the treatment. Alternatively or in combination with the consumption of less pain relief drugs, a patient may be less constipated than at the onset of the treatment. "Less” in this context may mean 5% less, 10% less, 20% less, 30% less, 40% less, 50% less, 60% less, 70% less, 80% less, 90% less. A patient may no longer need any pain relief drug.
- This improvement of quality of life and observed pain relief may be seen, detected or assessed after at least one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months or more of treatment in a patient and compared to the quality of life and observed pain relief at the onset of the treatment of said patient.
- An inhibition of the proliferation of tumor cells may be at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70% or 75%, or more. Proliferation of cells may be assessed using known techniques.
- An induction of tumor cell death may be at least 1%, 5%, 10%, 15%, 20%, 25%, or more.
- Tumor growth may be inhibited at least 5%, 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70% or 75%, or more.
- Tumor cell death may be assessed using techniques known to the skilled person.
- Tumor growth may be assessed using MRI or CT.
- tumor weight decrease or tumor growth may be inhibited at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70% or 75%, or more.
- Tumor weight or tumor growth may be assessed using techniques known to the skilled person.
- Example 5 To test the effect of antago-miR-155 molecule on tumour growth in an animal model in vivo, an experimental system as described in Example 5 may be used.
- a delay in occurrence of metastases and/or of tumor cell migration may be a delay of at least one week, one month, several months, one year or longer.
- the presence of metastases may be assessed using MRI, CT or Echography or techniques allowing the detection of circulating tumour cells (CTC).
- tumor growth may be delayed at least one week, one month, two months or more.
- an occurrence of metastases is delayed at least one week, two weeks, three weeks, four weeks, one months, two months, three months, four months, five months, six months or more.
- a decrease of the expression level of miR-155 molecule or equivalent or source thereof means a decrease of at least 10% of the expression level of the miRNA using qPCR, microarrays or Northern blot analysis.
- a decrease of the expression level of a miRNA molecule or equivalent or source thereof means a decrease of at least 15%, even more preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 90%, or 100 %.
- an expression level is determined ex vivo in a sample obtained from a subject (sample is derived from a tumor biopsy, blood, sputum, stool or urine).
- the molecules of the invention will generally be used in an amount effective to achieve the intended purpose.
- the molecule of the invention or its pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount.
- a therapeutically effective amount is an amount effective to ameliorate or prevent the symptom/s, or prolong the survival of the patient being treated.
- a therapeutically effective dose can be estimated initially from in vitro assays. Such information can be used to determine effective doses in humans.
- Therapeutically effective serum levels may be achieved by administering multiple doses. In cases of local administration or selective uptake, the effective local concentration of the proteins may not be related to plasma concentration.
- One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
- the amount of molecules administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the a fiction, the manner of administration and the judgment of the prescribing physician.
- the therapy may be repeated intermittently while symptoms detectable or even when they are not detectable.
- the therapy may be provided alone or in combination with other drugs or treatment (including surgery).
- a therapeutically effective dose of the molecules described herein will provide therapeutic benefit without causing substantial toxicity.
- Toxicity of the molecules described herein can be determined by standard pharmaceutical procedures in cell cultures and experimental animals (LD50, LD100). The dose ratio between toxic and therapeutic effect is the therapeutic index. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in human. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition, such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration.
- an effective amount of the antago-miR-155 of the present invention is administered to a cell, which may or may not be an animal.
- a therapeutically effective amount of the antago-miR-155 of the present invention is administered to an individual for the treatment of disease or condition.
- the term "effective amount" as used herein is defined as the amount of the antago-miR-155 molecule or any molecule, an equivalent such as a source of an antago-miR with capability to inhibit/suppress/block of miR-155 that are necessary to result in the desired physiological change in the cell or tissue to which it is administered.
- terapéuticaally effective amount is defined as the amount of the molecule of antago-miR-155 that achieves a desired effect with respect to a disease or condition associated with v- src, c-src -tyrosine kinase-induced cancers and/or any disease or condition associated with v-src, c-src-tyrosine kinase pathways.
- an amount of molecule that provides a physiological changes is considered an “effective amount” or a "therapeutically effective amount.”
- antago-miR-155 sequence may differ in the in vivo tests as compared to the human sequence.
- antago-miRNA that differs from the human sequence might be used to demonstrate therapeutic effect in the animal.
- Results obtained with this sequence tested in an animal may be extrapolated expected results in human with a corresponding antago-miRNA molecule.
- the nucleic acid molecule of the invention may be administered to a subject alone or in the form of a pharmaceutical composition for the treatment of a condition or disease.
- Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the antago-miR-155 into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- the antago-miR-155 may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
- Systemic formulations include those designed for administration by injection (subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal), as well as those designed for transdermal, transmucosal, inhalation, oral or pulmonary administration.
- antago-miR-155 may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
- the solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the nucleic acid molecule may be in powder form for constitution with a sterile pyrogen-free water, before use.
- the nucleic acid can be readily formulated by combining the molecule with pharmaceutically acceptable carriers.
- Such carriers enable the nucleic acid of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
- solid dosage forms may be sugar-coated or enteric- coated using standard techniques.
- the molecules may take the form of tablets, lozenges, etc. formulated in conventional manner.
- the molecule for use according to the present invention are conveniently delivered in the form of an aerosol spray. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
- the RNA molecules may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas.
- the molecule may also be formulated as a depot preparation.
- Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- other pharmaceutical delivery systems may be employed.
- the present invention involves in some embodiments delivering a nucleic acid into a cell to be related to a therapeutic application.
