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Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model.
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 Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
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2016 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, no 5, p. 974-982Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition.

METHODS: Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 × 50 mg/kg), and were imaged with PET using either (18)F-FDG or (124)I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining.

RESULTS: AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with (124)I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with (124)I-AbD19384 as well as (18)F-FDG uptake, were not significantly altered by AT13387 treatment.

CONCLUSION: We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues.

Place, publisher, year, edition, pages
2016. Vol. 43, no 5, p. 974-982
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-270260DOI: 10.1007/s00259-015-3260-xISI: 000373306800020PubMedID: 26627081OAI: oai:DiVA.org:uu-270260DiVA, id: diva2:888849
Funder
Swedish Cancer Society, CAN 2012/399; CAN 2014/661Swedish Research Council, 2013-30876-104113-30
Available from: 2015-12-22 Created: 2015-12-22 Last updated: 2018-02-18Bibliographically approved
In thesis
1. Precision medicine and targeted therapy: Turning the tables on cancer
Open this publication in new window or tab >>Precision medicine and targeted therapy: Turning the tables on cancer
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An extended understanding of the molecular characteristics of cancer has led to a revolution within the field of precision medicine. This thesis explores the utilization of two targets for precision medicine, namely, CD44v6 and murine double-minute 2 and X (MDM2/X).

A novel mini-antibody construct targeting CD44v6 (AbD19384), was assessed for possible use in radiodiagnostics, while a recombinant full-length anti-CD44v6 antibody based on the same construct, AbN44v6, was evaluated for radio-immunotherapy (RIT) following labeling with 177Lu and 131I. Additionally, normal tissue biodistribution and dosimetry was assessed for radiolabeled AbN44v6. The efficacy and mechanisms behind the observed effects of PM2 therapy, a novel stapled peptide that inhibits MDM2/X, were assessed in vitro and in vivo both as monotherapy and in combination with external beam radiotherapy (EBRT). Lastly, combination therapy using RIT (177Lu-AbN44v6) and PM2 was evaluated in an in vitro 3D tumor spheroid model.

AbD19384 successfully visualized CD44v6-positive xenografts. Similarly, radiolabeled AbN44v6 bound specifically to CD44v6, and RIT resulted in antigen-dependent, activity-dependent growth inhibition of in vitro 3D tumor spheroids. Biodistribution and dosimetry revealed low-level accumulation in normal tissues and low total effective doses of 0.1 mSv/MBq of injected radioconjugate. PM2-based therapy increased pro-apoptotic protein levels and caused growth inhibition of wt p53 cancer cell lines, which was amplified in combination with radiotherapy. In vivo studies of wt p53 and p53-knockout xenografts demonstrated the specificity of PM2 towards wt p53 cancers and established the potency of combining PM2-based therapy with EBRT.

The work presented in this thesis exemplifies the potency of combination treatments based on a precise understanding of the targeted cancer. Utilizing not one but several of the molecular characteristics of a specific cancer will help turn the tables on cancer and improve patient outcomes in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1430
Keyword
p53 cancers, PM2, radiosensitization, radio-immunotherapy, MDM2/X inhibition, combination therapy, targeted radionuclide therapy, CD44v6
National Category
Medical and Health Sciences
Research subject
Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-342030 (URN)978-91-513-0239-3 (ISBN)
Public defence
2018-04-06, Rudbecksalen, Dag Hammarskjölds Väg 20, Uppsala, 13:00 (English)
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Available from: 2018-03-13 Created: 2018-02-18 Last updated: 2018-04-24

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