Jing Yuqi, Bejarano Marcela Toro, Zaias Julia, Merchan Jaime R
Division of Hematology-Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue, Suite 3300, Miami, FL, 33136, USA.
Breast Cancer Res Treat. 2015 Jan;149(1):99-108. doi: 10.1007/s10549-014-3236-8. Epub 2014 Dec 18.
The urokinase receptor (uPAR) plays a critical role in breast cancer (BC) progression and metastases and is a validated target for novel therapies. The current study investigates the effects of MV-uPA, an oncolytic measles virus fully retargeted against uPAR in syngeneic and xenograft BC metastases models. In vitro replication and cytotoxicity of MVs retargeted against human (MV-h-uPA) or mouse (MV-m-uPA) uPAR were assessed in human and murine cancer and non-cancer mammary epithelial cells. The in vivo effects of species-specific uPAR retargeted MVs were assessed in syngeneic and xenograft models of experimental metastases, established by intravenous administration of luciferase expressing 4T1 or MDA-MD-231 cells. Metastases progression was assessed by in vivo bioluminescence imaging. Tumor targeting was evaluated by qRT-PCR of MV-N, rescue of viable viral particles, and immunostaining of MV particles in lungs from tumor bearing mice. In vitro, MV-h-uPA and MV-m-uPA selectively infected, replicated, and induced cytotoxicity in cancer compared to non-cancer cells in a species-specific manner. In vivo, MV-m-uPA delayed 4T1 lung metastases progression and prolonged survival. These effects were associated with identification of viable viral particles, viral RNA, and detection of MV-N by immunostaining from lung tissues in treated mice. In the human MDA-MB-231 metastases model, intravenous administration of MV-h-uPA markedly inhibited metastases progression and significantly improved survival, compared to controls. No significant treatment-related toxicity was observed in treated mice. The above preclinical findings strongly suggest that uPAR retargeted measles virotherapy is a novel and feasible systemic therapy strategy against metastatic breast cancer.
尿激酶受体（uPAR）在乳腺癌（BC）进展和转移中起关键作用，是新型疗法的一个经过验证的靶点。本研究调查了MV-uPA的作用，MV-uPA是一种在同基因和异种移植BC转移模型中完全重新靶向uPAR的溶瘤麻疹病毒。在人源和鼠源癌症及非癌症乳腺上皮细胞中评估了重新靶向人（MV-h-uPA）或小鼠（MV-m-uPA）uPAR的麻疹病毒（MVs）的体外复制和细胞毒性。通过静脉注射表达荧光素酶的4T1或MDA-MD-231细胞建立实验性转移的同基因和异种移植模型，评估物种特异性uPAR重新靶向的MVs的体内作用。通过体内生物发光成像评估转移进展。通过对MV-N进行qRT-PCR、挽救活病毒颗粒以及对荷瘤小鼠肺部的MV颗粒进行免疫染色来评估肿瘤靶向性。在体外，与非癌细胞相比，MV-h-uPA和MV-m-uPA以物种特异性方式选择性感染、复制并诱导癌细胞产生细胞毒性。在体内，MV-m-uPA延缓了4T1肺转移的进展并延长了生存期。这些作用与在治疗小鼠的肺组织中鉴定活病毒颗粒、病毒RNA以及通过免疫染色检测MV-N有关。在人MDA-MB-231转移模型中，与对照组相比，静脉注射MV-h-uPA显著抑制了转移进展并显著提高了生存期。在治疗小鼠中未观察到与治疗相关的明显毒性。上述临床前研究结果强烈表明，uPAR重新靶向的麻疹病毒疗法是一种针对转移性乳腺癌的新型且可行的全身治疗策略。