- Direct by direct delivery of nucleic acid by injection (U.S. Patent Nos. 5,981,274, 5780448A, 5736524A and 5702932A), including microinjection (US5789215A); by electroporation (US5384253A); by direct sonic loading (Fechheimer et al, 1987); by micro projectile bombardment (U.S. Patent Nos. 5610042A, 5550318A, 5538877 A);
- a vector that is a carrier nucleic acid molecule into which a nucleic acid sequence can be inserted; Using avidin fusion proteins (US6287792B1); by calcium phosphate precipitation (Graham and Van Der Eb, 1973; Rippe et al, 1990); by using DEAE -dextran followed by polyethylene glycol (US7122384B2); by liposome mediated transfection (U.S. Patent Nos. 5049388A and US6120798A, JP6382380B2); by photochemical internalization (W02008007073A2); by agitation with silicon carbide fibers (US5302523A); by PEG-mediated transformation of protoplasts (US4684611A);
- lipids such as DOTAP (or other cationic lipid), DDAB, DHDEAB, and DOPE and (2) non-lipid-based polymers like polyethylenimine, polyamidoamine, and dendrimers of these and other polymers.
- DOTAP cationic lipid
- DDAB DDAB
- DHDEAB DHDEAB
- DOPE non-lipid-based polymers like polyethylenimine, polyamidoamine, and dendrimers of these and other polymers.
- non-lipid-based polymers like polyethylenimine, polyamidoamine, and dendrimers of these and other polymers.
- DOTAP DOTAP
- cholesterol or a cholesterol derivative US6770291B2
- Carriers that stabilize and/or transport nucleic acids within cells enhance the stability and activity of nucleic acids because they should protect and guide the bound oligonucleotides once they are in cells.
- PNVP poly(N-vinylpyrrolidone)
- DDMC® cationic graft-copolymer
- JP2017149787A non-viral transfection reagent
- compositions of the present invention comprise an effective amount of antago-miR-155 molecule dissolved or dispersed in a pharmaceutically acceptable carrier.
- pharmaceutically acceptable refers to molecular entities and compositions that do not produce or produce acceptable adverse, allergic or other undesired reactions when administered to an animal, such as, for example, a human, as appropriate. Whether certain adverse effects are acceptable is determined based on the severity of the disease. Moreover, for animal or human administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety and purity standards as required by U.S. FDA or EMA Offices of Biological Standards.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof (Remington's Pharmaceutical Sciences).
- preservatives e.g., antibacterial agents, antifungal agents
- isotonic agents e.g., absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof (Remington's Pharmaceutical Sciences).
- the nucleic acid may comprise different types of carriers depending on whether it is to be administered in solid, liquid or aerosol form, and whether it need to be sterile for such routes of administration as injection.
- the present invention can be administered intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, inhalation, injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions, or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art
- the composition may comprise various antioxidants to retard oxidation of one or more component. Additionally, the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents.
- a carrier can be a solvent or dispersion medium comprising but not limited to, water, ethanol, polyol, lipids and combinations.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin; by the maintenance of the required particle size by dispersion in carriers such as, for example liquid polyol or lipids; by the use of surfactants.
- isotonic agents such as, for example, sugars, sodium chloride or combinations thereof.
- oligonucleotides as active medicine component is effective tool in anti-cancer therapy.
- the invention mentioned herein may be combined with standard treatments of disease or condition associated with v-src, c-src-tyrosine kinase cancers such as chemotherapy, radiotherapy or surgery.
- ANOVA A549 cells viability (ANOVA) detected by MTT-test on 7 days after treatment with naked antago-miR-155 10 pl/ml (1), DDMC 5 mg/ml (2), DDMC 7 mg/ml (3), DDMC 10 mg/ml (4)
- C. a Heat maps of the 13 differentially expressed genes levels in two independent microarray studies in A-549 lung adenocarcinoma cells after treatment using complexes of antago-miR-155 with DDMC vector on 11 th , 21 st and 31 st days after transfection. The heat map was produced by hierarchical clustering of the probeset data. Probesets for genes are represented by rows with the gene dendrogram at left.
- mice were treated with ⁇ SEMs (p ⁇ .05) for the following days.
- B Photographs of mice from the control (a.) and 1 st (b.) groups on the 20 th day after tumor inoculation.
- A. Annexin A4 translocation to the nucleus in labeled tumor cells from animals in the 1 st group a. Tumor cells from the control group (24 days after beginning the experiment); b. tumor cells from mice in the 1 st group (16 days after beginning the experiment); c. tumor cells from mice in the 1 st group (24 days after beginning the experiment). (Magnification 60x).
- Human pancreatic ductal adenocarcinoma cell line (ATCC® CRL-1420TM), Human glioblastoma cell line (ATCC® CRL-1620TM), Human neuroblastoma cell line (ATCC® CCL-127TM), Human retinoblastoma cell line (ATCC® HTB-18TM), Human colorectal adenocarcinoma cell line (ATCC HTB-37TM), Human lung non-small adenocarcinoma cell line (ATCC® CCL-185TM), RSV (Prague C strain)-induced (NCBI_TaxID: 11888) RVP3 cell line (RRID: CVCL_L978).
- ATCC® CRL-1420TM Human glioblastoma cell line
- Human neuroblastoma cell line (ATCC® CCL-127TM)
- Human retinoblastoma cell line (ATCC® HTB-18TM)
- Human colorectal adenocarcinoma cell line (AT
- Dulbecco Modified Eagle Medium (DMEM) medium, with 10% Fetal Bovine Serum, 2 mM 1-glutamine, 100 mg/ml penicillin, and 100 ME/ml streptomycin (GE Healthcare); Cationic graft-copolymer DDMC Vector® (2-diethylaminoethyl-dextran methyl methacrylate copolymer), a non-viral transfection reagent developed by Ryujyu Science Corp. (Aichi, Japan); The pmKate2-Annexin vector (mouse) was purchased by SID ALEX GROUP, s.r.o.
