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A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets

Li, Xiang; Huang, Chun-Hao; Sánchez-Rivera, Francisco J; Kennedy, Margaret C; Tschaharganeh, Darjus F; Morris, John P; Montinaro, Antonella; ... Lowe, Scott W; + view all (2022) A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets. Proceedings of the National Academy of Sciences , 119 (17) , Article e2110557119. 10.1073/pnas.2110557119. Green open access

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Abstract

SignificanceMany new cancer drugs fail at the clinical stage owing to poor efficacy and/or excessive toxicity, though whether this reflects shortcomings of the target or the drug is often unclear. To gain earlier insights into factors that can influence the therapeutic index of target inhibition in vivo, we combine inducible RNA interference and somatic engineering technologies to produce a cost-effective platform that enables systemic and inducible suppression of candidate target in normal tissues and tumor cells in the same mouse. By comparing the consequences of genetic and pharmacological CDK9 inhibition, we establish the utility of this platform to predict factors influencing the therapeutic index. Additionally, our studies provide support, and some cautionary notes, for the clinical development of CDK9 inhibitors.

Type: Article
Title: A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.2110557119
Publisher version: https://doi.org/10.1073/pnas.2110557119
Language: English
Additional information: Copyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Keywords: CDK9, hepatocellular carcinoma, mouse model, preclinical platform, Animals, Antineoplastic Agents, Cell Line, Tumor, Cyclin-Dependent Kinase 9, Mice, Neoplasms, RNA Interference
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10147825
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