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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose
Denis C Talbot1, Malcolm Ranson, Joanna Davies
1Department of Medical Oncology, University of Oxford, Oxford Radcliffe Hospitals NHS Trust, Oxford, United Kingdom. denis.talbot@medonc.ox.ac.uk
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.
Insights
This study shows that LY2181308, an antisense oligonucleotide targeting survivin, effectively reduces survivin expression in human tumors. The drug demonstrated tumor-specific effects and restored apoptosis, supporting further clinical trials for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Inhibitors of apoptosis (IAP) promote cancer cell survival.
- Survivin, an IAP, is overexpressed in many cancers, correlating with poor prognosis.
- LY2181308 is a novel antisense oligonucleotide (ASO) targeting survivin mRNA.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and pharmacodynamics of LY2181308 in a first-in-human dose-escalation study.
- To assess the molecularly targeted effects of LY2181308 on survivin expression in human tumors.
- To determine the feasibility of using LY2181308 in cancer patients who have exhausted standard therapies.
Main Methods:
- A phase 1, dose-escalation study of LY2181308 administered intravenously.
- Patients received loading doses followed by weekly maintenance doses.
- Tumor biopsies and [(11)C]LY2183108 PET imaging were used to assess drug accumulation and target engagement.
Main Results:
- LY2181308 was administered to 40 patients at doses up to 1,000 mg.
- At 750 mg, the drug accumulated in tumor tissue, reducing survivin gene and protein by 20%.
- Apoptotic signaling was restored in tumor cells, and pharmacokinetics aligned with preclinical models.
Conclusions:
- LY2181308 exhibits tumor-specific, molecularly targeted effects in humans.
- The observed effects support further investigation of LY2181308's therapeutic potential in cancer.
- This study validates the use of ASOs for targeting cancer-promoting genes like survivin.
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