Biomarker Identification of Radionuclide Therapy-induced Radiation Responses
Status:
Not yet recruiting
Trial end date:
2024-10-01
Target enrollment:
Participant gender:
Summary
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 explore dynamics of ctDNA levels and methylation patterns before and after
PRRT to provide more knowledge of the effect of radiation response on ctDNA.
This is a pilot study to validate the possibility of determining the radiation response of
PRRT with 177Lu-DOTATATE in PBMCs and ctDNA.