Ortiz Michael V, Roberts Stephen S, Glade Bender Julia, Shukla Neerav, Wexler Leonard H
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Front Oncol. 2019 Feb 26;9:108. doi: 10.3389/fonc.2019.00108. eCollection 2019.
Glypican 3 (GPC3) is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of pediatric solid embryonal tumors including the majority of hepatoblastomas, Wilms tumors, rhabdoid tumors, certain germ cell tumor subtypes, and a minority of rhabdomyosarcomas. Via both its core protein and heparan sulfate side chains, GPC3 activates the canonical Wnt/β-catenin pathway, which is frequently overexpressed in these malignancies. Loss of function mutations in lead to Simpson-Golabi-Behmel Syndrome, an X-linked overgrowth condition with a predisposition to GPC3-expressing cancers including hepatoblastoma and Wilms tumor. There are several immunotherapeutic approaches to targeting GPC3, including vaccines, monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, cytolytic T lymphocytes, and CAR T cells. These therapies offer a potentially novel means to target these pediatric solid embryonal tumors. A key pediatric-specific consideration of GPC3-targeted immunotherapeutics is that GPC3 can be physiologically expressed in normal tissues during the first year of life, particularly in the liver and kidney. In summary, this article reviews the current evidence for targeting childhood cancers with GPC3-directed immunotherapies.
磷脂酰肌醇蛋白聚糖3（GPC3）是一种硫酸乙酰肝素蛋白聚糖和细胞表面癌胚蛋白，在多种小儿实体胚胎肿瘤中高度表达，包括大多数肝母细胞瘤、肾母细胞瘤、横纹肌样瘤、某些生殖细胞肿瘤亚型以及少数横纹肌肉瘤。GPC3通过其核心蛋白和硫酸乙酰肝素侧链激活经典的Wnt/β-连环蛋白通路，该通路在这些恶性肿瘤中经常过度表达。GPC3功能丧失突变会导致辛普森-戈拉比-贝梅尔综合征，这是一种X连锁过度生长疾病，易患表达GPC3的癌症，包括肝母细胞瘤和肾母细胞瘤。针对GPC3有几种免疫治疗方法，包括疫苗、单克隆抗体、抗体药物偶联物、双特异性抗体、细胞溶解性T淋巴细胞和嵌合抗原受体T细胞（CAR T细胞）。这些疗法为靶向这些小儿实体胚胎肿瘤提供了一种潜在的新方法。针对GPC3的免疫治疗在儿科的一个关键特殊考虑因素是，GPC3在生命的第一年可在正常组织中生理性表达，尤其是在肝脏和肾脏。总之，本文综述了目前使用GPC3导向免疫疗法治疗儿童癌症的证据。
