Autotaxin catalyzes the formation of lysophosphatidic acid, which stimulates tumor growth and metastasis and decreases the effectiveness of cancer therapies. In breast cancer, autotaxin is secreted mainly by breast adipocytes, especially when stimulated by inflammatory cytokines produced by tumors. In this work, we studied the effects of an ATX inhibitor, GLPG1690, which is in phase III clinical trials for idiopathic pulmonary fibrosis, on responses to radiotherapy and chemotherapy in a syngeneic orthotopic mouse model of breast cancer. Tumors were treated with fractionated external beam irradiation, which was optimized to decrease tumor weight by approximately 80%. Mice were also dosed twice daily with GLPG1690 or vehicle beginning at 1 day before the radiation until 4 days after radiation was completed. GLPG1690 combined with irradiation did not decrease tumor growth further compared with radiation alone. However, GLPG1690 decreased the uptake of 3′-deoxy-3′-[18F]-fluorothymidine by tumors and the percentage of Ki67-positive cells. This was also associated with increased cleaved caspase-3 and decreased Bcl-2 levels in these tumors. GLPG1690 decreased irradiation-induced C-C motif chemokine ligand-11 in tumors and levels of IL9, IL12p40, macrophage colony-stimulating factor, and IFNγ in adipose tissue adjacent to the tumor. In other experiments, mice were treated with doxorubicin every 2 days after the tumors developed. GLPG1690 acted synergistically with doxorubicin to decrease tumor growth and the percentage of Ki67-positive cells. GLPG1690 also increased 4-hydroxynonenal-protein adducts in these tumors. These results indicate that inhibiting ATX provides a promising adjuvant to improve the outcomes of radiotherapy and chemotherapy for breast cancer.

中文翻译：

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用 GLPG1690 抑制 autotaxin 可提高放疗和化疗在乳腺癌小鼠模型中的疗效

自分泌运动因子催化溶血磷脂酸的形成，从而刺激肿瘤生长和转移并降低癌症治疗的有效性。在乳腺癌中，自分泌运动因子主要由乳腺脂肪细胞分泌，尤其是在受肿瘤产生的炎性细胞因子刺激时。在这项工作中，我们研究了 ATX 抑制剂 GLPG1690（它处于针对特发性肺纤维化的 III 期临床试验中）对同基因原位乳腺癌小鼠模型对放疗和化疗反应的影响。用分次外照射照射治疗肿瘤，该照射经过优化以减少约 80% 的肿瘤重量。在辐射前 1 天开始至辐射完成后 4 天，小鼠也每天给药两次 GLPG1690 或载体。与单独放疗相比，GLPG1690 联合放疗并未进一步降低肿瘤生长。然而，GLPG1690 降低了肿瘤对 3'-脱氧-3'-[18F]-氟胸苷的摄取和 Ki67 阳性细胞的百分比。这也与这些肿瘤中裂解的 caspase-3 增加和 Bcl-2 水平降低有关。GLPG1690 降低了肿瘤中辐射诱导的 CC 基序趋化因子配体 11 和肿瘤附近脂肪组织中 IL9、IL12p40、巨噬细胞集落刺激因子和 IFNγ 的水平。在其他实验中，小鼠在肿瘤发展后每 2 天接受一次阿霉素治疗。GLPG1690 与阿霉素协同作用以减少肿瘤生长和 Ki67 阳性细胞的百分比。GLPG1690 还增加了这些肿瘤中的 4-羟基壬烯醛蛋白加合物。