靶向叶酸受体α治疗卵巢癌的策略

Strategies for Targeting Folate Receptor Alpha in the Treatment of Ovarian Cancer

卵巢上皮癌(EOC)约占卵巢癌症发病率的95%,是全球妇科癌症死亡率的主要原因。目前对新诊断患者的标准治疗是卵巢肿瘤细胞减灭术加新辅助或术后铂类化疗。大多数患者最初对化疗有反应,但不幸的是,高达80%的患者最终会复发,导致患者死亡。血管生成抑制剂(如贝伐单抗)和聚ADP核糖聚合酶抑制剂(如olaparib)为一部分患者提供了一些临床益处,但只能延缓铂耐药性EOC的复发。而免疫检查点抑制剂(如抗PD1/L1单克隆抗体)的大规模临床试验也未能在EOC中提供临床益处。在过去几十年中,卵巢上皮癌的5年相对生存率仅得到有限的提高,从1995年的43%提高到2018年的50%。因此,铂耐药EOC患者的治疗选择非常有限,是一个主要的未满足的临床需求。叶酸受体α(FRα)由FOLR1基因编码,由于其在EOC细胞中普遍高表达,是一个有吸引力的治疗靶点。目前,第一种FRα靶向抗体偶联药物(ADC)-mirvetuximab soravtansine(Elahere)最近已被美国FDA批准用于治疗铂耐药卵巢上皮癌。Elahere的批准重新激发了人们开发其他FRα靶向药物治疗EOC以及其他适应症的热情。

Ovarian epithelial cancer(EOC)accounts for about 95%of the incidence rate of ovarian cancer,and is the main cause of mortality of gynecological cancer worldwide.The current standard treatment for newly diagnosed patients is ovarian tumor cell reduction surgery plus neoadjuvant or postoperative platinum based chemotherapy.Most patients initially respond to chemotherapy,but unfortunately,up to 80%of patients eventually relapse,leading to patient death.Angiogenesis inhibitors(such as bevacizumab)and poly(ADP ribose)polymerase inhib-itors(such as olaparib)provide some clinical benefits for some patients,but can only delay the recurrence of platinum resistant EOC.How-ever,large-scale clinical trials of immune checkpoint inhibitors(such as anti-PD1/L1 monoclonal antibodies)have also failed to provide clinical benefits in EOC.In the past few decades,the 5-year relative survival rate of ovarian epithelial cancer has only seen limited improve-ment,increasing from 43%in 1995 to 50%in 2018.Therefore,the treatment options for platinum resistant EOC patients are very limited,which is a major unmet clinical need.Folic acid receptor alpha(FR alpha)is encoded by the FOLR1 gene and is an attractive therapeutic target due to its widespread high expression in EOC cells.At present,the first FR alpha targeted antibody coupled drug(ADC)-mirvetux-imab soravtansine(Elahere)has recently been approved by the US FDA for the treatment of platinum resistant ovarian epithelial cancer.The approval of Elahere has reignited people's enthusiasm for developing other FR alpha targeted drugs to treat EOC and other indications.