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

PloS One
Nicole BäumerSebastian Bäumer

Abstract

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 EGF...Continue Reading

References

Jun 28, 2001·Oncogene·J Mendelsohn, J Baselga
Jul 23, 2004·The New England Journal of Medicine·David CunninghamEric Van Cutsem
Jun 14, 2005·Cancer Cell·Yardena SamuelsVictor E Velculescu
Apr 19, 2006·Cancer Research·Astrid LièvrePierre Laurent-Puig
Sep 5, 2008·Annual Review of Pathology·Nader Chalhoub, Suzanne J Baker
Apr 3, 2009·The New England Journal of Medicine·Eric Van CutsemPhilippe Rougier
Oct 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Martin L SosRoman K Thomas
Sep 11, 2010·Molecular Cancer·Tianhui Hu, Cunxi Li
Oct 20, 2010·Oncogene·E F DunnD L Wheeler
Nov 17, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Fabio Petrocca, Judy Lieberman
Jan 27, 2011·Cancer Research·Xiaoyan WangRosalie C Sears
Nov 18, 2011·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Lars Henning SchmidtCarsten Muller-Tidow
Feb 24, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiaoyun LiaoShuji Ogino
Jul 20, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Oct 3, 2012·Methods in Molecular Biology·Vineeth SurendranathFrank Buchholz
Mar 30, 2013·Science·Bert VogelsteinKenneth W Kinzler
Dec 24, 2013·Trends in Pharmacological Sciences·Min HuangMeiyu Geng
Jan 24, 2014·The New England Journal of Medicine·Richard R FurmanSusan M O'Brien
Jun 13, 2014·Science Translational Medicine·Sherry Y WuAnil K Sood
Aug 8, 2014·Cancer Discovery·Tina L YuanScott W Lowe
Dec 24, 2014·Nature Reviews. Cancer·Lauren M ThorpeJean J Zhao
Jan 16, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sebastian BäumerCarsten Müller-Tidow
May 16, 2015·Trends in Pharmacological Sciences·Peng WuMads H Clausen
Jun 29, 2015·Current Opinion in Pharmacology·Timothy A YapPaul Workman
Aug 13, 2015·Nature·Shany KorenMohamed Bentires-Alj
Aug 13, 2015·Nature·Alexandra Van KeymeulenCédric Blanpain
Sep 15, 2015·Acta Pharmacologica Sinica·Xiang WangLing-hua Meng
Sep 26, 2015·International Journal of Molecular Sciences·Sally TemrazAli Shamseddine
Nov 4, 2015·Annual Review of Pharmacology and Toxicology·John S Lazo, Elizabeth R Sharlow
Dec 4, 2015·Nature Protocols·Nicole BäumerSebastian Bäumer
Jan 23, 2016·OncoTargets and Therapy·Cristian MassacesiSamit Hirawat
Feb 11, 2016·PloS One·Alexander E YuehDustin A Deming
Jul 21, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·Z B MeiS Ogino
Jan 5, 2017·Nature Reviews. Cancer·Rodrigo DienstmannJosep Tabernero

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Methods Mentioned

BETA
GTPase
transgenic
gel filtration
xenograft
xenografts

Software Mentioned

esiRNA
NIH Image J

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