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

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.

• Authors: Denis C Talbot, Malcolm Ranson, Joanna Davies, Michael Lahn, Sophie Callies, Valérie André, Sunil Kadam, Michael Burgess, Christopher Slapak, Anna L Olsen, Peter J McHugh, Johann S de Bono, Julian Matthews, Azeem Saleem, Patricia Price
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 24 Pg. 6150-8 (Dec 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 21041181 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• LY 2181308
• Microtubule-Associated Proteins
• Oligonucleotides
• Oligonucleotides, Antisense
• Survivin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Evidence-Based Practice
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Genetic Therapy (methods)
• Humans
• Inhibitor of Apoptosis Proteins
• Male
• Microtubule-Associated Proteins (antagonists & inhibitors, genetics)
• Middle Aged
• Molecular Targeted Therapy
• Neoplasms (genetics, therapy)
• Oligonucleotides (administration & dosage, pharmacokinetics, pharmacology)
• Oligonucleotides, Antisense (pharmacology)
• Pilot Projects
• Survivin