- Example 1 Toxicity of antago-miR-155 with DDMC carrier, toxicity of antago-miR-155 with PNVP delivery system
- active compound antago-miR-155 was incorporated in two polymer carriers: in amphiphilic PNVP and in DDMC to choose the best polymer carrier with minimal toxicity and optimal transfection effectivity. These two complexes form the nanoparticle formulations of average diameter 100-500 nm. Administering naked nucleic acids is challenging due to their rapid degradation by RNases within and outside of cells. Method. MTT Assay. The MTT assay was used to evaluate all the cell lines described above and human monocytes and lymphocytes, and toxicity was evaluated at 8 days after transfection. The MTT assay method employed was that of da Silva Gasque, et al.
- DMSO dimethyl sulfoxide
- results The results of the two-way ANOVA revealed a strongly significant interactions (p ⁇ .05) between the doses of the DDMC vector and its toxic effect. Increasing the concentration of the DDMC vector increased its toxic effect on cells. However, the ANOVA results did not reveal such a tendency (p ⁇ .05) for the doses of PNVP and its toxic effect ( Figure I .A.).
- the toxicities of the DDMC and PNVP as delivery systems for the antago-miR-155 were investigated.
- the ANOVA results revealed that the presence of antago-miR-155 significantly affected the toxicity of the DDMC.
- the optimal doses of the DDMC/antago-miR-155 and PNVP/antago-miR-155 complexes that were non-toxic to cells were calculated.
- the recommended starting dose of the DDMC is 10 mg/ml.
- the results of the MTT assay showed that the DDMC was highly toxic at this dose.
- the optimal doses of this carrier for the different cell lines ranged from 5 to 7.5 mg/ml in the cell culture medium. In this concentration range, the level of cell viability was 85-90 %. At a dose of 10 mg/ml, the level of viability of the various cell lines ranged from 30 to 40 %. In the different cell lines, the level of toxicity slightly varied.
- the adhesive cell lines were the most resistant to DDMC-related toxicity.
- the cells that were the most highly resistant to DDMC -based toxicity were the cultured monocytes prepared from the peripheral blood cells of healthy men.
- Example 2 Transfection efficiency of antago-miR-155 with DDMC carrier, transfection efficiency of antago-miR-155 with PNVP delivery system
- the pmKate2-N vector vector, which is a mammalian expression vector encoding the far -red fluorescent protein mKate2 (Evrogene), was used as the nuclear transfection control. (Shcherbo et al, 2007). The cells were incubated for 40 days, with the transfection efficiency dynamics analyzed on days 7, 14, 30 and 40. Fluorescence microscopic images were used to quantitate the transfection efficiency levels before further processing of the cells. The controls were cells not given any treatment and cells treated with unloaded nanoparticles.
- PNVP/pmKate2 and DDMC vector/pmKate2 complexes were used in this study.
- the expression of mKate2 after treatment with the PNVP/pmKate2 complex was detected on day 11 -14.
- the maximum cell transfection rate observed after treatment with PNVP/pmKate2 complex was 98-100 % on the days 21 st -24 th days.
- the duration of transfection after treatment with the DDMC/pmKate2 complex was longer than that following treatment with the PNVP/pmKate2 complex.
- the expression of Kate2 protein continued for 35-40 days and then decreased, whereas the treatment of cells with the PNVP/pmKate2 complex prolonged transfection for 17-21 days. Supplementation of the medium with different doses of serum, ranging from 1 to 20 %, did not affect the transfection efficiency levels of the different cell lines.
- Table 1 Summary characteristics of the DDMC and PNVP as delivery systems for oligonucleotides.
- CaCo2 colorectal adenocarcinoma cells were transformed into CD117+ cells after treatment with antago- miR-155 and PNVP carrier.
- the morphology of the adenocarcinoma cells changed during the dynamic transformation. Cellular and nuclear forms, sizes and number were different when compared with control cells ( Figure 2).
- Cells had apoptotic changes such as: pyknosis of nuclei, apoptotic vesicles in the cytoplasm and in the extracellular medium, and increased cellular size.
- Toxicity The A549 (ATCC® CCL-185TM) human lung adenocarcinoma cell line was used for the MTT test and toxicity was detected 7 days after treatments.
- DDMC complex of DDMC with antago-miR-155 ( Figure 3).
- the concentration of DDMC was 5, 7 and 10 mg/ml of medium.
- the concentration of naked RNA oligonucleotide was 10 pl/ml of medium.
- the concentration of the DDMC complexes was 7 mg/ml of medium plus 10 pl/ml of medium RNA oligonucleotide.
- PCR products were loaded on 1.5 % agarose gel and electrophoresed then stained with Ethidium Bromide, exposed to a gel doc system and quantified with Quantity One Software (Bio-Rad). For comparison inner control - expression of beta-actin gene, and external control for which were used A549 cells without any treatments.
- the DDMC was toxic to cells at a concentration more than 10 pg/ ml ( Figure 3). In my experiments, I used concentration of DDMC 7 mg/ml. The toxicity was decreased after treatment with a complex of the DDMC and oligonucleotide (F observed ⁇ F crit). The transfection efficiency of the DDMC was lower than that particles of PNVP, which were used in previous studies; however, the transfection maximum was reached 11-14 days faster than that of the PNVP complexes (21 days). DDMC based particles in non-toxic concentrations had greater stability and increased cell transfection with low nucleic acid and DDMC concentrations.
- Treated cells had morphological and genetic changes to compare with non-treated cells. They had induced apoptotic genes, inhibited genes activating proliferation and had down-regulated genes controlling metastatic activity. Treated cells expressed markers, which did not expressed control cells without the treatment with antago-miR-155.
- DDMC or PNVP polymers as delivery system prolong the effect of active component (antago-miR-155) until 40 th day providing irreversible transformation of cancerous cells into non-cancerous cell form. These carriers prevent biodegradation of antago-miR-155 ( Figure 3).
- Example 5 Changes of lifespan and tumor growth in treated with antago-miR-155 with DDMC carrier and non-treated mice
- mice were injected subcutaneously in the interscapular region with an optimal concentration of 5xl0 4 of cells in 1 ml of culture medium (DMEM, 10 % FCS, and an antibiotic mixture of 100 pg/ml penicillin-streptomycin and 32 pg/ ml gentamicin).
