PhD defence T.G.A. (Thom) Reuvers

Brief summary:

The rise of targeted radionuclide therapy (TRT) has revolutionized the field of nuclear medicine the past years. As one of the most notable examples, peptide receptor radionuclide therapy (PRRT) employing [177Lu]Lu-[DOTA-Tyr3 ]octreotate (177Lu-DOTATATE) has been FDA- and EMA-approved for treatment of patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). During PRRT, somatostatin receptor subtype 2 (SSTR2), which is overexpressed on NET cells, is bound by the somatostatin analog octreotate, after which the coupled radionuclide lutetium-177 locally induces cellular damage during radioactive decay. Although PRRT was shown to increase progression-free survival and quality of life for GEP-NET patients, complete cures are rare and dose-limiting toxicity has been reported. Several methods for further improvement of PRRT have been proposed, including combination therapies, of which important examples are those with inhibitors of the DNA damage response (DDR). In addition, PRRT is actively being investigated for other tumor types, such as meningiomas. Most of the current knowledge on PRRT radiobiology is derived from studies on external beam radiotherapy (EBRT), ignoring vast physical differences between these two types of radiation. These include a.o. the dose rate, linear energy transfer (LET) and dose distribution. These physical differences might result in important biological differences, including the nature and dynamics of induced cellular (stress) responses and in vivo toxicity profile. Therefore, in order to further improve TRT-approaches such as PRRT for NETs and other tumor types, a better understanding of PRRT-specific radiobiology is warranted. However, preclinical research efforts into this subject are currently limited, which is caused by multiple factors, including a lack of relevant in vitro tumor models. In this thesis, the aim was to contribute to PRRT-specific radiobiological knowledge and use this for further therapy improvement. This was done by 1) comparing the NET cellular response between EBRT and PRRT; 2) investigating combinations of PRRT and various targeted therapies for the purpose of radiosensitization and 3) the development and validation of a patientderived culture model that can be used for radiobiological research for PRRT.