Deciphering the radiobiology of targeted radionuclide therapy: from subcellular to intra-tumoural analyses

Background and unmet needTargeted radionuclide therapies (TRTs) are a promising modality to treat patients with metastasized cancer. TRTs function via systemic administration of radiolabelled molecules (α- and β-particle emitters) designed to target tumour cells. However, the radiobiological effects of TRTs are poorly understood, and rational design of new modalities based on underlying cellular mechanisms is therefore not possible, resulting in suboptimal treatment strategies. Since most patients with advanced cancer cannot be cured at the moment, it is therefore my ultimate goal to improve TRT.Aim My ERC project aims to identify and quantitate specific radiobiological mechanisms of TRT-radiation effects in vitro and in vivo. ObjectivesThis unique multidisciplinary project will yield critical information on subcellular and intra-tumoural radiopharmaceutical uptake kinetics, DNA damage response kinetics and dose response simulations, and will profoundly increase our knowledge on TRT to push the field forward. I will determine cellular dosimetric parameters for α-TRT and β-TRT, determine effects of subcellular and intra-tumoural localizations of TRT on DNA damage induction and survival, image in vivo TRT efficacy and define effects of treatment heterogeneity to ultimately perform realistic dosimetric simulations in 2D and 3D cancer models. Besides using previously developed techniques, we will develop an innovative new imaging setup for high resolution imaging of TRT by intravital confocal microscopy to image real-time cellular processes of anti-cancer therapies in a living organism.Expected OutcomesOutcome of my project will not only increase our fundamental knowledge on TRT and yield a novel imaging modality, but additionally has high potential to contribute to improved treatment strategies and ultimately patient outcomes.