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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. and Beattie, Bradley J., et al. (2018) In Nature Communications 9(1).
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... (More)

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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@article{95b2ef6e-0974-4c3d-a141-3a2e6755896a,
  abstract     = {<p>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.</p>},
  articleno    = {1629},
  author       = {McDevitt, Michael R. and Thorek, Daniel L.J. and Hashimoto, Takeshi and Gondo, Tatsuo and Veach, Darren R. and Sharma, Sai Kiran and Kalidindi, Teja Muralidhar and Abou, Diane S. and Watson, Philip A. and Beattie, Bradley J. and Timmermand, Oskar Vilhemsson and Strand, Sven Erik and Lewis, Jason S. and Scardino, Peter T. and Scher, Howard I. and Lilja, Hans and Larson, Steven M. and Ulmert, David},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer},
  url          = {http://dx.doi.org/10.1038/s41467-018-04107-w},
  volume       = {9},
  year         = {2018},
}