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Imaging agents for in vivo molecular profiling of disseminated prostate cancer: Cellular processing of [In-111]-labeled CHX-A "DTPA-trastuzumab and anti-HER2 ABY-025 Affibody in prostate cancer cell lines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.ORCID iD: 0000-0001-6120-2683
2011 (English)In: Experimental and Therapeutic Medicine, ISSN 1792-0981, Vol. 2, no 3, 523-528 p.Article in journal (Refereed) Published
Abstract [en]

The treatment of disseminated prostate cancer remains a great challenge in current oncology practice. The proliferation of prostate cancer cells is testosterone-driven, but clonal selection during androgen deprivation therapy promotes the development of androgen-independent (hormone-refractory) cells, which become phenotypically dominant. Human epidermal growth factor receptor type 2 (HER2) is capable of activating the androgen receptor pathway, even in the absence of the ligand. The detection of phenotypic changes associated with the development of androgen independence may influence patient management, suggesting the initiation of a second-line therapy. This study aimed to establish the level of HER2 expression in a number of prostate cancer cell lines (LNCaP, PC3 and DU145) in order that they be used as models in further studies, and to evaluate the binding and cellular processing of [In-111]-labeled trastuzumab and the anti-HER2 synthetic Affibody molecule ABY-025 in these cell lines. The expression of HER2 was demonstrated and quantified in all three tested prostate cancer cell-lines. Studies on cellular processing demonstrated that internalization of both conjugates increased continuously during the whole incubation. The internalization rate was approximately equal for both monoclonal antibodies and Affibody molecules. In both cases, internalization was moderately rapid. Such features would definitely favor the use of radiometal labels for trastuzumab and, most likely, for affibody molecules. The level of HER2 expression in these cell lines is sufficient for in vivo molecular imaging.

Place, publisher, year, edition, pages
2011. Vol. 2, no 3, 523-528 p.
Keyword [en]
human epidermal growth factor receptor type 2, prostate cancer, trastuzumab, Affibody molecule, DU145, PC3, LNCaP, indium-111, in vitro, cellular processing
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-153296DOI: 10.3892/etm.2011.217ISI: 000289818200023OAI: oai:DiVA.org:uu-153296DiVA: diva2:416021
Available from: 2011-05-10 Created: 2011-05-10 Last updated: 2015-03-24Bibliographically approved
In thesis
1. Preclinical Development of Imaging Agents for HER2 Expression in Prostate Cancer Using Radiolabeled Affibody Molecules
Open this publication in new window or tab >>Preclinical Development of Imaging Agents for HER2 Expression in Prostate Cancer Using Radiolabeled Affibody Molecules
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is focused on pre-clinical evaluation of in vivo detection of HER2-expression in prostate cancer (PCa) patients and on the possibility of using targeted molecular imaging to personalize treatment of disseminated PCa. The work is divided into three distinct parts: (1) the establishment of a preclinical model for further studies, (2) imaging of HER2 in a murine model of PCa and (3) exploration of new treatment regimes against PCa. The characterized cell line panel reflect the heterogeneity of PCa in a way that one cell line never could, and is crucial for a better understanding of different developmental stages during the progression toward androgen independence. The possibility of molecular detection of HER2 in PCa was determined in vitro using 111In-labeled CHX-A’’DTPA-trastuzumab and anti-HER2 ABY-025 affibody molecules. A novel real-time assay for radiolabeled tracer kinetics on living cells was evaluated, in an attempt to bring early developmental work a step closer to the target environment (imaging in living systems). The second part demonstrated the possibility of imaging PCa xenografts, despite the low expression levels, and that  ABY-025 is better adapted for this than the therapeutic anti-HER2 antibody trastuzumab. The study also demonstrated that a residualizing radiometal-label further improves imaging contrast. A comparative study of a HER2-binding affibody molecule N-terminally conjugated to DOTA, NOTA or NODAGA highlighted the influence of the chelator on biodistribution and emphasized the importance of taking into account potential metastatic sited during tracer development. The final study used the previously established in vitro model to explore the hypothesis of using molecular imaging of HER2 to identify PCa patients that may benefit from complemental treatment.

One conclusion from this thesis is that for imaging of PCa, molecular biological context and expression of the molecular target are equally important to consider. Another, that evaluation of response to treatment also need to consider the effect on the overall phenotypic profile, and consequently what this could mean for the efficacy of the treatment. The results of this thesis are in a larger perspective related to how the heterogeneity of tumors may affect the models used for diagnostics and monitoring of cancer in general.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 179
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science; Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-207256 (URN)978-91-554-8764-5 (ISBN)
Public defence
2013-11-08, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-10-17 Created: 2013-09-11 Last updated: 2014-01-23

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Tolmachev, VladimirOrlova, Anna

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