Wingerter Arthur, El Malki Khalifa, Sandhoff Roger, Seidmann Larissa, Wagner Daniel-Christoph, Lehmann Nadine, Vewinger Nadine, Frauenknecht Katrin B M, Sommer Clemens J, Traub Frank, Kindler Thomas, Russo Alexandra, Otto Henrike, Lollert André, Staatz Gundula, Roth Lea, Paret Claudia, Faber Jörg
Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
University Cancer Center (UCT), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Cancers (Basel). 2021 Jan 29;13(3):520. doi: 10.3390/cancers13030520.
The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing's sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood-brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher's disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.
神经节苷脂GD2是儿童癌症的一个重要靶点。然而，迄今为止唯一被批准的靶向GD2的疗法是单克隆抗体迪努妥昔单抗，它用于治疗神经母细胞瘤。GD2作为其他肿瘤实体靶点的相关性仍有待阐明。在此，我们通过流式细胞术分析了不同儿科肿瘤实体中GD2的表达，并测试了两种靶向GD2的方法。H3K27M突变型弥漫性中线胶质瘤（H3K27M突变型DMG）样本显示GD2表达最高，所有细胞对抗原均呈强阳性。尤因肉瘤（ES）样本也显示高表达，但存在肿瘤内和肿瘤间的异质性。骨肉瘤表达低至中等，有高比例的GD2阴性细胞。迪努妥昔单抗β联合伊立替康和替莫唑胺用于治疗一名患有难治性ES的5岁女孩。疾病控制持续了12个月以上，直到检测到一个单一的部分GD2阴性的颅内转移灶。为了在H3K27M突变型DMG中靶向GD2，我们通过 eliglustat阻断神经节苷脂合成，因为迪努妥昔单抗不能穿过血脑屏障。Eliglustat是葡萄糖神经酰胺合酶的抑制剂，用于治疗患有戈谢病的儿童。Eliglustat在体外完全抑制了原发性H3K27M突变型DMG细胞的增殖。总之，我们的数据提供了证据表明迪努妥昔单抗可能对高GD2表达的肿瘤有效。此外，破坏H3K27M突变型DMG中的神经节苷脂代谢可能为这种高度致命的癌症开辟一种新的治疗选择。
