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

Michael R. McDevitt; Daniel L.J. Thorek; Takeshi Hashimoto; Tatsuo Gondo; Darren R. Veach; Sai Kiran Sharma; Teja Muralidhar Kalidindi; Diane S. Abou; Philip A. Watson; Bradley J. Beattie; Oskar Vilhemsson Timmermand; Sven Erik Strand; Jason S. Lewis; Peter T. Scardino; Howard I. Scher; Hans Lilja; Steven M. Larson; David Ulmert

doi:10.1038/s41467-018-04107-w

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

Michael R. McDevitt, Daniel L.J. Thorek, Takeshi Hashimoto, Tatsuo Gondo, Darren R. Veach, Sai Kiran Sharma, Teja Muralidhar Kalidindi, Diane S. Abou, Philip A. Watson, Bradley J. Beattie, Oskar Vilhemsson Timmermand, Sven Erik Strand, Jason S. Lewis, Peter T. Scardino, Howard I. Scher, Hans Lilja, Steven M. Larson, David Ulmert

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16 Scopus citations

Abstract

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.

Original language	English (US)
Article number	1629
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04107-w
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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McDevitt, M. R., Thorek, D. L. J., Hashimoto, T., Gondo, T., Veach, D. R., Sharma, S. K., Kalidindi, T. M., Abou, D. S., Watson, P. A., Beattie, B. J., Timmermand, O. V., Strand, S. E., Lewis, J. S., Scardino, P. T., Scher, H. I., Lilja, H., Larson, S. M., & Ulmert, D. (2018). Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer. Nature communications, 9(1), Article 1629. https://doi.org/10.1038/s41467-018-04107-w

McDevitt, MR, Thorek, DLJ, Hashimoto, T, Gondo, T, Veach, DR, Sharma, SK, Kalidindi, TM, Abou, DS, Watson, PA, Beattie, BJ, Timmermand, OV, Strand, SE, Lewis, JS, Scardino, PT, Scher, HI, Lilja, H, Larson, SM & Ulmert, D 2018, 'Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer', Nature communications, vol. 9, no. 1, 1629. https://doi.org/10.1038/s41467-018-04107-w

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abstract = "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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AU - Lewis, Jason S.

AU - Scardino, Peter T.

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AU - Lilja, Hans

AU - Larson, Steven M.

AU - Ulmert, David

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N2 - 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.

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

Abstract

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