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Genetic signature o...
Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy
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- Bicak, Mesude (author)
- Icahn School of Medicine at Mount Sinai
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- Lückerath, Katharina (author)
- University of California, Los Angeles
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- Kalidindi, Teja (author)
- Memorial Sloan-Kettering Cancer Center
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- Phelps, Michael E. (author)
- University of California, Los Angeles
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- Strand, Sven Erik (author)
- Lund University,Lunds universitet,Medicinsk strålningsfysik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Forskningsgruppen för Systemisk strålterapi,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Strålterapi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medical Radiation Physics, Lund,Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Systemic Radiation Therapy Group,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Radiation therapy,Section I,Department of Clinical Sciences, Lund
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- Morris, Michael J. (author)
- Memorial Sloan-Kettering Cancer Center
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- Radu, Caius G. (author)
- University of California, Los Angeles
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- Damoiseaux, Robert (author)
- University of California, Los Angeles
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- Peltola, Mari T. (author)
- University of Turku
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- Peekhaus, Norbert (author)
- University of California, Los Angeles
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- Ho, Austin (author)
- University of California, Los Angeles
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- Veach, Darren (author)
- Diaprost AB,Memorial Sloan-Kettering Cancer Center
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- Malmborg Hager, Ann Christin (author)
- Diaprost AB
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- Larson, Steven M. (author)
- Memorial Sloan-Kettering Cancer Center,Cornell University
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- Lilja, Hans (author)
- Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Clinical Chemistry, Malmö,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Memorial Sloan-Kettering Cancer Center,University of Oxford
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- McDevitt, Michael R. (author)
- Memorial Sloan-Kettering Cancer Center
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- Klein, Robert J. (author)
- Icahn School of Medicine at Mount Sinai
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- Ulmert, David (author)
- University of California, Los Angeles
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(creator_code:org_t)
- 2020-06-12
- 2020
- English 10 s.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 117:26, s. 15172-15181
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http://dx.doi.org/10...
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https://www.pnas.org...
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Abstract
Subject headings
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- Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- NATURVETENSKAP -- Fysik -- Annan fysik (hsv//swe)
- NATURAL SCIENCES -- Physical Sciences -- Other Physics Topics (hsv//eng)
Keyword
- 225Ac
- hK2
- hu11B6
- prostate cancer
- radiommunotherapy
Publication and Content Type
- art (subject category)
- ref (subject category)
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Bicak, Mesude
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Lückerath, Katha ...
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Kalidindi, Teja
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Phelps, Michael ...
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Strand, Sven Eri ...
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Morris, Michael ...
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Radu, Caius G.
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Damoiseaux, Robe ...
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Peltola, Mari T.
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Peekhaus, Norber ...
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Ho, Austin
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Veach, Darren
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Malmborg Hager, ...
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Larson, Steven M ...
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Lilja, Hans
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McDevitt, Michae ...
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Klein, Robert J.
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Ulmert, David
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