- the tumors were removed aseptically, freed of necrotic material, minced with scissors and frozen in culture medium with 20 % DMSO. Some samples were very finely minced in PBS for the staining of obtained cells with Leishman-Romanowski dye. All mice were kept in a temperature-controlled environment with a 12-hour light/dark cycle and free access to food and water. Animal care and experimental procedures were conducted in compliance with the Declaration of Helsinki and were approved by an institutional animal care committee.
- mice virus-induced model of human v-src c-src -tyrosine kinase-dependent cancers was used (Bister, 2015; Rubin, 2011).
- c-src -tyrosine kinase-dependent cancers was used (Bister, 2015; Rubin, 2011).
- the full recovery of mice inoculated with RVP3 virus-induced sarcoma cells was attained (the 2 nd group).
- Example 6 In vitro experiments with tumor cells from non-treated mice and mice with one treatment with antago-miR-155 with DDMC (1 st group)
- a portion of the tumor cells from the animals in the control group and the 1 st group was washed with PBS 3 times and put in culture medium. Twenty-four hours later, 10 pl/ml of pmKate2 -Annexin vector (mouse) and 3 pl/ml DDMC were added to the culture medium. Fluorescence was visualized every 72 hours, and images were acquired using fluorescence microscopy for the quantification of labeled cells. The percentage of cells expressing pmKate2 -Annexin deep-red fluorescent protein was calculated in magnification 40x and 60x.
- Immunofluorescence labeling of tumor cells from animals in the 1 st group with CD4+, CD117+ and Oct4+ One portion of the tumor cells from the animals in the control group and the 1 st group was washed with PBS 3 times and air-dried in the air. Then, immunofluorescence labeling was performed. Separated cells were stained with a CD4+/FITC staining reagent, CD117 purified mouse anti-human antibodies, and Oct4+, and were observed and imaged with fluorescence microscopy.
- the cells were stained with the Leishman-Romanowsky method. These cells were labeled with antibodies against CD4+, CD117+, and Oct4. Cells with morphologies corresponding to tumor cells, tumor stem cells, and apoptotic tumor cells were obtained. Immunofluorescence showed the expression of Oct4 and CD117+; however, CD4+ was not expressed in tumor cells from animals in the 1 st group ( Figure 6.B.).
- This invention is disclosure that antago-miR-155 treatment result in transformation of cancer cells into non-cancerous cell form.
- Cells taken from tumors of mice treated with under -optimal dozes of medicine with subsequent treatment in vitro with optimal doses of antago-miR-155 result in morphological changes and due to full transformation of cancerous cells into non-cancerous cell form.
- Example 7 Genetic changes of cells from treated with one (1 st group), two (2 nd group) injections of antago-miR-155 and non-treated (control) mice
- Samples preparations The tumors were removed aseptically, freed of necrotic material, minced with scissors and frozen in culture medium with 20 % DMSO. Spleen and lungs were washed with sterile PBS, cut into small pieces and frozen in culture medium with 20 % DMSO for subsequent RT-PCR. One portion of the cells obtained from different organs after mouse dissections was treated with lysis buffer from the RNeasy mini kit for the further isolation of total RNA, reverse transcription reaction and specific cDNA product amplification. Tumor samples obtained from the animals in the control group and the 1 st group, as well as spleens and lungs from all mice, were used for the RT- PCR analyses.
- PCR products were loaded on a 2 % agarose gel, electrophoresed, stained with ethidium bromide, exposed in a gel doc system and quantified using Quantity One software (Bio -Rad, Germany). For expression comparison, the betaactin gene was used as the internal control.
- mice were obtained the full recovery of mice from Rous sarcoma after two intravenous treatments with antago-miR-155 plus DDMC.
- the epigenetic modifications in tumor cells after antago-miR-155 with DDMC treatment resulted in the full transformation of sarcoma cells into other types of cells.
- the sarcoma cells lost their tumorigenic functions; this change was observed at the morphological and genetic levels.
- the present disclosure provides that, the complex of antago-miR-155 with the DDMC delivery system induced a full recovery from v-src, c-src -tyrosine kinase-induced cancer in mice. Processes of tumor regression were accompanied by the activation/induction of apoptosis and the inhibition of v-src, c-src-tyrosine kinase-associated pathways.
- This invention as proposed, to be adopt the antago-miR-155 as a new medicine for the treatment of v-src, c-src- tyrosine kinase-induced cancers, such as colon, prostate, lung and breast cancers.
- compositions of the present disclosure may comprise antago-miR-155 with pharmaceutically- acceptable carrier as treatment for v-src, c-src-tyrosine kinase-dependent cancers.
- the present disclosure provides that treatment of cancer cells with antago-miR-155 due to transformation of cancer cells into non-cancerous cells. This transformation based on gene expression changes result in cellular morphological transformations.
