PET imaging of targets and targeted anticancer therapies to shed light on personalized treatment strategies

Lemonitsa Hillegonda Mammatas

Research output: PhD ThesisPhd-Thesis - Research and graduation internal


This thesis focused on the value of different positron emission tomography (PET) imaging techniques visualizing targets and targeted anticancer therapies for future treatment tailoring. As a general introduction, chapter 1 provides an overview of the available literature on molecular imaging with PET for the improvement of personalized cancer care. Part I of this thesis focusses on visualizing targets: estrogen receptor (ER) and androgen receptor (AR) imaging in patients with breast cancer. Approximately 75% of the patients with breast cancer have an ER-positive tumor. The success rate of endocrine therapy relies heavily on the ER expression of the tumor. Recently, also AR expression emerged as a possible target of therapy, because it is present in 70–80% of the patients with breast cancer. In chapter 2, [18F]fluoroestradiol ([18F]FES) PET and [18F]fluorodihydrotestosterone ([18F]FDHT) PET are evaluated to assess whether uptake correlates with the levels of ER and AR expression in simultaneous biopsied metastases. In chapter 3, the interobserver variability in visual and quantitative assessment of [18F]FES and [18F]FDHT PET are determined, because reliable, observer- independent evaluation is necessary for application of these new techniques in clinical practice. Part II concerns strategies to optimize treatment with the targeted anticancer drug sorafenib, a small molecule protein kinase inhibitor. Sorafenib has activity against multiple targets involved in the growth, angiogenesis and spread of cancer including C-RAF, B-RAF, mutant B-RAF, vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptor β, FMS-like tyrosine kinase 3, c-Kit protein and RET receptor tyrosine kinase. Sorafenib has been approved for treatment of locally advanced and metastatic hepatocellular carcinoma, renal cell carcinoma and iodine-refractory differentiated thyroid carcinoma at a standard fixed dose of 400 mg twice daily in a continuous schedule. Currently, no biomarkers are available to predict response to sorafenib in an individual patient. In chapter 4, we examine whether [11C]sorafenib PET and [15O]H2O perfusion PET have the potential to predict the treatment efficacy of sorafenib. In chapter 5, the results of a phase I exposure escalation study are presented investigating an alternative high-dose, pulsatile schedule of sorafenib using drug monitoring in attempt to improve the efficacy of sorafenib. In conclusion, in this thesis it is shown that PET imaging of targets and targeted anticancer therapies leads to better understanding of target expression in different tumor lesions within one patient and visualization of the tumor accumulation and effects of therapy. Although the development of each tracer has challenges, such as its target affinity, physiological background uptake and metabolism, concordance between tracer uptake and target expression/drug accumulation in tumors, physical half-life, scanning logistics, and reliable observer-independent evaluation, PET imaging has the potential to lead to progress in personalized treatment strategies, which includes dose optimizing strategies and treatment (combination) choices for an individual patient with cancer.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Vrije Universiteit Amsterdam
  • Verheul, Henk, Supervisor
  • Lammertsma, Adriaan, Supervisor
  • Menke-van der Houven van Oordt, Willemien, Co-supervisor
  • Boven, Epie, Co-supervisor
Award date24 May 2021
Place of PublicationEnschede
Print ISBNs9789464191905
Publication statusPublished - 25 May 2021

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