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Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer

Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the...

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Autores principales: McDevitt, Michael R., Thorek, Daniel L. J., Hashimoto, Takeshi, Gondo, Tatsuo, Veach, Darren R., Sharma, Sai Kiran, Kalidindi, Teja Muralidhar, Abou, Diane S., Watson, Philip A., Beattie, Bradley J., Timmermand, Oskar Vilhemsson, Strand, Sven-Erik, Lewis, Jason S., Scardino, Peter T., Scher, Howard I., Lilja, Hans, Larson, Steven M., Ulmert, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915579/
https://www.ncbi.nlm.nih.gov/pubmed/29691406
http://dx.doi.org/10.1038/s41467-018-04107-w
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author McDevitt, Michael R.
Thorek, Daniel L. J.
Hashimoto, Takeshi
Gondo, Tatsuo
Veach, Darren R.
Sharma, Sai Kiran
Kalidindi, Teja Muralidhar
Abou, Diane S.
Watson, Philip A.
Beattie, Bradley J.
Timmermand, Oskar Vilhemsson
Strand, Sven-Erik
Lewis, Jason S.
Scardino, Peter T.
Scher, Howard I.
Lilja, Hans
Larson, Steven M.
Ulmert, David
author_facet McDevitt, Michael R.
Thorek, Daniel L. J.
Hashimoto, Takeshi
Gondo, Tatsuo
Veach, Darren R.
Sharma, Sai Kiran
Kalidindi, Teja Muralidhar
Abou, Diane S.
Watson, Philip A.
Beattie, Bradley J.
Timmermand, Oskar Vilhemsson
Strand, Sven-Erik
Lewis, Jason S.
Scardino, Peter T.
Scher, Howard I.
Lilja, Hans
Larson, Steven M.
Ulmert, David
author_sort McDevitt, Michael R.
collection PubMed
description Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.
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spelling pubmed-59155792018-04-27 Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer McDevitt, Michael R. Thorek, Daniel L. J. Hashimoto, Takeshi Gondo, Tatsuo Veach, Darren R. Sharma, Sai Kiran Kalidindi, Teja Muralidhar Abou, Diane S. Watson, Philip A. Beattie, Bradley J. Timmermand, Oskar Vilhemsson Strand, Sven-Erik Lewis, Jason S. Scardino, Peter T. Scher, Howard I. Lilja, Hans Larson, Steven M. Ulmert, David Nat Commun Article Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man. Nature Publishing Group UK 2018-04-24 /pmc/articles/PMC5915579/ /pubmed/29691406 http://dx.doi.org/10.1038/s41467-018-04107-w Text en © The Author(s) 2018 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/.
spellingShingle Article
McDevitt, Michael R.
Thorek, Daniel L. J.
Hashimoto, Takeshi
Gondo, Tatsuo
Veach, Darren R.
Sharma, Sai Kiran
Kalidindi, Teja Muralidhar
Abou, Diane S.
Watson, Philip A.
Beattie, Bradley J.
Timmermand, Oskar Vilhemsson
Strand, Sven-Erik
Lewis, Jason S.
Scardino, Peter T.
Scher, Howard I.
Lilja, Hans
Larson, Steven M.
Ulmert, David
Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
title Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
title_full Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
title_fullStr Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
title_full_unstemmed Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
title_short Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
title_sort feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915579/
https://www.ncbi.nlm.nih.gov/pubmed/29691406
http://dx.doi.org/10.1038/s41467-018-04107-w
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