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 secondgeneration 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

RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

“…Despite this, early proof-of-concept studies and encouraging phase 2 efficacy data demonstrate that with higher doses, generation-2.0 ASOs targeted to either survivin (LY2181308) or clusterin (OGX-011, custirsen) resulted in the inhibition of their target RNA and protein levels in tumor cells of cancer patients. 125,126 In the case of OGX-011, encouraging signs of clinical efficacy were also observed where increased time to progression-free survival was demonstrated in a phase 2 prostate cancer trial. 127,128 Unfortunately, however, a more recent evaluation of the top-line results from the phase 3 SYNERGY Trial of OGX-011 in advanced prostate cancer did not meet its primary end point.…”

In Reply: Response to Marioni

“…We agree that targeting survivin in HNSCC is a strategy worthy of exploration, though, at present, limited numbers of patients treated in clinical trials [2,3] …”

Positron emission tomography molecular imaging for drug development

“…in optimizing anti-cancer drugs [7], as up-regulation of pumps that exclude drugs from tumours is well described [8]. PET biodistribution studies can be integrated with conventional stable isotope DMPK studies [9] or with pharmacodynamic measures [10]. It is important to recognize, however, that it is the distribution of the radionuclide, not the molecule, that is directly measured in the PET experiment.…”