Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
In Vitro Therapy Modeling of HER2 Targeting Therapy in Disseminated Prostate Cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. (Orlova)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. (Orlova)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
Show others and affiliations
2014 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 45, no 5, 2153-2158 p.Article in journal (Refereed) Published
Abstract [en]

Prostate cancer (PCa) is the most common cancer type among men. Treatments against advanced PCa are limited and in many cases only palliative. In a later, androgent independent, stage of PCa androgen receptors can be activated without interaction with ligand, i.e., by receptors of tyrosine kinase (RTK) family in the outlaw pathway. Human epidermal growth factor receptors HER2 and EGFR belong to RTK-family. HER2 is one of the main actors in the outlaw pathway with EGFR as the preferable heterodimerizing partner. We hypothesized that information on HER2 expression in advanced PCa could be useful for selection of patients for anti-RTK therapy and monitoring of therapy response. A panel of PCa cell lines (LNCap, PC3, DU-145) was subjected to a 8-week treatment using drugs influencing the RTK: trastuzumab (anti‑HER2), 17-DMAG (Hsp90 inhibitor), alone or in combination, and their HER2 and EGFR expressions were compared with non-treated cells. Treatment with trastuzumab decreased proliferation of LNCap and DU-145 cell lines, while 17-DMAG and trastuzumab/17‑DMAG combination affected all three cell lines. HER2 expression was significantly increased in PC3 cells, the most resistant cell line. On the contrary, in responding cells (LNCap and DU-145) HER2 expression decreased, accompanied by increased EGFR expression. However, additional treatment of cells with cetuximab (anti‑EGFR) did not give any additive effect to trastuzumab. In this study the response to anti-RTK therapy proved to vary between different PCa cell lines. We have demonstrated that RTK targeting treatments may affect the phenotypic profile of PCa tumor cells that correlates with therapy outcome. Observation of such changes during treatment could be used for monitoring and an improved therapy outcome.

Place, publisher, year, edition, pages
2014. Vol. 45, no 5, 2153-2158 p.
Keyword [en]
prostate cancer, HER2, targeted therapy, molecular imaging, in vitro modeling
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-207258DOI: 10.3892/ijo.2014.2628ISI: 000342713900042Scopus ID: 25176024OAI: oai:DiVA.org:uu-207258DiVA: diva2:650772
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2013-09-23 Created: 2013-09-11 Last updated: 2017-12-06Bibliographically 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

Open Access in DiVA

fulltext(348 kB)122 downloads
File information
File name FULLTEXT01.pdfFile size 348 kBChecksum SHA-512
58eb3aa38ec925d4dbe6cc01408ae7f8a8647af4087d120172ce30c227998fcd0ab8da36d65492102e5c483859101f2f0cf80a5de52c44763d0c234e305e37dc
Type fulltextMimetype application/pdf

Other links

Publisher's full textScopus

Search in DiVA

By author/editor
Rosestedt, MariaAsplund, VeronikaOrlova, Anna
By organisation
Preclinical PET Platform
In the same journal
International Journal of Oncology
Radiology, Nuclear Medicine and Medical Imaging

Search outside of DiVA

GoogleGoogle Scholar
Total: 122 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 556 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf