The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors,Molecular Cancer Therapeutics

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The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2017-11-01 00:00:00 , DOI: 10.1158/1535-7163.mct-17-0241
Allison S. Harney _{1,

2,

3,

4} , George S. Karagiannis _{1,

3,

4} , Jeanine Pignatelli _{1,

4} , Bryan D. Smith ₅ , Ece Kadioglu ₆ , Scott C. Wise ₅ , Molly M. Hood ₅ , Michael D. Kaufman ₅ , Cynthia B. Leary ₅ , Wei-Ping Lu ₅ , Gada Al-Ani ₅ , Xiaoming Chen _{1,

4} , David Entenberg _{1,

3,

4} , Maja H. Oktay _{1,

3,

7} , Yarong Wang _{1,

3,

4} , Lawrence Chun ₈ , Michele De Palma ₆ , Joan G. Jones _{1,

3,

7,

9} , Daniel L. Flynn ₅ , John S. Condeelis _{1,

3,

4}

Affiliation

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486–501. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2327][1] [1]: /lookup/volpage/16/2327?iss=11

中文翻译：

选择性Tie2抑制剂Rebastinib阻止乳腺癌和胰腺神经内分泌肿瘤中Tie2Hi巨噬细胞的募集和功能。

肿瘤浸润性髓样细胞通过介导血管生成，肿瘤细胞浸润和转移来促进肿瘤进展，这可以抵消化学疗法，放射线和抗血管生成疗法的作用。在这里，我们显示了激酶转换控制抑制剂瑞巴斯汀抑制了Tie2，这是一种在转移性癌症小鼠模型中在内皮细胞和表达Tie2的巨噬细胞上表达的酪氨酸激酶受体。Rebastinib通过减少肿瘤转移微环境（TMEM）中的血管周围Tie2Hi / Vegf-AHi巨噬细胞介导的Tie2 +髓样细胞浸润，抗血管生成作用和阻断肿瘤细胞浸润来减少转移性乳腺癌原位小鼠模型中的肿瘤生长和转移。。瑞巴司替尼的抗肿瘤作用通过减少肿瘤体积，转移并改善总体生存率，增强了微管抑制化学治疗剂（eribulin或紫杉醇）的功效。Rebastinib对血管生成素/ Tie2信号转导的抑制作用损害了由肿瘤性Tie2 +巨噬细胞介导的肿瘤进展中的多个途径，包括TMEM依赖的传播和血管生成素/ Tie2依赖的血管生成。Rebastinib是一种在癌症患者中实现Tie2抑制的有前途的疗法。分子癌疗法；16（11）; 2486–501。©2017 AACR。本文在本期要点[p。2327] [1] [1]：/ lookup / volpage / 16/2327？iss = 11 Rebastinib对血管生成素/ Tie2信号转导的抑制作用损害了由肿瘤Tie2 +巨噬细胞介导的肿瘤进展的多种途径，包括TMEM依赖的传播和血管生成素/ Tie2依赖的血管生成。Rebastinib是一种在癌症患者中实现Tie2抑制的有前途的疗法。分子癌疗法；16（11）; 2486–501。©2017 AACR。本文在本期要点[p。2327] [1] [1]：/ lookup / volpage / 16/2327？iss = 11 Rebastinib对血管生成素/ Tie2信号转导的抑制作用损害了由肿瘤性Tie2 +巨噬细胞介导的肿瘤进展中的多个途径，包括TMEM依赖的传播和血管生成素/ Tie2依赖的血管生成。Rebastinib是一种在癌症患者中实现Tie2抑制的有前途的疗法。分子癌疗法；16（11）; 2486–501。©2017 AACR。本文在本期要点[p。2327] [1] [1]：/ lookup / volpage / 16/2327？iss = 11

更新日期：2017-11-10

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