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 and David Ulmert ()
Additional contact information
Michael R. McDevitt: Memorial Sloan Kettering Cancer Center
Daniel L. J. Thorek: Johns Hopkins School of Medicine
Takeshi Hashimoto: Tokyo Medical University
Tatsuo Gondo: Tokyo Medical University
Darren R. Veach: Memorial Sloan Kettering Cancer Center
Sai Kiran Sharma: Memorial Sloan Kettering Cancer Center
Teja Muralidhar Kalidindi: Memorial Sloan Kettering Cancer Center
Diane S. Abou: Johns Hopkins School of Medicine
Philip A. Watson: Memorial Sloan Kettering Cancer Center
Bradley J. Beattie: Memorial Sloan Kettering Cancer Center
Oskar Vilhemsson Timmermand: Lund University and Skåne University Hospital
Sven-Erik Strand: Lund University
Jason S. Lewis: Memorial Sloan Kettering Cancer Center
Peter T. Scardino: Memorial Sloan Kettering Cancer Center
Howard I. Scher: Weill Cornell Medical College
Hans Lilja: Memorial Sloan Kettering Cancer Center
Steven M. Larson: Memorial Sloan Kettering Cancer Center
David Ulmert: Lund University and Skåne University Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04107-w

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