- mice mus musculus c57bl/6 strain
- sncRNAs Non-coding RNA Res, 2019.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2020/075178 WO2022053130A1 (en) | 2020-09-09 | 2020-09-09 | Antago-mir-155 for treatment of v-src, c-src-tyrosine kinase-induced cancers |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2020/075178 WO2022053130A1 (en) | 2020-09-09 | 2020-09-09 | Antago-mir-155 for treatment of v-src, c-src-tyrosine kinase-induced cancers |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022053130A1 true WO2022053130A1 (en) | 2022-03-17 |
Family
ID=72561753
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2020/075178 WO2022053130A1 (en) | 2020-09-09 | 2020-09-09 | Antago-mir-155 for treatment of v-src, c-src-tyrosine kinase-induced cancers |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2022053130A1 (en) |
Citations (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4684611A (en) | 1982-02-11 | 1987-08-04 | Rijksuniversiteit Leiden | Process for the in-vitro transformation of plant protoplasts with plasmid DNA |
US4704362A (en) | 1977-11-08 | 1987-11-03 | Genentech, Inc. | Recombinant cloning vehicle microbial polypeptide expression |
US5049388A (en) | 1986-11-06 | 1991-09-17 | Research Development Foundation | Small particle aerosol liposome and liposome-drug combinations for medical use |
US5221619A (en) | 1977-11-08 | 1993-06-22 | Genentech, Inc. | Method and means for microbial polypeptide expression |
US5302523A (en) | 1989-06-21 | 1994-04-12 | Zeneca Limited | Transformation of plant cells |
US5384253A (en) | 1990-12-28 | 1995-01-24 | Dekalb Genetics Corporation | Genetic transformation of maize cells by electroporation of cells pretreated with pectin degrading enzymes |
US5538877A (en) | 1990-01-22 | 1996-07-23 | Dekalb Genetics Corporation | Method for preparing fertile transgenic corn plants |
US5550318A (en) | 1990-04-17 | 1996-08-27 | Dekalb Genetics Corporation | Methods and compositions for the production of stably transformed, fertile monocot plants and cells thereof |
US5610042A (en) | 1991-10-07 | 1997-03-11 | Ciba-Geigy Corporation | Methods for stable transformation of wheat |
US5702932A (en) | 1992-07-20 | 1997-12-30 | University Of Florida | Microinjection methods to transform arthropods with exogenous DNA |
US5736524A (en) | 1994-11-14 | 1998-04-07 | Merck & Co.,. Inc. | Polynucleotide tuberculosis vaccine |
US5780448A (en) | 1995-11-07 | 1998-07-14 | Ottawa Civic Hospital Loeb Research | DNA-based vaccination of fish |
US5789215A (en) | 1991-08-20 | 1998-08-04 | Genpharm International | Gene targeting in animal cells using isogenic DNA constructs |
US5981274A (en) | 1996-09-18 | 1999-11-09 | Tyrrell; D. Lorne J. | Recombinant hepatitis virus vectors |
US6120798A (en) | 1997-06-23 | 2000-09-19 | Alza Corporation | Liposome-entrapped polynucleotide composition and method |
US6287792B1 (en) | 1991-06-17 | 2001-09-11 | The Regents Of The University Of California | Drug delivery of antisense oligonucleotides and peptides to tissues in vivo and to cells using avidin-biotin technology |
US6770291B2 (en) | 1996-08-30 | 2004-08-03 | The United States Of America As Represented By The Department Of Health And Human Services | Liposome complexes for increased systemic delivery |
US7005445B2 (en) * | 2001-10-22 | 2006-02-28 | The Research Foundation Of State University Of New York | Protein kinase and phosphatase inhibitors and methods for designing them |
US7122384B2 (en) | 2002-11-06 | 2006-10-17 | E. I. Du Pont De Nemours And Company | Resonant light scattering microparticle methods |
CA2547038A1 (en) | 2005-05-13 | 2006-11-13 | Ethicon Endo-Surgery, Inc. | Apparatus useful for positioning a device on an endoscope |
US7173038B1 (en) | 1999-11-05 | 2007-02-06 | Astrazeneca Ab | Quinazoline derivatives as VEGF inhibitors |
WO2008007073A2 (en) | 2006-07-11 | 2008-01-17 | Pci Biotech As | Method for introducing sirna into cells by photochemical internalisation |
US7417148B2 (en) | 2003-11-06 | 2008-08-26 | Wyeth | 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML) |
US7638615B1 (en) | 2006-01-25 | 2009-12-29 | Evrogen IP Joint Stock Company | Fluorescent proteins and methods for using same |
US20110293653A1 (en) * | 2010-03-11 | 2011-12-01 | University Of Massachusetts | Antagonists of mir-155 for the treatment of inflammatory liver disease |
US8114874B2 (en) | 2005-12-23 | 2012-02-14 | Ariad Pharmaceuticals, Inc. | Substituted acetylenic imidazo[1,2-B]pyridazine compounds as kinase inhibitors |
US20120064122A1 (en) * | 2010-09-13 | 2012-03-15 | David Baltimore | Treatment of autoimmune inflammation using mir-155 |
CN105251008A (en) * | 2015-10-26 | 2016-01-20 | 上海交通大学医学院附属仁济医院 | Application of Micro RNA-155 antagonist in preparation of drug for treating scleroderma |
JP2017149787A (en) | 2012-02-23 | 2017-08-31 | 株式会社リュージュサイエンス | Delivery system of cationic polysaccharides copolymer |
WO2017144109A1 (en) | 2016-02-25 | 2017-08-31 | Remedica Ltd | Dasatinib formulation |
JP6382380B2 (en) | 2009-05-05 | 2018-08-29 | アルブータス・バイオファーマー・コーポレイション | Methods for delivering oligonucleotides to immune cells |
