Imaging DNA Damage Repair in vivo Following ¹⁷⁷Lu-DOTATATE Therapy

Abstract

Purpose: Molecular Radiotherapy (MRT) using ¹⁷⁷Lu-DOTATATE is a most effective therapy for the treatment of somatostatin receptor expressing neuroendocrine tumors (NETs). Despite its frequent and successful use in the clinic, little or no radiobiological considerations are taken into account at the time of treatment planning or delivery, and upon positive uptake of octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiological and DNA damage effects in the tumor. Here, we visualize and quantify the extent of DNA damage response following ¹⁷⁷Lu-DOTATATE therapy using SPECT imaging with ¹¹¹In-anti-γH2AX-TAT. This work is a proof-of-principle study of this in vivo non-invasive biodosimeter with beta-emitting therapeutic radiopharmaceuticals. Methods: Six cell lines were exposed to external beam radiotherapy (EBRT) or ¹⁷⁷Lu-DOTATATE, after which the number of γH2AX foci and clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor positive tumor xenografts were treated with ¹⁷⁷Lu-DOTATATE or sham-treated, and co-injected with ¹¹¹In-anti-γH2AX-TAT, ¹¹¹In-IgG-TAT control, or vehicle. Results: Clonogenic survival following EBRT was cell line specific, indicating varying levels of intrinsic radiosensitivity. In vitro, cell lines treated with ¹⁷⁷Lu-DOTATATE, clonogenic survival decreased and γH2AX foci increased in cells expressing high levels of somatostatin receptor subtype 2 (SST2). Ex vivo measurements revealed a partial correlation between ¹⁷⁷Lu-DOTATATE uptake and γH2AX foci induction between different regions of CA20948 xenograft tumors, suggesting different parts of the tumor may react differentially to ¹⁷⁷Lu-DOTATATE irradiation. Conclusion: ¹¹¹In-anti-γH2AX-TAT allows monitoring of DNA damage following ¹⁷⁷Lu-DOTATATE therapy, and reveals heterogeneous damage responses.