Discovery of tumoricidal DNA oligonucleotides by response-directed in vitro evolution

Noam Mamet, Yaniv Amir, Erez Lavi, Liron Bassali, Gil Harari, Itai Rusinek, Nir Skalka, Elinor Debby, Mor Greenberg, Adva Zamir, Anastasia Paz, Neria Reiss, Gil Loewenthal, Irit Avivi, Avichai Shimoni, Guy Neev, Almogit Abu-Horowitz, Ido Bachelet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number29
JournalCommunications Biology
Volume3
Issue number1
DOIs
StatePublished - 1 Dec 2020

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