Liu Dongli, Kaufmann Gunnar F, Breitmeyer James B, Dickson Kristie-Ann, Marsh Deborah J, Ford Caroline E
Gynaecological Cancer Research Group, School of Clinical Medicine, Faculty of Medicine & Health, University of New South Wales, Sydney, NSW 2052, Australia.
Oncternal Therapeutics, Inc., San Diego, CA 92130, USA.
Pharmaceutics. 2022 Apr 11;14(4):837. doi: 10.3390/pharmaceutics14040837.
The non-canonical Wnt signalling receptor ROR1 is aberrantly expressed in numerous cancers, including ovarian and endometrial cancer. We previously reported that silencing ROR1 could inhibit the proliferation and metastatic potential of ovarian and endometrial cancer cells in vitro. Zilovertamab is an ROR1-targeting humanised monoclonal antibody, with demonstrated safety and efficacy in clinical trials of several ROR1-related malignancies. The aim of this study was to investigate the potential of zilovertamab alone, or in combination with commonly utilised gynaecological cancer therapies (cisplatin, paclitaxel and the PARP inhibitor-Olaparib) on high-grade serous ovarian cancer (HGSOC), including models of platinum resistance and homologous recombination deficiency (CaOV3, CaOV3CisR, PEO1 and PEO4) and endometrial cancer (EC) cell lines (Ishikawa and KLE). The effect of zilovertamab (at 25 µg/mL or 50 µg/mL) +/- agents was investigated using the IncuCyte S3 Live Cell imaging system. Zilovertamab alone inhibited the proliferation of HGSOC and EC cells in vitro, including in models of platinum resistance and homologous recombination deficiency. In general, the addition of commonly used chemotherapies to a fixed dose of zilovertamab did not enhance the observed anti-proliferative activity. This study supports the potential of zilovertamab, or other ROR1-targeting therapies, for treating women with HGSOC and EC.
非经典Wnt信号受体ROR1在包括卵巢癌和子宫内膜癌在内的多种癌症中异常表达。我们之前报道过，沉默ROR1可在体外抑制卵巢癌和子宫内膜癌细胞的增殖及转移潜能。Zilovertamab是一种靶向ROR1的人源化单克隆抗体，在几种与ROR1相关的恶性肿瘤的临床试验中已证明其安全性和有效性。本研究的目的是探究Zilovertamab单独使用，或与常用的妇科癌症治疗药物（顺铂、紫杉醇和PARP抑制剂奥拉帕利）联合使用，对高级别浆液性卵巢癌（HGSOC）的作用，包括铂耐药和同源重组缺陷模型（CaOV3、CaOV3CisR、PEO1和PEO4）以及子宫内膜癌（EC）细胞系（Ishikawa和KLE）。使用IncuCyte S3活细胞成像系统研究了Zilovertamab（25μg/mL或50μg/mL）±药物的效果。单独使用Zilovertamab可在体外抑制HGSOC和EC细胞的增殖，包括铂耐药和同源重组缺陷模型。一般来说，在固定剂量的Zilovertamab中添加常用化疗药物并不会增强所观察到的抗增殖活性。本研究支持Zilovertamab或其他靶向ROR1的疗法用于治疗HGSOC和EC女性患者的潜力。
