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 | |
| State | Published - Dec 1 2018 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
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; 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.
In: Nature Communications, Vol. 9, No. 1, 1629, 01.12.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
AU - McDevitt, Michael R.
AU - Thorek, Daniel L.J.
AU - Hashimoto, Takeshi
AU - Gondo, Tatsuo
AU - Veach, Darren R.
AU - Sharma, Sai Kiran
AU - Kalidindi, Teja Muralidhar
AU - Abou, Diane
AU - Watson, Philip A.
AU - Beattie, Bradley J.
AU - Timmermand, Oskar Vilhemsson
AU - Strand, Sven Erik
AU - Lewis, Jason S.
AU - Scardino, Peter T.
AU - Scher, Howard I.
AU - Lilja, Hans
AU - Larson, Steven M.
AU - Ulmert, David
PY - 2018/12/1
Y1 - 2018/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85045977181&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045977181&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04107-w
DO - 10.1038/s41467-018-04107-w
M3 - Article
C2 - 29691406
AN - SCOPUS:85045977181
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1629
ER -