Towards Novel Differentiation Therapies for Neuroblastoma.

神经母细胞瘤的新型分化疗法。

• 批准号: 10618379
• 负责人: Eveline Barbieri
• 金额: $ 34.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618379
• 关键词: Automobile Driving; Behavior; Biological; Cell Differentiation process; Cell Line; Cellular Metabolic Process; Cessation of life; ChIP-seq; Child; Chromatin; Chromatin Modeling; Data; Development; Differentiation Therapy; Energy Metabolism; Epigenetic Process; Event; Failure; Freezing; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Histones; Infant; Lighting; Link; Literature; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolic Control; Metabolism; Methyltransferase; Modeling; Molecular; Molecular Chaperones; Nerve Block; Neural Crest; Neuroblastoma; Outcome; Pathway interactions; Patients; Phenocopy; Phenotype; Polyamines; Prognosis; Proliferating; Regulation; Research; Resistance; SETDB1 gene; Sampling; Signal Transduction; TP53 gene; Testing; Transcriptional Regulation; Treatment Efficacy; Tretinoin; Tumorigenicity; Undifferentiated; Work; gain of function; in vivo; innovation; insight; loss of function; metabolomics; neuroblast; neuroblastoma cell; novel; novel strategies; prevent; progenitor; programs; recruit; response; therapy resistant; transcriptome sequencing; tumor; tumor metabolism; tumorigenesis

Neuroblastoma (NB) is a neural crest-derived malignancy that accounts for approximately 15% of pediatric cancer deaths. Importantly, NB arises from a failure of sympathoadrenal progenitors to differentiate. Furthermore, the degree of tumor differentiation strongly correlates with NB outcome, as the most undifferentiated tumors are predictive of poor overall survival. We have recently identified a novel pathway that is capable of restricting NB differentiation, and this pathway involves de-regulation of the histone chaperone CHAF1A (chromatin assembling factor-1A). CHAF1A is a major epigenetic and transcriptional regulator and its aberrant expression has recently been linked to tumorigenesis in numerous cancers. We found that high CHAF1A expression strongly predicts poor NB survival and an undifferentiated phenotype. Importantly, we show that CHAF1A is necessary for in vivo tumor establishment and growth, restricts NB differentiation, and rewires distinct metabolic programs. Thus, our guiding hypothesis is that NB remains frozen in a highly undifferentiated state in part due to CHAF1A-mediated suppression of differentiation programs and metabolic reprogramming. Our working model is that by blocking CHAF1A functions, we can drive NB to differentiate. The specific aims of this proposal will test these hypotheses and determine: 1) the contribution of CHAF1A to NB resistance to differentiation therapy, 2) the molecular mechanisms through which CHAF1A blocks NB differentiation and reprograms tumor metabolism, and 3) how CHAF1A metabolic reprogramming alters NB tumorigenesis and response to differentiation therapy. We expect to uncover the molecular mechanisms by which CHAF1A opposes NB differentiation and to identify genes and pathways that alter tumor metabolism in CHAF1A-driven tumorigenesis. We expect that the proposed research will also more generally provide new insight into the transcriptional regulation of NB differentiation and energy metabolism in NB progression and resistance to therapy. These studies will be significant as these findings will lead to develop novel differentiation therapies for NB.

神经母细胞瘤 (NB) 是一种神经嵴源性恶性肿瘤，约占儿科肿瘤的 15% 癌症死亡。重要的是，NB 是由于交感肾上腺祖细胞无法分化而引起的。 此外，肿瘤分化程度与 NB 结局密切相关，因为 未分化的肿瘤预示着总体生存率较差。我们最近发现了一条新途径 能够限制 NB 分化，并且该途径涉及组蛋白伴侣的失调 CHAF1A（染色质组装因子-1A）。 CHAF1A 是一种主要的表观遗传和转录调节因子，其 最近，异常表达与多种癌症的肿瘤发生有关。我们发现高 CHAF1A 表达强烈预测 NB 存活率低和未分化表型。重要的是，我们展示了 CHAF1A 对于体内肿瘤的建立和生长是必需的，限制 NB 分化并重新布线 不同的代谢程序。因此，我们的指导假设是 NB 仍然冻结在高度未分化的状态中。 这种状态部分归因于 CHAF1A 介导的分化程序和代谢重编程的抑制。 我们的工作模型是通过阻断CHAF1A功能，带动NB差异化。具体目标 该提案将测试这些假设并确定：1) CHAF1A 对 NB 耐药性的贡献 分化治疗，2) CHAF1A 阻断 NB 分化的分子机制和 重新编程肿瘤代谢，3) CHAF1A 代谢重新编程如何改变 NB 肿瘤发生和 对分化治疗的反应。我们期望揭示 CHAF1A 对抗的分子机制 NB 分化并鉴定改变 CHAF1A 驱动的肿瘤代谢的基因和途径 肿瘤发生。我们期望所提出的研究也将更普遍地提供新的见解 NB分化和能量代谢的转录调控在NB进展和抗性中的作用 治疗。这些研究将具有重要意义，因为这些发现将导致开发新的分化疗法 注意。