期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04107-w
关键词
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资金
- Imaging and Radiation Sciences Program (IMRAS), US National Institutes of Health (NIH) [P30 CA008748, P30 CA006973]
- NIH [P30 CA008748-48, S10 RR020892-01, S10 RR028889-01, R01CA166078, R01CA55349, P30CA008748, P01CA33049, F31CA167863, R01CA201035]
- Geoffrey Beene Cancer Research Center
- MSKCC [P50-CA086438]
- Memorial Sloan Kettering Center for Molecular Imaging and Nanotechnology (CMINT)
- Commonwealth Foundation for Cancer Research
- Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center
- Steve Wynn Prostate Cancer Foundation Young Investigator Award (PCF-YIA)
- Patrick C. Walsh Fund
- Knut and Alice Wallenberg Foundation
- Bertha Kamprad Foundation
- David H. Koch PCF-YIA
- Ludwig Center for Cancer Immunotherapy at MSKCC
- National Cancer Institute [P50-CA86438, R01CA160816, R01 CA175491]
- Swedish Cancer Society
- Swedish National Health Foundation (ALF)
- Swedish Research Council
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program in the UK
- Swedish Cancer Society [14-0722]
- Swedish Research Council (VR-MH) [2016-02974]
- MSKCC SPORE in Prostate Cancer [P50 CA92629]
- David H. Koch Fund of the PCF
- Sidney Kimmel Center for Prostate and Urologic Cancers
- NATIONAL CANCER INSTITUTE [R01CA166078, P50CA086438, R01CA055349, R01CA175491, P01CA033049, F31CA167863, R01CA201035, P50CA092629, R01CA160816, P30CA006973, P30CA008748] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR028889, S10RR020892] Funding Source: NIH RePORTER
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.
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