Combined use of ¹⁷⁷Lu‐DOTATATE peptide receptor radionuclide therapy and fluzoparib for treatment of well‐differentiated neuroendocrine tumors: A preclinical study

Abstract

Peptide receptor radionuclide therapy ( 177 Lu-DOTATATE) causes DNA strand breaks and has been validated for well-differentiated neuroendocrine tumor treatment.Poly-(ADP-ribose)-polymerase inhibitors have also been used for malignant tumors with deficient DNA repair. We aimed to determine whether the poly-(ADP-ribose)polymerase inhibitor fluzoparib could enhance the anti-tumor effects of 177 Lu-DOTATATE in neuroendocrine tumor cells and xenografts. The neuroendocrine characteristics of NCI-H727 bronchial carcinoid cells were evaluated by immunofluorescence staining. The synergistic effects of fluzoparib and 177 Lu-DOTATATE were evaluated by cell proliferation and flow cytometry assays. Tumor response and the side effects of combination therapy were also assessed in xenograft mice treated with 77 Lu-DOTATATE and fluzoparib alone or in combination. Somatostatin receptors were specifically expressed in NCI-H727 cells and tumor xenografts. 177 Lu-DOTATATE (22.20 MBq mL -1 ) and fluzoparib (50 µm) inhibited cell proliferation by 16.6% and 35.6%, respectively, compared to 73.2% in cells treated with their combination. Tumor cell proliferation was significantly suppressed by 177 Lu-DOTATATE (22.20 MBq mL -1 , 4.4-fold) and fluzoparib (50 µm, 2.1-fold). 177 Lu-DOTATATE caused

Understanding the Radiobiological Mechanisms Induced by 177Lu-DOTATATE in Comparison to External Beam Radiation Therapy

“…Olaparib radiosensitized cells to both 177 Lu-DOTATATE and EBRT, although not in all cell lines, and the synergistic effect was more pronounced in combination with EBRT (lower CDI and larger AF) compared to 177 Lu-DOTATATE. This radiosensitizing effect was previously shown by other groups with EBRT [ 25 , 26 ] and in SSTR-expressing xenograft mouse models using talazoparib [ 27 ] or fluzoparib [ 28 ] in combination with 177 Lu-DOTATATE. Nonetheless, the greater amount of DNA lesions generated by the higher dose rate of EBRT compared to 177 Lu-DOTATATE may lead to a higher number of cytotoxic DSBs following PARP inhibition (PARPi), and therefore may explain the higher radiosensitizing potential.…”

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

“…However, no information is available on the development of fibrosis and diarrhea and increased production of 5-HT in animals after the implantation of NCI-H727 cells. Therefore, its use as a model for CS has been not confirmed yet [ 69 , 70 , 71 ].…”

DNA Damage by Radiopharmaceuticals and Mechanisms of Cellular Repair

“…Additionally, Fu et al showed that the PARPi, fluzoparib, could potentiate the antitumor effect of 177 Lu-DOTATATE in NCI-H727 cells synergistically. This effect was achieved by arresting the cell cycle in the G1 phase and reducing the tumor volume [187]. Furthermore, the combination therapy of 177 Lu-DOTATATE with PARPi, Olaparib, reduced survival in different cell lines compared to RPT monotherapy [137].…”