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

Kol, K. J-D., 2019, [Groningen]: Rijksuniversiteit Groningen. 175 p.

Research output: ThesisThesis fully internal (DIV)

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  • Title and contents

    Final publisher's version, 806 KB, PDF document

  • Chapter 1

    Final publisher's version, 1.66 MB, PDF document

  • Chapter 2

    Final publisher's version, 4.96 MB, PDF document

  • Chapter 3

    Final publisher's version, 3.01 MB, PDF document

  • Chapter 4

    Final publisher's version, 6.71 MB, PDF document

  • Chapter 5

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  • Chapter 6

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  • Chapter 7

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  • Chapter 8

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  • Appendix 1

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  • Complete thesis

    Final publisher's version, 30.8 MB, PDF document

  • Propositions

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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
Award date30-Jan-2019
Place of Publication[Groningen]
Print ISBNs978-94-034-1339-6
Electronic ISBNs978-94-034-1338-9
Publication statusPublished - 2019

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