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The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
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2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 34, 35652-35666 p.Article in journal (Refereed) Published
Abstract [en]

Overexpression of heat shock protein 90 (HSP90) is associated with increased tumor cell survival and radioresistance. In this study we explored the efficacy of the novel HSP90 inhibitor AT13387 and examined its radiosensitizing effects in combination with gamma-radiation in 2D and 3D structures as well as mice-xenografts. AT13387 induced effective cytotoxic activity and radiosensitized cancer cells in monolayer and tumor spheroid models, where low drug doses triggered significant synergistic effects on cell survival together with radiation. Furthermore, AT13387 treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected client proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated proteins recurred after 8-24 h. These results were confirmed in vivo where AT13387 treated tumors displayed effective downregulation of HSP90 and its oncogenic client proteins. In conclusion, our results demonstrate that AT13387 is a potent new cancer drug and effective radiosensitizer in vitro with an excellent in vivo efficacy. AT13387 treatment has the potential to improve external beam therapy and radionuclide therapy outcomes and restore treatment efficacy in cancers that are resistant to initial therapeutic regimes.

Place, publisher, year, edition, pages
2015. Vol. 6, no 34, 35652-35666 p.
Keyword [en]
HSP90 inhibitors, radiation, DNA repair, EGFR, CD44, Radioresistance, Radio-­immuno targeting
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-247054DOI: 10.18632/oncotarget.5363ISI: 000366111900051PubMedID: 26452257OAI: oai:DiVA.org:uu-247054DiVA: diva2:794659
Available from: 2015-03-12 Created: 2015-03-12 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Towards Personalized Cancer Therapy: New Diagnostic Biomarkers and Radiosensitization Strategies
Open this publication in new window or tab >>Towards Personalized Cancer Therapy: New Diagnostic Biomarkers and Radiosensitization Strategies
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on the evaluation of biomarkers for radio-immunodiagnostics and radio-immunotherapy and on radiosensitization strategies after HSP90 inhibition, as a step towards more personalized cancer medicine. There is a need to develop new tracers that target cancer-specific biomarkers to improve diagnostic imaging, as well as to combine treatment strategies to potentiate synergistic effects. Special focus has been on the cell surface molecule CD44 and its oncogenic variants, which were found to exhibit unique expression patterns in head and neck squamous cell carcinoma (HNSCC). The variant CD44v6 seems to be a promising target, because it is overexpressed in this cancer type and is associated with radioresistance. Two new radioconjugates that target CD44v6, namely, the Fab fragment AbD15179 and the bivalent fragment AbD19384, were investigated with regard to specificity, biodistribution and imaging performance. Both conjugates were able to efficiently target CD44v6-positive tumors in vitro and in vivo. PET imaging of CD44v6 with 124I-AbD19384 revealed many advantages compared with the clinical standard 18F-FDG. Furthermore, the efficacy of the novel HSP90 inhibitor AT13387 and its potential use in combination with radiation treatment were evaluated. AT13387 proved to be a potent new cancer drug with favorable pharmacokinetics. Synergistic combination effects at clinically relevant drug and radiation doses are promising for both radiation dose reduction and minimization of side effects, or for an improved therapeutic response. The AT13387 investigation indicated that CD44v6 is not dependent on the molecular chaperone HSP90, and therefore, radio-immunotargeting of CD44v6 in combination with the HSP90 inhibitor AT13387 might potentiate treatment outcomes. However, EGFR expression levels did correlate with HSP90 inhibition, and therefore, molecular imaging of EGFR-positive tumors may be used to assess the treatment response to HSP90 inhibitors.

In conclusion, these results demonstrate how tumor targeting with radiolabeled vectors and chemotherapeutic compounds can provide more specific and sensitive diagnostic tools and treatment options, which can lead to customized treatment decisions and a functional diagnosis that provides more precise and safer drug prescribing, as well as a more effective treatment for each patient.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1085
Keyword
tumor targeting, radionuclide targeting, HSP90 inhibition, AT13387, radiosensitization, molecular imaging, combination treatment, EGFR, CD44v6
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging Cell and Molecular Biology
Research subject
Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-247539 (URN)978-91-554-9207-6 (ISBN)
Public defence
2015-05-13, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, 751 85 Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-04-21 Created: 2015-03-20 Last updated: 2015-07-07

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