Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer Journal Article
| Authors: | 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. |
| Article Title: | Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer |
| 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. © 2018 The Author(s). |
| Keywords: | survival; cancer survival; controlled study; protein expression; unclassified drug; androgen; cytotoxic agent; nonhuman; cancer radiotherapy; nuclear magnetic resonance imaging; mouse; dna damage; dna repair; animal experiment; animal model; protein; enzyme activity; immunoreactivity; animalia; monoclonal antibody; dna; drug distribution; drug clearance; androgen receptor; prostate adenocarcinoma; upregulation; antibody; enzyme; disease; alpha radiation; primates; actinium 225; cancer; human; male; article; kallikrein peptidase 2; monoclonal antibody hu11b6; monoclonal antibody hu11b6 actinium 225; monoclonal antibody hu11b6 zr 89 |
| Journal Title: | Nature Communications |
| Volume: | 9 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-04-24 |
| Start Page: | 1629 |
| Language: | English |
| DOI: | 10.1038/s41467-018-04107-w |
| PROVIDER: | scopus |
| PMCID: | PMC5915579 |
| PUBMED: | 29691406 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2018 -- Source: Scopus |
