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Downregulation of PIK3CA via antibody-esiRNA-complexes suppresses human xenograft tumor growth

Precision cancer therapy requires on the one hand detailed knowledge about a tumor’s driver oncogenes and on the other hand an effective targeted therapy that specifically inhibits these oncogenes. While the determination of genomic landscape of a tumor has reached a very precise level, the respecti...

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Hauptverfasser: Bäumer, Nicole (VerfasserIn) , Rehkämper, Jan (VerfasserIn) , Appel, Neele (VerfasserIn) , Terheyden, Lisa (VerfasserIn) , Hartmann, Wolfgang (VerfasserIn) , Wardelmann, Eva (VerfasserIn) , Buchholz, Frank (VerfasserIn) , Müller-Tidow, Carsten (VerfasserIn) , Berdel, Wolfgang E. (VerfasserIn) , Bäumer, Sebastian (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: July 12, 2018
In: PLOS ONE
Year: 2018, Jahrgang: 13, Heft: 7, Pages: 1-22
ISSN:1932-6203
DOI:10.1371/journal.pone.0200163
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.pone.0200163
Verlag, lizenzpflichtig, Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200163
Volltext
Verfasserangaben:Nicole Bäumer, Jan Rehkämper, Neele Appel, Lisa Terheyden, Wolfgang Hartmann, Eva Wardelmann, Frank Buchholz, Carsten Müller-Tidow, Wolfgang E. Berdel, Sebastian Bäumer
Beschreibung
Zusammenfassung:Precision cancer therapy requires on the one hand detailed knowledge about a tumor’s driver oncogenes and on the other hand an effective targeted therapy that specifically inhibits these oncogenes. While the determination of genomic landscape of a tumor has reached a very precise level, the respective therapy options are scarce. The application of small inhibitory (si) RNAs is a promising field of investigation. Here, we present the effective in vivo-treatment of colorectal cancer (CRC) xenograft tumors with antibody-complexed, endoribonuclease-prepared small inhibitory (esi)RNAs. We chose heterogeneous endoribonuclease-prepared siRNA pools (esiRNAs) against the frequently mutated genes PIK3CA and KRAS and coupled them to the anti-EGFR antibody cetuximab, which was internalized specifically into the tumor cells. esiRNA pools have been shown to exhibit superior specificity in target gene knockdown compared to classic siRNAs. We identified a significant decrease in tumor growth upon this treatment due to decreased tumor cell proliferation. The ex vivo-analysis of the xenograft CRC tumors revealed the expected downregulation of the intended direct targets PIK3CA and KRAS on protein level. Moreover, known downstream targets for EGFR signaling such as p-ERK, p-AKT, and c-MYC were decreased as well. We therefore propose the use of antibody-esiRNA complexes as a novel experimental treatment option against key components of the EGFR signaling cascade.
Beschreibung:Gesehen am 22.06.2020
Beschreibung:Online Resource
ISSN:1932-6203
DOI:10.1371/journal.pone.0200163

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