Novel Therapeutic Approaches for the Treatment of Neuroblastoma

侵袭性癌症通常在生长控制癌基因中具有激活突变和失活突变。 肿瘤抑制基因的突变。在神经母细胞瘤中，MYCN 癌基因的扩增和 ATRX 肿瘤抑制基因失活与高风险疾病和不良预后相关。 在这里，我们表明 ATRX 突变和 MYCN 扩增在所有年龄段都是相互排斥的 和神经母细胞瘤的阶段。使用人类细胞系和小鼠模型，我们发现升高 MYCN 表达和 ATRX 突变是不相容的。 MYCN 水平升高促进新陈代谢 重编程、线粒体功能障碍、活性氧生成和 DNA 复制 压力。 ATRX-组蛋白伴侣缺陷引起的复制应激的组合 复合物和由 MYCN 介导的代谢重编程诱导的结果导致合成致死。 因此，ATRX 和 MYCN 代表了一个不寻常的例子，其中肿瘤抑制因子失活 基因和癌基因的激活是不相容的。在本提案中，我们将利用这种合成 致死率以改善高风险和/或复发性神经母细胞瘤患者的预后。具体来说， 我们将使用分子靶向治疗来扰乱 MYCN 扩增中的 ATRX 依赖性过程 神经母细胞瘤并破坏 ATRX 缺陷肿瘤中 MYCN 依赖性过程。在这个 转化研究提案中，我们将同时针对肿瘤细胞和肿瘤微环境。 所有已发表和未发表的数据均通过儿童实体瘤网络免费共享 加速神经母细胞瘤的发现。这些研究的结果将用于设计下一步 圣裘德神经母细胞瘤临床试验。

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX–histone chaperone complex and that induced by MYCN-mediated metabolic reprogramming leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. In this proposal, we will exploit this synthetic lethality to improve outcomes for patients with high-risk and/or recurrent neuroblastoma. Specifically, we will use molecular targeted therapeutics to perturb ATRX-dependent processes in MYCN amplified neuroblastomas and to disrupt MYCN-dependent processes in ATRX deficient tumors. In this translational research proposal, we will target both the tumor cells and the tumor microenvironment. All published and unpublished data are freely shared through the Childhood Solid Tumor Network to accelerate discovery on neuroblastoma. The results of these studies will be used to design the next neuroblastoma clinical trials at St. Jude.