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Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic
Pharmaceutics ( IF 4.9 ) Pub Date : 2020-10-20 , DOI: 10.3390/pharmaceutics12100996
Walid Kamoun , Elden Swindell , Christine Pien , Lia Luus , Jason Cain , Minh Pham , Irawati Kandela , Zhaohua Richard Huang , Suresh K. Tipparaju , Alexander Koshkaryev , Vasileios Askoxylakis , Dmitri B. Kirpotin , Troy Bloom , Mari Mino-Kenudson , James D. Marks , Alena Zalutskaya , Wiam Bshara , Carl Morrison , Daryl C. Drummond

Ephrin receptor A2 (EphA2) is a member of the Ephrin/Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, and its expression is in many cases associated with poor prognosis. We recently developed a novel EphA2-targeting antibody-directed nanotherapeutic encapsulating a labile prodrug of docetaxel (EphA2-ILs-DTXp) for the treatment of EphA2-expressing malignancies. Here, we characterized the expression of EphA2 in bladder cancer using immunohistochemistry in 177 human bladder cancer samples and determined the preclinical efficacy of EphA2-ILs-DTXp in four EphA2-positive patient-derived xenograft (PDX) models of the disease, either as a monotherapy, or in combination with gemcitabine. EphA2 expression was detected in 80–100% of bladder cancer samples and correlated with shorter patient survival. EphA2 was found to be expressed in tumor cells and/or tumor-associated blood vessels in both primary and metastatic lesions with a concordance rate of approximately 90%. The EphA2-targeted antibody-directed nanotherapeutic EphA2-ILs-DTXp controlled tumor growth, mediated greater regression, and was more active than free docetaxel at equitoxic dosing in all four EphA2-positive bladder cancer PDX models. Combination of EphA2-ILs-DTXp and gemcitabine in one PDX model led to improved tumor growth control compared to monotherapies or the combination of free docetaxel and gemcitabine. These data demonstrating the prevalence of EphA2 in bladder cancers and efficacy of EphA2-ILs-DTXp in PDX models support the clinical exploration of EphA2 targeting in bladder cancer.

中文翻译:

使用新型抗体导向的Nanotherapeutic靶向膀胱癌中的EphA2

Ephrin受体A2(EphA2)是Ephrin / Eph受体细胞间信号传导分子家族的成员,在细胞增殖,分化和迁移中起关键作用。EphA2在广泛的癌症中过表达,在许多情况下其表达与不良预后有关。我们最近开发了一种新型的靶向EphA2的抗体导向的纳米疗法,该疗法封装了多西他赛的不稳定前药(EphA2-ILs-DTXp),用于治疗表达EphA2的恶性肿瘤。在这里,我们使用免疫组织化学方法在177例人类膀胱癌样品中表征了EphA2在膀胱癌中的表达,并确定了EphA2-ILs-DTXp在四种EphA2阳性患者源性异种移植(PDX)模型中的临床前疗效,单一疗法,或与吉西他滨联用。在80-100%的膀胱癌样本中检测到EphA2表达,并且与患者生存期较短有关。发现EphA2在原发灶和转移灶中均在肿瘤细胞和/或肿瘤相关血管中表达,一致率约为90%。在所有四个EphA2阳性膀胱癌PDX模型中,以EphA2靶向的抗体导向的纳米治疗性EphA2-ILs-DTXp控制肿瘤生长,介导更大的消退,并且在游离试验中比游离多西他赛更具活性。与单一疗法或游离多西他赛和吉西他滨的组合相比,在一个PDX模型中EphA2-ILs-DTXp和吉西他滨的组合可改善肿瘤的生长控制。
更新日期:2020-10-20
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