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 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

doi:10.1038/s41467-018-04107-w

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

Journal Article · 24 April 2018 · Nature Communications

DOI: https://doi.org/10.1038/s41467-018-04107-w · OSTI ID:1624093

^[1]; Thorek, Daniel L. J. ^[2]; Hashimoto, Takeshi ^[3]; Gondo, Tatsuo ^[3];

^[4]; Sharma, Sai Kiran ^[5]; Kalidindi, Teja Muralidhar ^[6]; Abou, Diane S. ^[7]; Watson, Philip A. ^[8]; Beattie, Bradley J. ^[9]; Timmermand, Oskar Vilhemsson ^[10];

^[11];

^[12]; Scardino, Peter T. ^[13]; Scher, Howard I. ^[14];

^[15]; Larson, Steven M. ^[16]; Ulmert, David ^[17]

Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology; Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Radiology
Johns Hopkins School of Medicine, Baltimore, MD (United States). Sidney Kimmel Comprehensive Cancer Center. Dept. of Radiology and Radiological Science. Division of Nuclear Medicine and Molecular Imaging; Johns Hopkins School of Medicine, Baltimore, MD (United States). Sidney Kimmel Comprehensive Cancer Center. Dept. of Oncology. Cancer Molecular and Functional Imaging Program
Tokyo Medical Univ. (Japan). Dept. of Urology
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology; Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Radiology; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology. Radiochemistry and Imaging Sciences Service
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology. Radiochemistry and Imaging Sciences Service
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology
Johns Hopkins School of Medicine, Baltimore, MD (United States). Sidney Kimmel Comprehensive Cancer Center. Dept. of Radiology and Radiological Science. Division of Nuclear Medicine and Molecular Imaging
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Human Oncology and Pathogenesis Program
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Medical Physics
Lund Univ. (Sweden). Skåne Univ. Hospital. Clinical Sciences. Division of Oncology
Lund Univ. (Sweden). Medical Radiation Physics. Dept. of Clinical Sciences
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology; Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Radiology; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology. Radiochemistry and Imaging Sciences Service; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Molecular Pharmacology Program
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Surgery. Urology Service; Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Urology
Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Urology; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Medicine. Genitourinary Oncology Service
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Surgery. Urology Service; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Medicine. Genitourinary Oncology Service; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Lab. Medicine; Univ. of Oxford (United Kingdom). Nuffield Dept. of Surgical Sciences; Lund Univ. (Sweden). Dept. of Translational Medicine
Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Radiology; Cornell Univ., Ithaca, NY (United States). Weill Medical College. Dept. of Radiology; Memorial Sloan Kettering Cancer Center, New York, NY (United States).Molecular Pharmacology; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Nuclear Medicine Service
Lund Univ. (Sweden). Skåne Univ. Hospital. Clinical Sciences. Division of Oncology; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Molecular Pharmacology

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.

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Research Organization:: Memorial Sloan Kettering Cancer Center, New York, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Nuclear Physics (NP)

Grant/Contract Number:: FG02-00ER41132

OSTI ID:: 1624093

Journal Information:: Nature Communications, Vol. 9, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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PSMA expression in the Hi‐Myc model; extended utility of a representative model of prostate adenocarcinoma for biological insight and as a drug discovery tool Simons, Brian W.; Turtle, Norman F.; Ulmert, David H. The Prostate, Vol. 79, Issue 6 https://doi.org/10.1002/pros.23770	journal	January 2019