Combined use of 177 Lu-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 cell cycle arrest mainly at G1 phase, whereas fluzoparib caused arrest at G2/M phase, and combined treatment with both agents caused cell cycle arrest at G1 phase, similar to ¹⁷⁷ Lu-DOTATATE alone. The volume of tumor xenografts was reduced by 18.6% in mice receiving combined treatment, compared to 4.9% and 11.4% in mice treated with ¹⁷⁷ Lu-DOTATATE or fluzoparib alone. Fluzoparib can potentiate the anti-tumor effect of ¹⁷⁷ Lu-DOTATATE in NCI-H727 cells in a synergistic manner by arresting the cell cycle at G1 phase. Further preclinical and clinical studies are warranted to validate these findings.

Keywords: 177Lu-DOTATATE; fluzoparib; neuroendocrine tumor; peptide receptor radionuclide therapy; poly-(ADP-ribose) polymerase inhibitor.