@article{9665438b4e524b6f8d9ea6283a99ede5,
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",
note = "Funding Information: The authors thank Dr. David A. Scheinberg for his intellectual input. For technical support and expertise we thank Dr. Pat Zanzonico, director and Dr. Mihaela E. Lupu, of the MSKCC Small Animal Imaging Core Facility, Mr. Muc Du and Mr. Simon Marim of the Cornell Bioimaging Core Facility, and Dr. Heather Martin of the MSKCC veterinary staff. Isotopes used in this research were supplied in part by the United States Department of Energy Office of Science, Isotope Program, Office of Nuclear Physics. This study was supported in part by the Imaging and Radiation Sciences Program (IMRAS), US National Institutes of Health (NIH) grants P30 CA008748 (MSK Cancer Center Support Grant) and P30 CA006973 (Johns Hopkins University Cancer Center Support Grant). The MSKCC Small-Animal Imaging Core Facility is supported in part by NIH grants P30 CA008748-48, S10 RR020892-01, S10 RR028889-01 and the Geoffrey Beene Cancer Research Center. We also acknowledge Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center and the Radiochemistry & Molecular Imaging Probe Core (P50-CA086438), all of MSKCC. M.R.M. was supported by NIH R01CA166078, R01CA55349, P30CA008748, P01CA33049, F31CA167863, the Memorial Sloan Kettering Center for Molecular Imaging and Nanotechnology (CMINT), Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and The Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center. D.L.J.T. was supported by the Steve Wynn Prostate Cancer Foundation Young Investigator Award (PCF-YIA), the Patrick C. Walsh Fund, and NIH R01CA201035. D.U. was supported, in part, by the Knut and Alice Wal-lenberg Foundation, the Bertha Kamprad Foundation, and the David H. Koch PCF-YIA. S. M.L. was supported by the Ludwig Center for Cancer Immunotherapy at MSKCC and the National Cancer Institute (P50-CA86438). S.E.S. was supported by the Swedish Cancer Society and Swedish National Health Foundation (ALF) and Swedish Research Council. H. L. was supported, in part, by the National Cancer Institute [R01CA160816, R01 CA175491], the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program in the UK, the Swedish Cancer Society (project no. 14-0722), and the Swedish Research Council (VR-MH project no. 2016-02974). P.T.S. and H.L. were supported in part by the MSKCC SPORE in Prostate Cancer (P50 CA92629), the David H. Koch Fund of the PCF, and the Sidney Kimmel Center for Prostate and Urologic Cancers. Funding Information: The authors thank Dr. David A. Scheinberg for his intellectual input. For technical support and expertise we thank Dr. Pat Zanzonico, director and Dr. Mihaela E. Lupu, of the MSKCC Small Animal Imaging Core Facility, Mr. Muc Du and Mr. Simon Marim of the Cornell Bioimaging Core Facility, and Dr. Heather Martin of the MSKCC veterinary staff. Isotopes used in this research were supplied in part by the United States Department of Energy Office of Science, Isotope Program, Office of Nuclear Physics. This study was supported in part by the Imaging and Radiation Sciences Program (IMRAS), US National Institutes of Health (NIH) grants P30 CA008748 (MSK Cancer Center Support Grant) and P30 CA006973 (Johns Hopkins University Cancer Center Support Grant). The MSKCC Small-Animal Imaging Core Facility is supported in part by NIH grants P30 CA008748-48, S10 RR020892-01, S10 RR028889-01 and the Geoffrey Beene Cancer Research Center. We also acknowledge Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center and the Radiochemistry & Molecular Imaging Probe Core (P50-CA086438), all of MSKCC. M.R.M. was supported by NIH R01CA166078, R01CA55349, P30CA008748, P01CA33049, F31CA167863, the Memorial Sloan Kettering Center for Molecular Imaging and Nanotechnology (CMINT), Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and The Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center. D.L.J.T. was supported by the Steve Wynn Prostate Cancer Foundation Young Investigator Award (PCF-YIA), the Patrick C. Walsh Fund, and NIH R01CA201035. D.U. was supported, in part, by the Knut and Alice Wallenberg Foundation, the Bertha Kamprad Foundation, and the David H. Koch PCF-YIA. S. M.L. was supported by the Ludwig Center for Cancer Immunotherapy at MSKCC and the National Cancer Institute (P50-CA86438). S.E.S. was supported by the Swedish Cancer Society and Swedish National Health Foundation (ALF) and Swedish Research Council. H. L. was supported, in part, by the National Cancer Institute [R01CA160816, R01 CA175491], the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program in the UK, the Swedish Cancer Society (project no. 14-0722), and the Swedish Research Council (VR-MH project no. 2016-02974). P.T.S. and H.L. were supported in part by the MSKCC SPORE in Prostate Cancer (P50 CA92629), the David H. Koch Fund of the PCF, and the Sidney Kimmel Center for Prostate and Urologic Cancers. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-018-04107-w",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}