PhD defence E.A.M. (Eline) Ruigrok

Summary:

This thesis describes the preclinical assessment of PCa specific radiotracers with the aim of improving the treatment efficacy and increasing therapeutic safety. 

In Chapter 2 we give an overview of the current preclinical research in the field regarding PCa targeted radionuclide therapy using PSMA-specific radiotracers, which is mainly focused on the development of novel PSMA-specific tracers. Regarding clinical trials, the small molecule inhibitors PSMA-617 and PSMA-I&T are most often applied for PSMA-TRT. However, both tracers have never been directly compared to each other in terms of tumor binding characteristics and their binding to healthy PSMA expressing organs. In Chapter 3 we extensively assesed in a preclinical setting which of the PSMA tracers PSMA-617, PSMA-I&T and nanobody JVZ-007, has the most optimal therapeutic characteristics and best safety profile. 

Additional to this evaluation, we investigated several methods to enhance the therapeutic effects of TRT in PCa models in vitro and in vivo. In Chapter 4 we analyzed if combining PSMA-TRT with PARPi led to synergistically increased therapeutic efficacy. In Chapter 5, we used another method to increase the therapeutic effects of PSMA-TRT, by the use of alpha particle emitting actinium-225 instead of lutetium-177. Here we conducted an in vitro study to determine the relative biological effectiveness of actinium-225 labeled PSMA-I&T compared to lutetium-177 labeled PSMA-I&T. 

Finally, to aid safe clinical implementation, it is crucial that PCa TRTs are evaluated for their in vivo toxicity profiles. In Chapter 6, we focused on the in vivo safety of NeoB, a radiotracer targeting the GRPR. Here, we evaluated the acute, early and late toxicity correlated to the dose of lutetium-177 labeled NeoB.