Towards Novel Differentiation Therapies for Neuroblastoma.

神经母细胞瘤的新型分化疗法。

• 批准号: 9906859
• 负责人: Eveline Barbieri
• 金额: $ 35.92万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906859
• 关键词: Automobile Driving; Behavior; Biological; Cell Differentiation process; Cell Line; Cellular Metabolic Process; Cessation of life; ChIP-seq; Child; Chromatin; 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; Regulation; Research; Resistance; SETDB1 gene; Sampling; Signal Transduction; TP53 gene; Testing; Transcriptional Regulation; Treatment Efficacy; Tretinoin; Tumorigenicity; Undifferentiated; Work; base; in vivo; innovation; insight; loss of function; metabolomics; neuroblast; neuroblastoma cell; novel; novel strategies; outcome forecast; 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）是一种神经嵴来源的恶性肿瘤，约占15%的儿童 癌症死亡重要的是，NB是由交感肾上腺祖细胞分化失败引起的。 此外，肿瘤分化程度与NB结果密切相关，因为大多数肿瘤分化程度与NB的预后密切相关。 未分化的肿瘤预示着较差的总存活率。我们最近发现了一种新的途径， 能够限制NB分化，并且该途径涉及组蛋白伴侣的失调 CHAF 1A（染色质组装因子-1A）。CHAF 1A是一种主要的表观遗传和转录调节因子， 异常表达最近与许多癌症中的肿瘤发生有关。我们发现， CHAF 1A表达强烈预测NB存活率差和未分化表型。重要的是，我们显示 CHAF 1A是体内肿瘤建立和生长所必需的，限制NB分化， 不同的代谢程序因此，我们的指导假设是，NB仍然冻结在一个高度未分化的细胞中。 部分原因是CHAF 1A介导的分化程序和代谢重编程的抑制。 我们的工作模型是，通过阻止CHAF 1A功能，我们可以驱动NB实现差异化。的具体目标 该提案将测试这些假设并确定：1）CHAF 1A对NB抗性的贡献， 分化治疗，2）CHAF 1A阻断NB分化的分子机制， 3）CHAF 1A代谢重编程如何改变NB肿瘤发生， 对分化治疗的反应。我们希望揭示CHAF 1A对抗肿瘤的分子机制。 NB分化，并确定改变CHAF 1A驱动的肿瘤代谢的基因和途径。 肿瘤发生我们预计，拟议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 疗法这些研究将是重要的，因为这些发现将导致开发新的分化疗法， NB.