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Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex

Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical pep...

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Autores principales: Brisuda, Antonín, Ho, James C. S., Kandiyal, Pancham S., Ng, Justin T-Y., Ambite, Ines, Butler, Daniel S. C., Háček, Jaromir, Wan, Murphy Lam Yim, Tran, Thi Hien, Nadeem, Aftab, Tran, Tuan Hiep, Hastings, Anna, Storm, Petter, Fortunati, Daniel L., Esmaeili, Parisa, Novotna, Hana, Horňák, Jakub, Mu, Y. G., Mok, K. H., Babjuk, Marek, Svanborg, Catharina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187399/
https://www.ncbi.nlm.nih.gov/pubmed/34103518
http://dx.doi.org/10.1038/s41467-021-23748-y
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author Brisuda, Antonín
Ho, James C. S.
Kandiyal, Pancham S.
Ng, Justin T-Y.
Ambite, Ines
Butler, Daniel S. C.
Háček, Jaromir
Wan, Murphy Lam Yim
Tran, Thi Hien
Nadeem, Aftab
Tran, Tuan Hiep
Hastings, Anna
Storm, Petter
Fortunati, Daniel L.
Esmaeili, Parisa
Novotna, Hana
Horňák, Jakub
Mu, Y. G.
Mok, K. H.
Babjuk, Marek
Svanborg, Catharina
author_facet Brisuda, Antonín
Ho, James C. S.
Kandiyal, Pancham S.
Ng, Justin T-Y.
Ambite, Ines
Butler, Daniel S. C.
Háček, Jaromir
Wan, Murphy Lam Yim
Tran, Thi Hien
Nadeem, Aftab
Tran, Tuan Hiep
Hastings, Anna
Storm, Petter
Fortunati, Daniel L.
Esmaeili, Parisa
Novotna, Hana
Horňák, Jakub
Mu, Y. G.
Mok, K. H.
Babjuk, Marek
Svanborg, Catharina
author_sort Brisuda, Antonín
collection PubMed
description Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.
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spelling pubmed-81873992021-06-11 Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex Brisuda, Antonín Ho, James C. S. Kandiyal, Pancham S. Ng, Justin T-Y. Ambite, Ines Butler, Daniel S. C. Háček, Jaromir Wan, Murphy Lam Yim Tran, Thi Hien Nadeem, Aftab Tran, Tuan Hiep Hastings, Anna Storm, Petter Fortunati, Daniel L. Esmaeili, Parisa Novotna, Hana Horňák, Jakub Mu, Y. G. Mok, K. H. Babjuk, Marek Svanborg, Catharina Nat Commun Article Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need. Nature Publishing Group UK 2021-06-08 /pmc/articles/PMC8187399/ /pubmed/34103518 http://dx.doi.org/10.1038/s41467-021-23748-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Brisuda, Antonín
Ho, James C. S.
Kandiyal, Pancham S.
Ng, Justin T-Y.
Ambite, Ines
Butler, Daniel S. C.
Háček, Jaromir
Wan, Murphy Lam Yim
Tran, Thi Hien
Nadeem, Aftab
Tran, Tuan Hiep
Hastings, Anna
Storm, Petter
Fortunati, Daniel L.
Esmaeili, Parisa
Novotna, Hana
Horňák, Jakub
Mu, Y. G.
Mok, K. H.
Babjuk, Marek
Svanborg, Catharina
Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
title Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
title_full Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
title_fullStr Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
title_full_unstemmed Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
title_short Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
title_sort bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187399/
https://www.ncbi.nlm.nih.gov/pubmed/34103518
http://dx.doi.org/10.1038/s41467-021-23748-y
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