Development of new radiopharmaceuticals for molecular imaging in oncology

PhD ceremony: Mr. E.C.F. Dijkers, 11.00 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Development of new radiopharmaceuticals for molecular imaging in oncology

Promotor(s): prof. E.G.E. de Vries, prof. R.A. Dierckx, prof. J.G.W. Kosterink

Faculty: Medical Sciences

In recent years many new anti-cancer drugs have been developed. Predicting their clinical efficacy in the individual patient remains difficult. Non-invasive nuclear imaging techniques such as ‘Single Photon Emission Computed Tomography’ (SPECT) and ‘Positron Emission Tomography’ (PET) can potentially support patient selection for drug treatment and response evaluation. In this thesis, two important targets of current and future anti-cancer drugs were studied: the ‘human epidermal growth factor receptor 2’ (HER2) and the extrinsic apoptotic pathway.

The newly developed PET tracer 89Zr-trastuzumab showed high and HER2 specific tumor uptake in preclinical models, at a good spatial resolution. The first in man application of 89Zr-trastuzumab illustrated that this PET tracer is suitable for visualization and quantification of HER2 positive tumor lesions in patients with metastasized breast cancer. The dose depends on whether a patient is trastuzumab naïve or not. Furthermore, the pro-apoptotic proteins rhTRAIL and mapatumumab were radioactively labeled and bio-distribution and tumor accumulation were studied in preclinical models with a human xenograft with high or low TRAIL-R1 and TRAIL-R2 death receptor expression. RhTRAIL and mapatumumab could efficiently be radiolabeled and used to study pharmacokinetics. In patients with metastasized disease, the radioactive mapatumumab proved to be potentially suitable to select patients for the mapatumumab anti-tumor therapy in advance. Finally, it was demonstrated that large amounts of protein (e.g. scFv425:TRAIL) could be produced by using a ‘solid-support cell growth matrix system’.