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

Journal article

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: Talbot, D; Ranson, M; Davies, J; Lahn, M; Callies, S

• Publication status: Published
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
• Volume: 16
• Issue: 24
• Pages: 6150-6158
• Publication date: 2010-12-01
• DOI: 10.1158/1078-0432.ccr-10-1932
• EISSN: 1557-3265
• ISSN: 1078-0432
• Language: English
• Keywords: Aged; Neoplasms; Middle Aged; Pilot Projects; Male; Aged, 80 and over; Genetic Therapy; Dose-Response Relationship, Drug; Female; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Molecular Targeted Therapy; Humans; Down-Regulation; Inhibitor of Apoptosis Proteins; Oligonucleotides, Antisense; Oligonucleotides; Evidence-Based Practice; Microtubule-Associated Proteins; Adult