Elucidating the Role of Epigenetic Plasticity in anti-GD2 Immunotherapy Response

阐明表观遗传可塑性在抗 GD2 免疫治疗反应中的作用

• 批准号: 10400577
• 负责人: Nathaniel Mabe
• 金额: $ 6.97万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400577
• 关键词: Adrenergic Agents; Age; Biology; Categories; Cell Line; Cell surface; Cells; ChIP-seq; Chemoresistance; Clinical; Communities; Data; Development; Diagnosis; Differentiation Therapy; Down-Regulation; Ectopic Expression; Enzymes; Epigenetic Process; Epithelial; Ewings sarcoma; Future; GD3-synthase; Ganglioside GD2; Gangliosides; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Histology; Immunotherapy; Incidence; Link; MYCN gene; Malignant Childhood Neoplasm; Mesenchymal; Mesenchymal Cell Neoplasm; Metabolism; Monoclonal Antibodies; Neuroblastoma; Operative Surgical Procedures; Pathway interactions; Patient-Focused Outcomes; Patients; Ploidies; Radiation; Recurrence; Regimen; Regulation; Reporting; Risk; Role; Solid Neoplasm; Stem cell transplant; Surface; Surface Antigens; Testing; Tissue-Specific Gene Expression; Tumor Antigens; Tumor Subtype; base; chemotherapy; clinically relevant; cohort; combinatorial; design; epigenetic regulation; epigenetic silencing; epithelial to mesenchymal transition; high risk; improved; in vitro testing; in vivo; insight; interest; member; multimodality; neoplastic cell; neuroblastoma cell; novel; novel therapeutic intervention; novel therapeutics; osteosarcoma; overexpression; patient derived xenograft model; patient stratification; pediatric patients; programs; promoter; resistance mechanism; response; restoration; success; transcription factor; transcriptome sequencing; tumor

Project Summary Ganglioside GD2 is expressed on the cell surface of numerous pediatric cancers, including Ewing sarcoma, osteosarcoma, and neuroblastoma. In 2015, FDA approval of the anti-GD2 immunotherapy dinutuximab represented a paradigm shift in the treatment of neuroblastoma by significantly reducing the incidence of tumor recurrence. Despite dinutuximab's success, dinutuximab fails ~30% of neuroblastoma patients. Reports suggest that the degree of surface GD2 expression correlates with clinical response to dinutuximab. However, the cellular mechanisms governing GD2 regulation in tumor cells remain unknown. Correlation of surface GD2 expression with RNA-sequencing in a large cohort of neuroblastoma cell lines revealed that GD2 expression is associated with a mesenchymal epigenetic program. Epithelial-to-Mesenchymal Transition (EMT) has been widely studied in epithelial solid tumors for its purported role in chemoresistance. However, there have been no reports linking an adrenergic-to-mesenchymal transition (AMT) epigenetic program to regulation of surface antigen GD2, making this relationship of intense interest to the neuroblastoma community. In this proposal, AIM 1 will elucidate the relationship between AMT and GD2 expression by rigorously testing the sufficiency and necessity of the neuroblastoma-specific AMT transcription factor PRRX1 to regulate GD2. Further, loss of GD2 expression via AMT will be tested in vitro and in vivo for loss of response to dinutuximab. Aim 2 will evaluate the pathways underlying loss of GD2 expression. Preliminary data suggest that mesenchymal cell lines and tumors express markedly reduced GD3 synthase via epigenetic silencing at the gene promoter. We will evaluate whether AMT directly regulates GD3 synthase, and whether restoration of its expression rescues response to dinutuximab. These findings will directly link epigenetic state to the downregulation of tumor antigen GD2 and response to dinutuximab. Further, these studies may help inform rational combinatorial strategies to enhance anti-GD2 therapies in neuroblastoma, and could provide a framework for future studies in other GD2-expressing pediatric cancers.

项目概要 神经节苷脂 GD2 在许多儿科癌症的细胞表面表达，包括尤文肉瘤、 骨肉瘤和神经母细胞瘤。 2015年，FDA批准抗GD2免疫疗法dinutuximab 通过显着降低肿瘤的发生率，代表了神经母细胞瘤治疗的范式转变 复发。尽管 dinutuximab 取得了成功，但 dinutuximab 对约 30% 的神经母细胞瘤患者无效。报告 表明表面 GD2 表达程度与 dinutuximab 的临床反应相关。然而， 肿瘤细胞中控制 GD2 调节的细胞机制仍不清楚。表面GD2相关性 在一大群神经母细胞瘤细胞系中进行的 RNA 测序表明，GD2 的表达 与间充质表观遗传程序相关。上皮间质转化（EMT） 由于其据称在化疗耐药中的作用，在上皮实体瘤中得到了广泛研究。然而，已经有 没有报道将肾上腺素能间质转化（AMT）表观遗传程序与表面调节联系起来 抗原 GD2，使得神经母细胞瘤界对这种关系产生了浓厚的兴趣。在这个提案中， AIM 1将通过严格测试充分性来阐明AMT和GD2表达之间的关系 以及神经母细胞瘤特异性 AMT 转录因子 PRRX1 调节 GD2 的必要性。此外，损失 将在体外和体内测试通过 AMT 的 GD2 表达是否对 dinutuximab 反应丧失。目标2将 评估 GD2 表达缺失的潜在途径。初步数据表明间充质细胞 通过基因启动子的表观遗传沉默，细胞系和肿瘤表达的 GD3 合酶显着降低。我们 将评估 AMT 是否直接调节 GD3 合酶，以及恢复其表达是否可以挽救 对 dinutuximab 的反应。这些发现将表观遗传状态与肿瘤的下调直接联系起来 抗原 GD2 和对 dinutuximab 的反应。此外，这些研究可能有助于为合理的组合提供信息 增强神经母细胞瘤抗 GD2 治疗的策略，并可以为未来的研究提供框架 在其他表达 GD2 的儿科癌症中。