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Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma

BACKGROUND: Lymphoma is a common cancer in dogs. While most dogs receiving chemotherapy experience remission, very few are cured, and median survival times are generally in the 12-month range. Novel approaches to treatment are unquestionably needed. The Inhibitor of Apoptosis Protein (IAP) family me...

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Autores principales: Thamm, Douglas H., Joseph, Jenette K., Rose, Barbara J., Meuten, Travis K., Weishaar, Kristen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092583/
https://www.ncbi.nlm.nih.gov/pubmed/32209084
http://dx.doi.org/10.1186/s12917-020-02317-3
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author Thamm, Douglas H.
Joseph, Jenette K.
Rose, Barbara J.
Meuten, Travis K.
Weishaar, Kristen M.
author_facet Thamm, Douglas H.
Joseph, Jenette K.
Rose, Barbara J.
Meuten, Travis K.
Weishaar, Kristen M.
author_sort Thamm, Douglas H.
collection PubMed
description BACKGROUND: Lymphoma is a common cancer in dogs. While most dogs receiving chemotherapy experience remission, very few are cured, and median survival times are generally in the 12-month range. Novel approaches to treatment are unquestionably needed. The Inhibitor of Apoptosis Protein (IAP) family member survivin, which is one of the most commonly overexpressed proteins in human cancer, plays a key role in apoptosis resistance, a major cause of drug-resistant treatment failure. Survivin targeting therapies have shown promise preclinically; however, none have been evaluated in dogs to date. The goal of the current study was to determine the safety and pharmacodynamic effects of systemic administration of the anti-survivin locked nucleic acid antisense oligonucleotide EZN-3042 in dogs with lymphoma. RESULTS: We performed a prospective phase-I clinical trial in dogs with biopsy-accessible peripheral nodal lymphoma. Eighteen dogs were treated with EZN-3042 as a 2-h IV infusion at 5 dose levels, from 3.25 to 8.25 mg/kg twice weekly for 3 treatments. No dose-limiting toxicities were encountered. Reduction in tumor survivin mRNA and protein were observed in 3 of 5 evaluable dogs at the 8.25 mg/kg dose cohort. CONCLUSIONS: In conclusion, reduced survivin expression was demonstrated in lymphoma tissues in the majority of dogs treated with EZN-3042 at 8.25 mg/kg twice weekly, which was associated with minimal adverse effects. This dose may be used in future studies of EZN-3042/chemotherapy combinations in dogs with spontaneous lymphoma and other cancers.
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spelling pubmed-70925832020-03-27 Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma Thamm, Douglas H. Joseph, Jenette K. Rose, Barbara J. Meuten, Travis K. Weishaar, Kristen M. BMC Vet Res Research Article BACKGROUND: Lymphoma is a common cancer in dogs. While most dogs receiving chemotherapy experience remission, very few are cured, and median survival times are generally in the 12-month range. Novel approaches to treatment are unquestionably needed. The Inhibitor of Apoptosis Protein (IAP) family member survivin, which is one of the most commonly overexpressed proteins in human cancer, plays a key role in apoptosis resistance, a major cause of drug-resistant treatment failure. Survivin targeting therapies have shown promise preclinically; however, none have been evaluated in dogs to date. The goal of the current study was to determine the safety and pharmacodynamic effects of systemic administration of the anti-survivin locked nucleic acid antisense oligonucleotide EZN-3042 in dogs with lymphoma. RESULTS: We performed a prospective phase-I clinical trial in dogs with biopsy-accessible peripheral nodal lymphoma. Eighteen dogs were treated with EZN-3042 as a 2-h IV infusion at 5 dose levels, from 3.25 to 8.25 mg/kg twice weekly for 3 treatments. No dose-limiting toxicities were encountered. Reduction in tumor survivin mRNA and protein were observed in 3 of 5 evaluable dogs at the 8.25 mg/kg dose cohort. CONCLUSIONS: In conclusion, reduced survivin expression was demonstrated in lymphoma tissues in the majority of dogs treated with EZN-3042 at 8.25 mg/kg twice weekly, which was associated with minimal adverse effects. This dose may be used in future studies of EZN-3042/chemotherapy combinations in dogs with spontaneous lymphoma and other cancers. BioMed Central 2020-03-24 /pmc/articles/PMC7092583/ /pubmed/32209084 http://dx.doi.org/10.1186/s12917-020-02317-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Thamm, Douglas H.
Joseph, Jenette K.
Rose, Barbara J.
Meuten, Travis K.
Weishaar, Kristen M.
Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma
title Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma
title_full Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma
title_fullStr Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma
title_full_unstemmed Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma
title_short Phase-I trial of survivin inhibition with EZN-3042 in dogs with spontaneous lymphoma
title_sort phase-i trial of survivin inhibition with ezn-3042 in dogs with spontaneous lymphoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092583/
https://www.ncbi.nlm.nih.gov/pubmed/32209084
http://dx.doi.org/10.1186/s12917-020-02317-3
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