Preclinical evaluation and molecular imaging of HER family dynamics to guide cancer therapy

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    Abstract

    Insight in changes in membrane expression of human epidermal growth factor receptor (HER) proteins (also known as receptor dynamics) as a result of cancer treatment with HER-targeted agents would be of major interest for clinical decision making. HER-targeted agents affect many processes involved in HER dynamics, but also influence dynamics of other plasma membrane proteins, such as the immune checkpoint PD-L1. Non-invasive molecular imaging could potentially be used as a tool to monitor receptor dynamics. Therefore, the aim was to gain more insight in the effect of HER-targeting agents on HER and PD-L1 dynamics to provide a rationale for future combination therapies. In addition, HER tracers for molecular imaging to evaluate drug tumor targeting, organ distribution and target dynamics were explored.
    Effects of anti-EGFR monoclonal antibodies imgatuzumab and cetuximab on EGFR dynamics, intracellular signaling and survival were studied in a panel of human EGFR wild-type NSCLC cell lines. We monitored whether changes in EGFR dynamics affect antibody-dependent cellular cytotoxicity responses and tumor cell growth inhibition. Additionally, a PET imaging tracer based on imgatuzumab was employed to study effects of circulating EGFR protein in blood on tumor tracer uptake. A HER3-directed PET tracer was used to visualize HER3 protein dynamics in response to a HER2-targeting therapeutic agent. Finally, we identified EGFR-related signaling pathways regulating PD-L1 membrane expression in EGFR wild-type NSCLC and provided a rationale to explore combinations of immune checkpoint inhibitors with other targeted agents.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • de Jong, Steven, Supervisor
    • de Vries, Liesbeth, Supervisor
    • Terwisscha Van Scheltinga, Antonius, Co-supervisor
    • Hendrikse, N. Harry, Assessment committee, External person
    • Groen, Harry, Assessment committee
    • Kruyt, Frank, Assessment committee
    Award date30-Jan-2019
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-034-1339-6
    Electronic ISBNs978-94-034-1338-9
    Publication statusPublished - 2019

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