US20180353468A1 (en) * | 2007-07-25 | 2018-12-13 | Eisai R&D Management Co., Ltd. | Multikinase inhibitors for use in the treatment of cancer |
-
2020
- 2020-09-09 WO PCT/EP2020/075178 patent/WO2022053130A1/en active Application Filing
Patent Citations (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4704362A (en) | 1977-11-08 | 1987-11-03 | Genentech, Inc. | Recombinant cloning vehicle microbial polypeptide expression |
US5221619A (en) | 1977-11-08 | 1993-06-22 | Genentech, Inc. | Method and means for microbial polypeptide expression |
US4684611A (en) | 1982-02-11 | 1987-08-04 | Rijksuniversiteit Leiden | Process for the in-vitro transformation of plant protoplasts with plasmid DNA |
US5049388A (en) | 1986-11-06 | 1991-09-17 | Research Development Foundation | Small particle aerosol liposome and liposome-drug combinations for medical use |
US5302523A (en) | 1989-06-21 | 1994-04-12 | Zeneca Limited | Transformation of plant cells |
US5538877A (en) | 1990-01-22 | 1996-07-23 | Dekalb Genetics Corporation | Method for preparing fertile transgenic corn plants |
US5550318A (en) | 1990-04-17 | 1996-08-27 | Dekalb Genetics Corporation | Methods and compositions for the production of stably transformed, fertile monocot plants and cells thereof |
US5384253A (en) | 1990-12-28 | 1995-01-24 | Dekalb Genetics Corporation | Genetic transformation of maize cells by electroporation of cells pretreated with pectin degrading enzymes |
US6287792B1 (en) | 1991-06-17 | 2001-09-11 | The Regents Of The University Of California | Drug delivery of antisense oligonucleotides and peptides to tissues in vivo and to cells using avidin-biotin technology |
US5789215A (en) | 1991-08-20 | 1998-08-04 | Genpharm International | Gene targeting in animal cells using isogenic DNA constructs |
US5610042A (en) | 1991-10-07 | 1997-03-11 | Ciba-Geigy Corporation | Methods for stable transformation of wheat |
US5702932A (en) | 1992-07-20 | 1997-12-30 | University Of Florida | Microinjection methods to transform arthropods with exogenous DNA |
US5736524A (en) | 1994-11-14 | 1998-04-07 | Merck & Co.,. Inc. | Polynucleotide tuberculosis vaccine |
US5780448A (en) | 1995-11-07 | 1998-07-14 | Ottawa Civic Hospital Loeb Research | DNA-based vaccination of fish |
US6770291B2 (en) | 1996-08-30 | 2004-08-03 | The United States Of America As Represented By The Department Of Health And Human Services | Liposome complexes for increased systemic delivery |
US5981274A (en) | 1996-09-18 | 1999-11-09 | Tyrrell; D. Lorne J. | Recombinant hepatitis virus vectors |
US6120798A (en) | 1997-06-23 | 2000-09-19 | Alza Corporation | Liposome-entrapped polynucleotide composition and method |
US7173038B1 (en) | 1999-11-05 | 2007-02-06 | Astrazeneca Ab | Quinazoline derivatives as VEGF inhibitors |
US7005445B2 (en) * | 2001-10-22 | 2006-02-28 | The Research Foundation Of State University Of New York | Protein kinase and phosphatase inhibitors and methods for designing them |
US7122384B2 (en) | 2002-11-06 | 2006-10-17 | E. I. Du Pont De Nemours And Company | Resonant light scattering microparticle methods |
US7417148B2 (en) | 2003-11-06 | 2008-08-26 | Wyeth | 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML) |
CA2547038A1 (en) | 2005-05-13 | 2006-11-13 | Ethicon Endo-Surgery, Inc. | Apparatus useful for positioning a device on an endoscope |
US8114874B2 (en) | 2005-12-23 | 2012-02-14 | Ariad Pharmaceuticals, Inc. | Substituted acetylenic imidazo[1,2-B]pyridazine compounds as kinase inhibitors |
US7638615B1 (en) | 2006-01-25 | 2009-12-29 | Evrogen IP Joint Stock Company | Fluorescent proteins and methods for using same |
WO2008007073A2 (en) | 2006-07-11 | 2008-01-17 | Pci Biotech As | Method for introducing sirna into cells by photochemical internalisation |
US20180353468A1 (en) * | 2007-07-25 | 2018-12-13 | Eisai R&D Management Co., Ltd. | Multikinase inhibitors for use in the treatment of cancer |
JP6382380B2 (en) | 2009-05-05 | 2018-08-29 | アルブータス・バイオファーマー・コーポレイション | Methods for delivering oligonucleotides to immune cells |
US20110293653A1 (en) * | 2010-03-11 | 2011-12-01 | University Of Massachusetts | Antagonists of mir-155 for the treatment of inflammatory liver disease |
US20120064122A1 (en) * | 2010-09-13 | 2012-03-15 | David Baltimore | Treatment of autoimmune inflammation using mir-155 |
JP2017149787A (en) | 2012-02-23 | 2017-08-31 | 株式会社リュージュサイエンス | Delivery system of cationic polysaccharides copolymer |
CN105251008A (en) * | 2015-10-26 | 2016-01-20 | 上海交通大学医学院附属仁济医院 | Application of Micro RNA-155 antagonist in preparation of drug for treating scleroderma |
WO2017144109A1 (en) | 2016-02-25 | 2017-08-31 | Remedica Ltd | Dasatinib formulation |
Non-Patent Citations (45)
Title |
---|
"NCBI", Database accession no. J02342.1. |
"NCBI_TaxID", Database accession no. 11888 |
ABBAS A.K.LICHTMAN A.H.PILLAI S.: "In: Cellular and molecular immunology", vol. 177, 2007, ELSEVIER INC, article "Lymphocyte development and the rearrangement and expression of antigen receptor genes" |
ASEM, vol. 9, 2017, pages 426 - 31 |
