Combined use of <sup>177</sup> Lu‐DOTATATE peptide receptor radionuclide therapy and fluzoparib for treatment of well‐differentiated neuroendocrine tumors: A preclinical study
Jingjing Fu, Fan Qiu, Cati Raluca Stolniceanu, Fei Yu, Shiming Zang, Yili Xiang, Yue Huang, Milovan Matović, Cipriana Ştefănescu, Qiyun Tang, Feng Wang
Abstract
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 µ m ) 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 µ m , 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.