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; David Ulmert

doi:10.1038/s41467-018-04107-w

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, David Ulmert

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

Sammanfattning

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.

Originalspråk	engelska
Artikelnummer	1629
Tidskrift	Nature Communications
Volym	9
Nummer	1
DOI	https://doi.org/10.1038/s41467-018-04107-w
Status	Published - 2018 dec. 1

Ämnesklassifikation (UKÄ)

Cancer och onkologi
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Annan fysik

FN:s Globala mål

Denna forskningsoutput relaterar till följande Globala mål

Tillgång till dokument

10.1038/s41467-018-04107-w

Andra filer och länkar

Link to publication in Scopus

Citera det här

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. (2018). Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer. Nature Communications, 9(1), Artikel 1629. https://doi.org/10.1038/s41467-018-04107-w

@article{95b2ef6e09744c3da1413a2e6755896a,

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.",

author = "McDevitt, {Michael R.} and Thorek, {Daniel L.J.} and Takeshi Hashimoto and Tatsuo Gondo 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 Hans Lilja and Larson, {Steven M.} and David Ulmert",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-04107-w",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

McDevitt, MR, Thorek, DLJ, Hashimoto, T, Gondo, T, Veach, DR, Sharma, SK, Kalidindi, TM, Abou, DS, Watson, PA, Beattie, BJ, Timmermand, OV , Strand, SE, Lewis, JS, Scardino, PT, Scher, HI, Lilja, H, Larson, SM & Ulmert, D 2018, 'Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer', Nature Communications, vol. 9, nr. 1, 1629. https://doi.org/10.1038/s41467-018-04107-w

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 S.

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

U2 - 10.1038/s41467-018-04107-w

DO - 10.1038/s41467-018-04107-w

M3 - Article

C2 - 29691406

AN - SCOPUS:85045977181

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1629

ER -

Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer

Sammanfattning

Ämnesklassifikation (UKÄ)

FN:s Globala mål

Tillgång till dokument

Andra filer och länkar

Fingeravtryck

Citera det här