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- Title
Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer.
- Authors
McDevitt, Michael R.; Thorek, Daniel L. J.; Takeshi Hashimoto; Tatsuo Gondo; 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
- 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 molecularlyspecific 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.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-04107-w