First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement Journal Article
| Authors: | Tabernero, J.; Shapiro, G. I.; LoRusso, P. M.; Cervantes, A.; Schwartz, G. K.; Weiss, G. J.; Paz-Ares, L.; Cho, D. C.; Infante, J. R.; Alsina, M.; Gounder, M. M.; Falzone, R.; Harrop, J.; White, A. C. S.; Toudjarska, I.; Bumcrot, D.; Meyers, R. E.; Hinkle, G.; Svrzikapa, N.; Hutabarat, R. M.; Clausen, V. A.; Cehelsky, J.; Nochur, S. V.; Gamba-Vitalo, C.; Vaishnaw, A. K.; Sah, D. W. Y.; Gollob, J. A.; Burris, H. A. 3rd |
| Article Title: | First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement |
| Abstract: | 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 findings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel first-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specific multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology. ©2013 American Association for Cancer Research. |
| Keywords: | vasculotropin; adult; clinical article; controlled study; human tissue; protein expression; aged; middle aged; vascular endothelial growth factor a; unclassified drug; human cell; disease course; fatigue; splenectomy; drug dose reduction; drug safety; nonhuman; recommended drug dose; liver neoplasms; alpha interferon; nuclear magnetic resonance imaging; lymph node metastasis; endometrium cancer; animals; mice; reverse transcription polymerase chain reaction; computer assisted tomography; liver toxicity; multiple cycle treatment; gene expression; interleukin 1 receptor blocking agent; interleukin 1beta; animal model; small interfering rna; rna, small interfering; rna interference; dexamethasone; tumor biopsy; antineoplastic activity; tumor regression; mice, scid; xenograft model antitumor assays; cell line, tumor; histology; asthenia; fever; liver failure; liver metastasis; cytokines; death; tumor necrosis factor alpha; gamma interferon; rna, messenger; paracetamol; liver tumor; interleukin 6; single drug dose; nausea and vomiting; liver resection; nanoparticles; down regulation; liver function test; phase 1 clinical trial; gamma interferon inducible protein 10; blood flow; granulocyte colony stimulating factor; drug tolerance; interleukin 12; kinesin; complement component c4; diphenhydramine; phase 2 clinical trial (topic); ranitidine; hydroxyzine; haplorhini; famotidine; complement component c3; aln vsp; solid lipid nanoparticle |
| Journal Title: | Cancer Discovery |
| Volume: | 3 |
| Issue: | 4 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-04-01 |
| Start Page: | 406 |
| End Page: | 417 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-12-0429 |
| PROVIDER: | scopus |
| PUBMED: | 23358650 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 3 June 2013" - "Source: Scopus" |
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