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First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement.

Abstract：

UNLABELLED:RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer. SIGNIFICANCE:The fi ndings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel fi rst-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specifi c multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Tabernero J,Shapiro GI,LoRusso PM,Cervantes A,Schwartz GK,Weiss GJ,Paz-Ares L,Cho DC,Infante JR,Alsina M,Gounder MM,Falzone R,Harrop J,White AC,Toudjarska I,Bumcrot D,Meyers RE,Hinkle G,Svrzikapa N,Hutabarat RM,Cl

doi

10.1158/2159-8290.CD-12-0429

subject

Has Abstract

pub_date

2013-04-01 00:00:00

pages

406-17

issue

4

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-12-0429

journal_volume

3

pub_type

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