Discovery of tumoricidal DNA oligonucleotides by response-directed in vitro evolution
Drug discovery is challenged by ineffectiveness of drugs against variable and evolving diseases, and adverse effects due to poor selectivity. We describe a robust platform which potentially addresses these limitations. The platform enables rapid discovery of DNA oligonucleotides evolved in vitro for...
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| Veröffentlicht in: | Communications biology 2020-01, Vol.3 (1), p.29-29, Article 29 |
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| creator | Mamet, Noam Amir, Yaniv Lavi, Erez Bassali, Liron Harari, Gil Rusinek, Itai Skalka, Nir Debby, Elinor Greenberg, Mor Zamir, Adva Paz, Anastasia Reiss, Neria Loewenthal, Gil Avivi, Irit Shimoni, Avichai Neev, Guy Abu-Horowitz, Almogit Bachelet, Ido |
| description | Drug discovery is challenged by ineffectiveness of drugs against variable and evolving diseases, and adverse effects due to poor selectivity. We describe a robust platform which potentially addresses these limitations. The platform enables rapid discovery of DNA oligonucleotides evolved in vitro for exerting specific and selective biological responses in target cells. The process operates without a priori target knowledge (mutations, biomarkers, etc). We report the discovery of oligonucleotides with direct, selective cytotoxicity towards cell lines, as well as patient-derived solid and hematological tumors. A specific oligonucleotide termed E8, induced selective apoptosis in triple-negative breast cancer (TNBC) cells. Polyethylene glycol-modified E8 exhibited favorable biodistribution in animals, persisting in tumors up to 48-hours after injection. E8 inhibited tumors by 50% within 10 days of treatment in patient-derived xenograft mice, and was effective in ex vivo organ cultures from chemotherapy-resistant TNBC patients. These findings highlight a drug discovery model which is target-tailored and on-demand.
Noam Mamet et al. describe a platform for rapid de novo discovery of DNA oligonucleotides that directly and selectively induce apoptosis in cancer cells. They report target-tailored discovery of tumoricidal oligonucleotides against tumor cell lines as well as patient-derived tumors. |
| doi_str_mv | 10.1038/s42003-020-0756-0 |
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Noam Mamet et al. describe a platform for rapid de novo discovery of DNA oligonucleotides that directly and selectively induce apoptosis in cancer cells. 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Noam Mamet et al. describe a platform for rapid de novo discovery of DNA oligonucleotides that directly and selectively induce apoptosis in cancer cells. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Communications biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mamet, Noam</au><au>Amir, Yaniv</au><au>Lavi, Erez</au><au>Bassali, Liron</au><au>Harari, Gil</au><au>Rusinek, Itai</au><au>Skalka, Nir</au><au>Debby, Elinor</au><au>Greenberg, Mor</au><au>Zamir, Adva</au><au>Paz, Anastasia</au><au>Reiss, Neria</au><au>Loewenthal, Gil</au><au>Avivi, Irit</au><au>Shimoni, Avichai</au><au>Neev, Guy</au><au>Abu-Horowitz, Almogit</au><au>Bachelet, Ido</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of tumoricidal DNA oligonucleotides by response-directed in vitro evolution</atitle><jtitle>Communications biology</jtitle><stitle>Commun Biol</stitle><stitle>COMMUN BIOL</stitle><addtitle>Commun Biol</addtitle><date>2020-01-15</date><risdate>2020</risdate><volume>3</volume><issue>1</issue><spage>29</spage><epage>29</epage><pages>29-29</pages><artnum>29</artnum><issn>2399-3642</issn><eissn>2399-3642</eissn><abstract>Drug discovery is challenged by ineffectiveness of drugs against variable and evolving diseases, and adverse effects due to poor selectivity. We describe a robust platform which potentially addresses these limitations. The platform enables rapid discovery of DNA oligonucleotides evolved in vitro for exerting specific and selective biological responses in target cells. The process operates without a priori target knowledge (mutations, biomarkers, etc). We report the discovery of oligonucleotides with direct, selective cytotoxicity towards cell lines, as well as patient-derived solid and hematological tumors. A specific oligonucleotide termed E8, induced selective apoptosis in triple-negative breast cancer (TNBC) cells. Polyethylene glycol-modified E8 exhibited favorable biodistribution in animals, persisting in tumors up to 48-hours after injection. E8 inhibited tumors by 50% within 10 days of treatment in patient-derived xenograft mice, and was effective in ex vivo organ cultures from chemotherapy-resistant TNBC patients. These findings highlight a drug discovery model which is target-tailored and on-demand.
Noam Mamet et al. describe a platform for rapid de novo discovery of DNA oligonucleotides that directly and selectively induce apoptosis in cancer cells. They report target-tailored discovery of tumoricidal oligonucleotides against tumor cell lines as well as patient-derived tumors.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31941992</pmid><doi>10.1038/s42003-020-0756-0</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-1089-1172</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 38/23 38/47 631/154 631/1647/2163 Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Base Sequence Biology Biomedical and Life Sciences Breast cancer Cell Line, Tumor Cells, Cultured Chemotherapy Cytotoxicity Deoxyribonucleic acid Disease Models, Animal DNA Drug discovery Drug Discovery - methods Drug Screening Assays, Antitumor High-Throughput Nucleotide Sequencing Humans Kinases Life Sciences Life Sciences & Biomedicine Life Sciences & Biomedicine - Other Topics Mice Models, Molecular Molecular Conformation Multidisciplinary Sciences Nucleic Acid Conformation Oligodeoxyribonucleotides - chemistry Oligodeoxyribonucleotides - pharmacology Oligodeoxyribonucleotides - therapeutic use Oligonucleotides Polyethylene glycol Science & Technology Science & Technology - Other Topics Structure-Activity Relationship Tissue Distribution Tumor cell lines Tumors Xenograft Model Antitumor Assays Xenografts |
| title | Discovery of tumoricidal DNA oligonucleotides by response-directed in vitro evolution |
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