Wu Florence T H, Man Shan, Xu Ping, Chow Annabelle, Paez-Ribes Marta, Lee Christina R, Pirie-Shepherd Steven R, Emmenegger Urban, Kerbel Robert S
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
Cancer Res. 2016 Dec 1;76(23):6988-7000. doi: 10.1158/0008-5472.CAN-16-0888. Epub 2016 Sep 20.
Antiangiogenic tyrosine kinase inhibitors (TKI) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III clinical trials. Angiopoietin-2 (Ang2) is a proangiogenic and proinflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models. In the MDA-MB-231.LM2-4 human breast cancer model, adjuvant sunitinib was ineffective, whereas adjuvant CVX-060 delayed the progression of pulmonary or distant lymphatic metastases; however, overall survival was only improved with the adjuvant use of a VEGF-A/Ang2-bispecific CovX-body (CVX-241) but not when CVX-060 is combined with sunitinib. Adjuvant CVX-241 also showed promise in the EMT-6/CDDP murine breast cancer model, with or without an immune checkpoint inhibitor (anti-PD-L1). In the RENCA model of mouse renal cancer, however, combining CVX-060 with sunitinib in the adjuvant setting was superior to CVX-241 as treatment for postsurgical lung metastases. In the HCT116 and HT29 xenograft models of colorectal cancer, both CVX-060 and regorafenib inhibited liver metastases. Overall, our preclinical findings suggest differential strategies by which Ang2 blockers can be successfully combined with VEGF pathway targeting in the adjuvant setting to treat micrometastatic disease-particularly, in combination with VEGF-A blockers (but not VEGFR2 TKIs) in resected breast cancer; in combination with VEGFR2 TKIs in resected kidney cancer; and as single agents or with VEGFR2 TKIs in resected colorectal cancer. Cancer Res; 76(23); 6988-7000. ©2016 AACR.
靶向血管内皮生长因子受体2（VEGFR2）的抗血管生成酪氨酸激酶抑制剂（TKI）在III期临床试验中作为微转移疾病的辅助治疗并不有效。血管生成素-2（Ang2）是一种促血管生成和促炎的血管破坏剂，可与血管内皮生长因子（VEGF）协同作用。本研究的目的是测试CVX-060（一种Ang2特异性CovX体）是否能与靶向VEGFR2的TKI（舒尼替尼或瑞戈非尼）联合使用，以成功治疗多种原位植入的人肿瘤异种移植和同基因小鼠肿瘤模型中的术后转移性疾病。在MDA-MB-231.LM2-4人乳腺癌模型中，辅助性舒尼替尼无效，而辅助性CVX-060可延缓肺或远处淋巴转移的进展；然而，只有辅助使用VEGF-A/Ang2双特异性CovX体（CVX-241）才能提高总生存期，而CVX-060与舒尼替尼联合使用时则不能。辅助性CVX-241在EMT-6/CDDP小鼠乳腺癌模型中也显示出前景，无论是否联合免疫检查点抑制剂（抗PD-L1）。然而，在小鼠肾癌的RENCA模型中，在辅助治疗中，将CVX-060与舒尼替尼联合使用在治疗术后肺转移方面优于CVX-241。在结直肠癌的HCT116和HT29异种移植模型中，CVX-060和瑞戈非尼均能抑制肝转移。总体而言，我们的临床前研究结果表明，在辅助治疗中，Ang2阻滞剂与VEGF通路靶向治疗联合使用以治疗微转移疾病的策略存在差异——特别是在切除的乳腺癌中，与VEGF-A阻滞剂（而非VEGFR2 TKI）联合使用；在切除的肾癌中，与VEGFR2 TKI联合使用；在切除的结直肠癌中，作为单一药物或与VEGFR2 TKI联合使用。癌症研究；76(23)；6988 - 7000。©2016美国癌症研究协会。
