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: 10514877
• 负责人: Nathaniel Mabe
• 金额: $ 0.25万
• 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/10514877
• 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; Funding; 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 (from the funded application) 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.

项目摘要（来自资助申请） 神经节苷脂GD 2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GD 2免疫疗法dinutuximab 通过显著降低肿瘤的发生率， 复发尽管dinutuximab的成功，dinutuximab失败约30%的神经母细胞瘤患者。报告 表明表面GD 2表达的程度与对dinutuximab的临床应答相关。然而，在这方面， 在肿瘤细胞中控制GD 2调节的细胞机制仍然未知。表面GD 2的相关性 在一个大的神经母细胞瘤细胞系群体中，用RNA测序显示GD 2表达是 与间充质表观遗传程序有关上皮-间充质转化（EMT） 由于其在化学抗性中的作用而在上皮实体瘤中被广泛研究。但是有 没有报告将肾上腺素能向间充质转化（AMT）表观遗传程序与调节表面 抗原GD 2，使这种关系的强烈兴趣的神经母细胞瘤社区。在这项提案中， AIM 1将通过严格测试其充分性来阐明AMT和GD 2表达之间的关系 以及神经母细胞瘤特异性AMT转录因子PRRX 1调节GD 2的必要性。此外，损失 将在体外和体内检测通过AMT表达的GD 2对dinutuximab的应答丧失。目标2将 评估GD 2表达缺失的潜在途径。初步数据表明间充质细胞 细胞系和肿瘤通过基因启动子处的表观遗传沉默表达显著降低的GD 3合酶。我们 将评估AMT是否直接调节GD 3合酶，以及其表达的恢复是否能挽救 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GD 2和对dinutuximab的应答。此外，这些研究可能有助于告知合理的组合 加强神经母细胞瘤抗GD 2治疗的策略，并为未来的研究提供框架 在其他表达GD 2的儿科癌症中。

项目成果

VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system.

• DOI: 10.1172/jci.insight.158755
• 发表时间: 2022-10-10
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: So, Jonathan;Mabe, Nathaniel W.;Englinger, Bernhard;Chow, Kin-Hoe;Moyer, Sydney M.;Yerrum, Smitha;Trissal, Maria C.;Marques, Joana G.;Kwon, Jason J.;Shim, Brian;Pal, Sangita;Panditharatna, Eshini;Quinn, Thomas;Schaefer, Daniel A.;Jeong, Daeun;Mayhew, David L.;Hwang, Justin;Beroukhim, Rameen;Ligon, Keith L.;Stegmaier, Kimberly;Filbin, Mariella G.;Hahn, William C.
• 通讯作者: Hahn, William C.