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Towards Personalized Cancer Therapy: New Diagnostic Biomarkers and Radiosensitization Strategies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
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 [en]
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: urn:nbn:se:uu:diva-247539ISBN: 978-91-554-9207-6 (print)OAI: oai:DiVA.org:uu-247539DiVA: diva2:797005
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
List of papers
1. Characterization of CD44 variant expression in head and neck squamous cell carcinomas
Open this publication in new window or tab >>Characterization of CD44 variant expression in head and neck squamous cell carcinomas
2014 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 3, 2053-2062 p.Article in journal (Refereed) Published
Abstract [en]

CD44 is a complex family of molecules, associated with aggressive malignancies and cancer stem cells. However, the role of CD44 variants in tumor progression and treatment resistance is not clear. In this study, the expression of CD44 and its variants was assessed in head and neck squamous cell carcinomas (HNSCC). Furthermore, subpopulations of cells expressing high amounts of CD44 variants were identified and characterized, for e.g., cell cycle phase and radioresistance. Results revealed high and homogenous CD44 and CD44v7 expression in four cell lines and CD44v4 and CD44v6 in three cell lines. CD44v3 was highly expressed in two cell lines, whereas CD44v5, CD44v7/8, CD44v10, CD133, and CD24 demonstrated no or moderate expression. Moreover, a subpopulation of very high CD44v4 expression was identified, which is independent of cell phase, demonstrating increased proliferation and radioresistance. In cell starvation experiments designed to enrich for cancer stem cells, a large population with dramatically increased expression of CD44, CD44v3, CD44v6, and CD44v7 was formed. Expression was independent of cell phase, and cells demonstrated increased radioresistance and migration rate. Our results demonstrate that the heterogeneity of tumor cells has important clinical implications for the treatment of HNSCC and that some of the CD44 variants may be associated with increased radioresistance. Highly expressed CD44 variants could make interesting candidates for selective cancer targeting.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-221093 (URN)10.1007/s13277-013-1272-3 (DOI)000333536300041 ()24122205 (PubMedID)
Available from: 2014-03-25 Created: 2014-03-25 Last updated: 2017-12-05Bibliographically approved
2. In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study
Open this publication in new window or tab >>In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study
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2014 (English)In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 4, 11Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Patients with squamous cell carcinoma in the head and neck region (HNSCC) offer a diagnostic challenge due to difficulties to detect small tumours and metastases. Imaging methods available are not sufficient, and radio-immunodiagnostics could increase specificity and sensitivity of diagnostics. The objective of this study was to evaluate, for the first time, the in vivo properties of the radiolabelled CD44v6-targeting fragment AbD15179 and to assess its utility as a targeting agent for radio-immunodiagnostics of CD44v6-expressing tumours.

METHODS: The fully human CD44v6-targeting Fab fragment AbD15179 was labelled with 111In or 125I, as models for radionuclides suitable for imaging with SPECT or PET. Species specificity, antigen specificity and internalization properties were first assessed in vitro. In vivo specificity and biodistribution were then evaluated in tumour-bearing mice using a dual-tumour and dual-isotope setup.

RESULTS: Both species-specific and antigen-specific binding of the conjugates were demonstrated in vitro, with no detectable internalization. The in vivo studies demonstrated specific tumour binding and favourable tumour targeting properties for both conjugates, albeit with higher tumour uptake, slower tumour dissociation, higher tumour-to-blood ratio and higher CD44v6 sensitivity for the 111In-labelled fragment. In contrast, the 125I-Fab demonstrated more favourable tumour-to-organ ratios for liver, spleen and kidneys.

CONCLUSIONS: We conclude that AbD15179 efficiently targets CD44v6-expressing squamous cell carcinoma xenografts, and particularly, the 111In-Fab displayed high and specific tumour uptake. CD44v6 emerges as a suitable target for radio-immunodiagnostics, and a fully human antibody fragment such as AbD15179 can enable further clinical imaging studies.

Keyword
Radio-immunodiagnostics, Antibody fragment, CD44v6, Molecular imaging, Fab, I-125, In-111
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-221094 (URN)10.1186/2191-219X-4-11 (DOI)000357859200001 ()24598405 (PubMedID)
Available from: 2014-03-25 Created: 2014-03-25 Last updated: 2017-12-05Bibliographically approved
3. Molecular imaging of CD44v6-expressing squamous cell carcinoma using a novel engineered bivalent antibody fragment
Open this publication in new window or tab >>Molecular imaging of CD44v6-expressing squamous cell carcinoma using a novel engineered bivalent antibody fragment
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(English)Article in journal (Refereed) Submitted
Keyword
Head and neck cancer, 125I, 124I, F(ab´)2, AbD19384, CD44v6, small animal studies, PET imaging
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-247056 (URN)
Available from: 2015-03-12 Created: 2015-03-12 Last updated: 2015-07-07
4. The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells
Open this publication in new window or tab >>The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells
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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.

Keyword
HSP90 inhibitors, radiation, DNA repair, EGFR, CD44, Radioresistance, Radio-­immuno targeting
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-247054 (URN)10.18632/oncotarget.5363 (DOI)000366111900051 ()26452257 (PubMedID)
Available from: 2015-03-12 Created: 2015-03-12 Last updated: 2017-12-04Bibliographically approved
5. Evaluation of biomarkers for imaging and radio-immunotherapy in combination with HSP90 inhibition in squamous cell carcinomas
Open this publication in new window or tab >>Evaluation of biomarkers for imaging and radio-immunotherapy in combination with HSP90 inhibition in squamous cell carcinomas
Show others...
(English)Manuscript (preprint) (Other academic)
Keyword
HSP90 inhibitor, Head and neck cancer, F(ab´)2, AbD19384, CD44v6, PET imaging, AT13387, 124I, EGFR, CD44v6, radio-­immunotherapy, treatment response
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-247055 (URN)
Available from: 2015-03-12 Created: 2015-03-12 Last updated: 2015-07-07

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