Biomarker Identification of Radionuclide Therapy-induced Radiation Responses

Peptide receptor radionuclide therapy (PRRT) with \[177Lu\]Lu-DOTA-\[Tyr3\]octreotate (177Lu-DOTATATE) is a form of internal radiation treatment for patients with neuroendocrine tumors (NET) to reduce tumor growth and stabilize disease. Due to limited response rates, there is a need to improve this therapy. A better understanding of therapeutic radiobiological responses, such as transcriptional and DNA damage responses, could contribute to identification of biomarkers for toxicity and/or efficacy prediction. Easy access to biological samples for biomarker discovery would be via a so-called liquid biopsy (drawing blood) to collect healthy peripheral blood mononuclear cells (PBMCs) or circulating tumor DNA (ctDNA) for further investigation. Exposure to ionizing radiation (IR) such as by PRRT leads to complex cellular responses including activation of the DNA damage response and changes in gene expression which can differ between individuals. This was previously shown for ex vivo external beam radiation of blood cells in which radiation responsive genes were identified. These genes were also similarly up- or downregulated following in vivo exposure to total-body irradiation of patients. In addition, different studies have shown a good correlation between radiation dose to the blood and DNA double strand break induction in PBMCs for various PRRT-like treatments. These results show that such events can be measured in PBMCs and indicate that ex vivo irradiation can mimic the in vivo transcriptional regulation and DNA damage induction. Therefore, to identify PRRT-induced cellular responses, the investigators will analyze the effects of 177Lu-DOTATATE IR on the transcriptional regulation in PBMCs and compare this regulation to radiation dose and DNA damage induction. In addition, it was shown that levels of ctDNA can be associated with treatment response and anticancer treatment is also shown to influence ctDNA methylation patterns. The investigators will therefore explor