Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies

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 i...

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Main Author: Spiegelberg, Diana
Format: Doctoral Thesis
Language:English
Published: Uppsala universitet, Medicinsk strålningsvetenskap 2015
Subjects:
Online Access:http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-247539
http://nbn-resolving.de/urn:isbn:978-91-554-9207-6
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spelling ndltd-UPSALLA1-oai-DiVA.org-uu-2475392015-07-08T04:51:00ZTowards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization StrategiesengSpiegelberg, DianaUppsala universitet, Medicinsk strålningsvetenskapUppsala2015tumor targetingradionuclide targetingHSP90 inhibitionAT13387radiosensitizationmolecular imagingcombination treatmentEGFRCD44v6This 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. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-247539urn:isbn:978-91-554-9207-6Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1085application/pdfinfo:eu-repo/semantics/openAccess
collection NDLTD
language English
format Doctoral Thesis
sources NDLTD
topic tumor targeting
radionuclide targeting
HSP90 inhibition
AT13387
radiosensitization
molecular imaging
combination treatment
EGFR
CD44v6
spellingShingle tumor targeting
radionuclide targeting
HSP90 inhibition
AT13387
radiosensitization
molecular imaging
combination treatment
EGFR
CD44v6
Spiegelberg, Diana
Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies
description 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.
author Spiegelberg, Diana
author_facet Spiegelberg, Diana
author_sort Spiegelberg, Diana
title Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies
title_short Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies
title_full Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies
title_fullStr Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies
title_full_unstemmed Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies
title_sort towards personalized cancer therapy : new diagnostic biomarkers and radiosensitization strategies
publisher Uppsala universitet, Medicinsk strålningsvetenskap
publishDate 2015
url http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-247539
http://nbn-resolving.de/urn:isbn:978-91-554-9207-6
work_keys_str_mv AT spiegelbergdiana towardspersonalizedcancertherapynewdiagnosticbiomarkersandradiosensitizationstrategies
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