Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study.
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 s...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2010
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| _version_ | 1826304476782264320 |
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| author | Talbot, D Ranson, M Davies, J Lahn, M Callies, S André, V Kadam, S Burgess, M Slapak, C Olsen, A McHugh, P de Bono, J Matthews, J Saleem, A Price, P |
| author_facet | Talbot, D Ranson, M Davies, J Lahn, M Callies, S André, V Kadam, S Burgess, M Slapak, C Olsen, A McHugh, P de Bono, J Matthews, J Saleem, A Price, P |
| author_sort | Talbot, D |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:18:23Z |
| format | Journal article |
| id | oxford-uuid:f1ded953-c976-41ac-b946-1ecb0f8c4a50 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:18:23Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:f1ded953-c976-41ac-b946-1ecb0f8c4a502022-03-27T11:59:19ZTumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f1ded953-c976-41ac-b946-1ecb0f8c4a50EnglishSymplectic Elements at Oxford2010Talbot, DRanson, MDavies, JLahn, MCallies, SAndré, VKadam, SBurgess, MSlapak, COlsen, AMcHugh, Pde Bono, JMatthews, JSaleem, APrice, PPURPOSE: 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. |
| spellingShingle | Talbot, D Ranson, M Davies, J Lahn, M Callies, S André, V Kadam, S Burgess, M Slapak, C Olsen, A McHugh, P de Bono, J Matthews, J Saleem, A Price, P Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. |
| title | Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. |
| title_full | Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. |
| title_fullStr | Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. |
| title_full_unstemmed | Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. |
| title_short | Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study. |
| title_sort | tumor survivin is downregulated by the antisense oligonucleotide ly2181308 a proof of concept first in human dose study |
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