BISTER K.: "Discovery of oncogenes: The advent of molecular cancer research", PNAS, vol. 112, 2015, pages 15259 - 60 |
COX D.N.CHAO A.BAKER J.CHANG L.QIAO D.LIN H.: "A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal", GENES DEV, vol. 12, 2008, pages 3715 - 3727, XP002927399 |
DA SILVA GASQUE K.C.AL-AHJ L.P.OLIVEIRA R.C.MAGALHAES A.C.: "Cell density and solvent are critical parameters affecting formazan evaluation in MTT assay", BRAZ. ARCH. BIOL. TECHNOL., vol. 57, 2014, pages 381 |
DATABASE Geneseq [online] 27 August 2015 (2015-08-27), "Anti-miRNA (hsa-miR-155*) oligonucleotide.", XP002803294, retrieved from EBI accession no. GSN:BCC02611 Database accession no. BCC02611 * |
DUE H.SVENDSEN P.BODKER J.S.SCHMITZ A.BOGSTED M.: "miR-155 as a biomarker in B-cell malignancies", BIOMED RESEARCH INT, vol. 2016, no. 14, 2016 |
FECHHEIMER MBOYLAN J.F.PARKER S.SISKEN J.E.PATEL G.L.ZIMMER S.G.: "Transfection of mammalian cells with plasmid DNA by scrape loading and sonication loading", PNAS, vol. 84, 1987, pages 8463 - 8467, XP000700111, DOI: 10.1073/pnas.84.23.8463 |
FERNANDEZ S.DESPLAT V.VILLACRECES A.GUITART A.V.MILPIED N.PIGNEUX A.VIGON I.PASQUET J.-M.DUMAS P.-Y.: "Targeting tyrosine kinase in acute myeloid leukemia: Why, who and how?", INT J MOL SCI, vol. 20, no. 14, 2019, pages 3429 |
GARGALIONIS A.N.KARAMOUZIS M.V.PAPAVASSILIOU A.G.: "The molecular rationale of Src inhibition in colorectal carcinomas", INT J CANCER, vol. 134, 2014, pages 2019 - 29, XP055519764, DOI: 10.1002/ijc.28299 |
GIGLIONE C.GONFLONI S.PARMEGGIANI A.: "Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm", EUR J BIOCHEM, vol. 268, 2001, pages 3275 - 83 |
GRAHAM F.LVAN DER EB A.J.: "A new technique for the assay of infectivity of human adenovirus 5 DNA", VIROLOGY, vol. 52, 1973, pages 456 - 67, XP023052128, DOI: 10.1016/0042-6822(73)90341-3 |
HANAHAN DWEINBERG R.A.: "Hallmarks of cancer: The next generation", CELL, vol. 144, 2011, pages 646 - 674, XP028185429, DOI: 10.1016/j.cell.2011.02.013 |
HANNA J.SAHA K.PANDO B.VAN ZON J.LENGNER C.J.CREYGHTON M.P.VAN OUDENAARDEN A.JAENISCH R.: "Direct cell reprogramming is a stochastic process amenable to acceleration", NAT, vol. 462, 2009, pages 595 - 601, XP055014858, DOI: 10.1038/nature08592 |
HUFFAKER T.B.O'CONNELL R.M.: "miR-155 - SOCS1 as a functional axis: satisfying the burden of proof", IMMUNITY, vol. 43, 2015, pages 3 - 4 |
IRBY R.B.YEATMAN T.J.: "Role of Src expression and activation in human cancers", ONCOGENE, vol. 19, 2000, pages 5636 - 42 |
KACZKOWSKI B.TANAKA Y.KAWAJI H.SANDELIN A.ANDERSSON R.: "Transcriptome analysis of recurrently deregulated genes across multiple cancers identifies new pan-cancer biomarkers", CANCER RES, vol. 76, 2016, pages 216 - 226, XP055368841, DOI: 10.1158/0008-5472.CAN-15-0484 |
KLIMENKO O.V.SHTILMAN M.I.: "Reprogramming of CaCo2 colorectal cancer cells into CD4+ cells.", TOX. REP., 2019 |
KLIMENKO O.V.SIDOROV A.V.: "The full recovery of mice (mus musculus c57bl/6 strain) from virus-induced sarcoma after treatment with a complex of DDMC delivery system and sncRNAs", NON-CODING RNA RES, 2019 |
KLIMENKO OXANA V. ET AL: "The full recovery of mice (Mus Musculus C57BL/6 strain) from virus-induced sarcoma after treatment with a complex of DDMC delivery system and sncRNAs", NON-CODING RNA RESEARCH, vol. 4, no. 2, 1 June 2019 (2019-06-01), pages 69 - 78, XP055810409, ISSN: 2468-0540, DOI: 10.1016/j.ncrna.2019.03.001 * |
LAM J.K.W.CHOW M.Y.T.ZHANG Y.LEUNG S.W.S.: "siRNA versus miRNA as therapeutic for gene silencing", MOL THER-NUCLEIC ACIDS, vol. 4, 2015, pages e252 |
LEWIS S.M.KUMARI S.: "Guidelines on standard operating procedures for hematology", WHO, 2000, pages 41 - 47 |
LYTLE J.R.YARIO T.A.STEITZ J.A.: "Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5'UTR as in the 3'UTR", PNAS, vol. 104, 2007, pages 9667 - 9672 |
NAIDU SGAROFALO M.: "MicroRNAs: an emerging paradigm in lung cancer chemoresistance", FRONTIER MED, vol. 2, 2015, pages 77 - 84 |
NATH S.GHATAK D.DAS P.ROYCHOUDHURY S.: "Transcriptional control of mitosis: deregulation and cancer", FRONTIER ENDOCRINOL, vol. 6, 2015, pages 1 - 10 |
NISHIKAWA S.ISHII H.HARAGUCHI N.KANO Y.FUKUSUMI T.: "microRNA-based cancer cell reprogramming technology", EXP HER MED, vol. 4, 2012, pages 8 - 14 |
NISHIKAWA S.ISHII H.HARAGUCHI N.KANO Y.FUKUSUMI T.: "MicroRNA-based cancer cell reprogramming technology", EXP THER MED, vol. 4, 2012, pages 8 - 14 |
PUIS L.N.EADENS M.MESSERSMITH W.: "Current status of Src inhibitors in solid tumor malignancies", ONCOLOGIST, vol. 16, 2011, pages 566 - 78 |
REMINGTON J.P.GENNARO A.R.: "Remington's Pharmaceutical Sciences", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329 |
RIPPE R.A.BRENNER D.A.LEFFERT H.L.: "DNA-mediated gene transfer into adult rat hepatocytes in primary culture", MOL CELL BIOL, vol. 10, 1990, pages 689 - 95 |
ROTHSCHILD S.I.GAUTSCHI O.: "Src kinase inhibitors in the treatment of lung cancer: rationale and clinical data", CLIN INVEST, vol. 2, 2012, pages 387 - 396 |
RUBIN H.: "The early history of tumor virology: Rous, RIF, and RAV.", PNAS, vol. 108, 2011, pages 14389 - 96 |
