Nagano Kazuya, Higashisaka Kazuma, Tsunoda Shin-Ichi, Tsutsumi Yasuo
Graduate School of Pharmaceutical Sciences, Osaka University.
National Institute of Biomedical Innovation, Health and Nutrition.
Yakugaku Zasshi. 2018;138(7):903-909. doi: 10.1248/yakushi.17-00220-1.
Human epidermal growth factor receptor 2 (Her2)-targeting antibodies and anti-hormone therapy are effective for most breast cancer patients. However, such approaches are not viable with resistant cases or in triple-negative breast cancer (TNBC) patients, given the lack of Her2 and estrogen and progesterone receptors in these patients. Thus, new drug targets are urgently required. From this perspective, we searched for novel drug targets using proteomic analysis, and identified Eph receptor A10 (EphA10), which is elevated in breast cancer cells as compared to normal breast tissue. Here, we evaluated the potential of EphA10 as a drug target by analyzing its protein expression profile/function in cancer cells, and then by using an anti-EphA10 antibody to treat EphA10-expressing tumor-bearing mice. Protein expression profile analysis showed that EphA10 was expressed in various breast cancer subtypes, including TNBCs, with no expression observed in normal tissues, apart from the testes. Moreover, functional analysis of the cancer cells revealed that ligand-dependent proliferation was observed in EphA10-expressed cancer cells. Thus, we developed our novel anti-EphA10 antibody, which binds to EphA10 with high specificity and affinity at the nanomolar level. Finally, therapeutic analysis indicated that tumor growth was significantly suppressed in the mAb-treated mice in a dose-dependent manner. These results suggest that the EphA10-targeting therapy may be a novel therapeutic option for the management of breast cancer, including in TNBCs which aren't currently treated with molecular-targeted agents. Consequently, we hope that these findings will contribute to the development of a new targeting therapy for refractory breast cancer patients.
人表皮生长因子受体2（Her2）靶向抗体和抗激素疗法对大多数乳腺癌患者有效。然而，鉴于这些患者缺乏Her2以及雌激素和孕激素受体，对于耐药病例或三阴性乳腺癌（TNBC）患者而言，此类方法不可行。因此，迫切需要新的药物靶点。从这个角度出发，我们通过蛋白质组学分析寻找新的药物靶点，并鉴定出与正常乳腺组织相比在乳腺癌细胞中表达上调的Eph受体A10（EphA10）。在此，我们通过分析EphA10在癌细胞中的蛋白质表达谱/功能，然后使用抗EphA10抗体治疗表达EphA10的荷瘤小鼠，来评估EphA10作为药物靶点的潜力。蛋白质表达谱分析表明，EphA10在包括TNBC在内的各种乳腺癌亚型中均有表达，除睾丸外，在正常组织中未观察到表达。此外，对癌细胞的功能分析显示，在表达EphA10的癌细胞中观察到配体依赖性增殖。因此，我们开发了新型抗EphA10抗体，其在纳摩尔水平上以高特异性和亲和力与EphA10结合。最后，治疗分析表明，单克隆抗体治疗的小鼠肿瘤生长以剂量依赖性方式显著受到抑制。这些结果表明，靶向EphA10的治疗可能是治疗乳腺癌的一种新的治疗选择，包括目前未用分子靶向药物治疗的TNBC。因此，我们希望这些发现将有助于为难治性乳腺癌患者开发新的靶向治疗方法。
