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Clin Cancer Res. 2010 Dec 15;16(24):6150-8. doi: 10.1158/1078-0432.CCR-10-1932. Epub 2010 Nov 1.

Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study.

Author information

1
Department of Medical Oncology, University of Oxford, Oxford Radcliffe Hospitals NHS Trust, Oxford, United Kingdom. denis.talbot@medonc.ox.ac.uk

Erratum in

  • Clin Cancer Res. 2011 Apr 15;17(8):2602.

Abstract

PURPOSE:

Enhanced tumor cell survival through expression of inhibitors of apoptosis (IAP) is a hallmark of cancer. Survivin, an IAP absent from most normal tissues, is overexpressed in many malignancies and associated with a poorer prognosis. We report the first-in-human dose study of LY2181308, a second-generation antisense oligonucleotide (ASO) directed against survivin mRNA.

PATIENTS AND METHODS:

A dose-escalation study evaluating the safety, pharmacokinetics, and pharmacodynamics of LY2181308 administered intravenously for 3 hours as a loading dose on 3 consecutive days and followed by weekly maintenance doses. Patients were eligible after signing informed consent, had exhausted approved anticancer therapies and agreed to undergo pre- and posttreatment tumor biopsies to evaluate reduction of survivin protein and gene expression.

RESULTS:

A total of 40 patients were treated with LY2181308 at doses of 100 to 1,000 mg. Twenty-six patients were evaluated at the recommended phase 2 dose of 750 mg, at which level serial tumor sampling and [(11)C]LY2183108 PET (positron emission tomography) imaging demonstrated that ASO accumulated within tumor tissue, reduced survivin gene and protein expression by 20% and restored apoptotic signaling in tumor cells in vivo. Pharmacokinetics were consistent with preclinical modeling, exhibiting rapid tissue distribution, and terminal half-life of 31 days.

CONCLUSIONS:

The tumor-specific, molecularly targeted effects demonstrated by this ASO in man underpin confirmatory studies evaluating its therapeutic efficacy in cancer.

PMID:
21041181
DOI:
10.1158/1078-0432.CCR-10-1932
[Indexed for MEDLINE]
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