RYNDITCH A.V.GERIK I.LGOTAK V.YATSULA B.A.SVOBODA J.: "Absence of the avian sarcoma virus genes in the transformed mammalian cells", BIOPLOLYMERS CELL, vol. 1, 1985, pages 92 - 8 |
SAINEROVA H.SVOBODA J.: "Stability of C-banded and C-bandless microchromosomes in clonal sublines of the RVP3 mouse tumor grown serially in vivo", CANCER GENETICS CYTOGENETICS, vol. 3, 1981, pages 93 - 9, XP025212871, DOI: 10.1016/0165-4608(81)90063-7 |
SHCHERBO D.MERZLYAK E.M.CHEPURNYKH T.VFRADKOV A.F.ERMAKOVA G.V.SOLOVIEVA E.A.LUKYANOV K.A.BOGDANOVA E.A.ZARAISKY A.G.LUKYANOV S.: "Bright far-red fluorescent protein for whole-body imaging", NAT METH, vol. 4, 2007, pages 741, XP002497715, DOI: 10.1038/NMETH1083 |
SUDOL M.: "From Rous sarcoma virus to plasminogen activator, src oncogene and cancer management", ONCOGENE, vol. 30, 2011, pages 3003 - 10 |
VARAMBALLY S.CAO Q.MANI R.S.SHANKAR S.WANGX.ATEEQ B.: "Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer", SCI, vol. 322, 2008, pages 1695 - 1699 |
VARKARIS A.KATSIAMPOURA A.D.ARAUJO J.C.GALLICK G.E.CORN P.G.: "Src signaling pathways in prostate cancer", CANCER METASTASIS REV, vol. 33, 2014, pages 595 - 606 |
VOLINIA S.CALIN G.A.LIU C.G.AMBS S.CIMMINO A. A: "microRNA expression signature of human solid tumors defines cancer gene targets", PNAS, vol. 103, 2006, pages 2257 - 2261 |
WAN J.XIA L.XU W.LU N.: "Expression and function of miR-155 in diseases of the gastrointestinal tract", INT J MOL SCI, vol. 17, 2016, pages 709 |
WANG F.ZHOU J.ZHANG Y.WANG Y.CHENG L.: "The prognostic value of miR-21 and miR-155 in non-small-cell lung cancer: a meta-analysis", PLOS ONE, vol. 43, 2015, pages 813 - 820 |
ZANG Y.S.ZHONG Y.F.FANG Z.LI B.AN J.: "MiR-155 inhibits the sensitivity of lung cancer cells to cisplatin via negative regulation of Apaf-1 expression", CANCER GENE THER, vol. 19, 2012, pages 773 - 778 |
ZHANG S.HUANG W.C.ZHANG L.LOWERY F.J.DING Z.GUO H.WANG H.HUANG S.SAHIN A.A.ALDAPE K.D.: "SRC family kinases as novel therapeutic targets to breast cancer brain metastases", CANCER RES, vol. 73, 2013, pages 5764 - 74 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018214137B2 (en) | MiRNA and its diagnostic therapeutic uses in diseases or conditions associated with melanoma, or in diseases or conditions associated with activated BRAF pathway | |
Zhang et al. | Combination treatment with doxorubicin and microRNA-21 inhibitor synergistically augments anticancer activity through upregulation of tumor suppressing genes | |
AU2017353907B2 (en) | 5-halouracil-modified microRNAs and their use in the treatment of cancer | |
Yang et al. | The role of miR-100-mediated Notch pathway in apoptosis of gastric tumor cells | |
US20210038732A1 (en) | Anticancer microrna and lipid formulations thereof | |
Zhang et al. | MicroRNA‑3653 inhibits the growth and metastasis of hepatocellular carcinoma by inhibiting ITGB1 | |
Zhao et al. | Raltitrexed inhibits HepG2 cell proliferation via G0/G1 cell cycle arrest | |
WO2021028081A1 (en) | New treatments involving mirna-193a | |
CA2812650C (en) | Use of mirnas for the diagnosis, prophylaxis, treatment and follow-up of diseases involving macroautophagy abnormalities | |
US11236337B2 (en) | 5-halouracil-modified microRNAs and their use in the treatment of cancer | |
WO2022053130A1 (en) | Antago-mir-155 for treatment of v-src, c-src-tyrosine kinase-induced cancers | |
Mu et al. | Expression of miR-124 in gastric adenocarcinoma and the effect on proliferation and invasion of gastric adenocarcinoma SCG-7901 cells | |
US20220090076A1 (en) | 5-halouracil-modified micrornas and their use in the treatment of cancer | |
Huang et al. | Effects of hTERT antisense oligodeoxynucleotide on cell apoptosis and expression of hTERT and bcl-2 mRNA in keloid fibroblasts. | |
US20230136088A1 (en) | miRNA-193a for Promoting Immunogenic Cell Death | |
CN113476606A (en) | Application of UPK1A-AS1 inhibitor in preparation of antitumor drugs | |
Klimenko et al. | The full recovery of mice (Mus Musculus C57BL/6 strain) from virus–induced sarcoma after treatment with a complex of DDMC delivery system and sncRNAs | |
US10087444B2 (en) | MicroRNA composition for the treatment of neuroblastoma | |
CN111534516B (en) | Target inhibitor of SNORD83A gene and application thereof | |
Tselios et al. | Signaling pathways that overactivate metabolism and drive neoplasia, in rhabdomyosarcoma. | |
CA3175539A1 (en) | Modified short-interfering rna compositions and their use in the treatment of cancer | |
Camero | Expression levels and role of the de novo DNA methyltransferases in rhabdomyosarcoma | |
Cunha | On the development of a novel targeted miRNA-based therapy towards glioblastoma | |
EP2358372A1 (en) | Microrna-mediated regulation of ubc9 expression in cancer cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20775205 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2020775205 Country of ref document: EP Effective date: 20230411 |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 20775205 Country of ref document: EP Kind code of ref document: A1 |