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Neuroblastoma reliance on DNMT1 through amplified MYCN

神经母细胞瘤通过扩增 MYCN 依赖 DNMT1

基本信息

批准号：
10410501
负责人：
Anthony Charles Faber
金额：
$ 34.8万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410501
关键词：
Affect Age Antibodies Biology Cell Culture Techniques Chemicals Child Childhood Clinic Clinical Clinical Trials Collection Combined Modality Therapy Cytosine DNA Dangerousness Data Decitabine Disease Drug Targeting Enrollment Eye FDA approved Feedback Future GD2 synthase Genes Genetic study Genetically Engineered Mouse Genome Goals Grant Hypermethylation Immune response Immunocompetent Knowledge MYCN gene Maintenance Maintenance Therapy Malignant Childhood Neoplasm Malignant Neoplasms Methylation Methyltransferase Modeling Mus Neuroblastoma Patients Pharmaceutical Preparations Pharmacologic Substance Phase Regulation Research Design Research Personnel Role Testing Time Translating Tretinoin Tumor Suppressor Genes Tumor Suppressor Proteins cancer therapy clinically actionable clinically relevant efficacy testing epigenomics genome wide methylation high risk humanized mouse in vivo inhibitor mouse model next generation novel novel therapeutics patient derived xenograft model preclinical study programs research clinical testing resistance gene

项目摘要

Project Summary: MYCN-amplified neuroblastoma is a deadly disease. Despite years of evidence that amplified MYCN drives this dangerous subset of NB, no indirect or direct inhibitors of MYCN have been demonstrated clinically, and thus, new therapies for MYCN-amplified NB remains a high-level priority in pediatric cancer therapy. In this current proposal, we demonstrate that DNA (cytosine-5)- methyltransferase 1 (DNMT1) inhibition is synthetic lethal to MYCN amplified NBs. In addition, we have found DNMT1 inhibitors act as MYCN inhibitors, creating a feedback that can be exploited pharmaceutically. As the DNMT1 inhibitor decitabine is clinically approved, and guadecitabine (SGI- 110) is in clinical trials with our clinical collaborator serving as PI in one of the trials (John Glod, NCI Pediatric Branch), this grant aims to further define the sensitivity of DNMT1 inhibitors in MYCN- amplified NB. Objectives: Our objective is to test the hypothesis that DNMT1 inhibitors are synthetic lethal to amplified MYCN in NB, and that amplified MYCN drives DNMT1 expression to cause global methylation including at key tumor suppressor loci, as well as suppression of a key synthase gene of GD2. As GD2 synthase expression increases rapidly with DNMT1 inhibitors, we propose DNMT1 inhibitors can be rationally combined with the anti-GD2 inhibitor dinutuximab, used routinely in the maintenance phase of MYCN-amplified NBs. Specific Aims: Specific Aim 1. Characterize the sensitivity to, and mechanism of, DNMT1 inhibition in MYCN-amplified neuroblastoma Specific Aim 2: Determine the efficacy and tolerability of DNMT1 inhibitors in diverse mouse models of MYCN- amplified neuroblastoma, alone and in combination with standard maintenance therapy Study Design: We have found that DNMT1 inhibition is effective in MYCN-amplified NB. We will further characterize the role of amplified MYCN in DNMT1 inhibitor sensitivity, using cell culture models where we will manipulate MYCN expression, and verify that the activity we see in both chemically and biologically distinct DNMT1 inhibitors is in fact on-target through DNMT1 genetic studies. We will perform ChIP and other studies to explore whether MYCN directly regulates DNMT1 to effect the methylation of the genome. We will determine more closely what the key DNMT1 targets are in MYCN-amplified NB. Additionally, we will interrogate a collection of MYCN-amplified mouse models, including GEMMS and PDXs, to determine the activity of both decitabine and guadecitabine. Lastly, we have found DNMT1 inhibition affects GD2 synthesis and key retinoic acid (RA) resistant genes, and we will determine whether DNMT1 inhibitors sensitize to the anti-GD2 antibody dinutuximab and to RA in vivo , both of which ire used for maintenance therapy in MYCN-amplified NB.

项目摘要：MYCN 扩增的神经母细胞瘤是一种致命的疾病。尽管多年来的证据表明扩增的 MYCN 会驱动这种危险的 NB 子集，目前还没有 MYCN 的间接或直接抑制剂临床证明，因此，MYCN 扩增 NB 的新疗法仍然是治疗中的高度优先事项小儿癌症治疗。在当前的提案中，我们证明 DNA（胞嘧啶-5）- 甲基转移酶 1 (DNMT1) 抑制对 MYCN 扩增的 NB 具有合成致死作用。此外，我们还有发现 DNMT1 抑制剂充当 MYCN 抑制剂，产生可利用的反馈药学上。随着DNMT1抑制剂地西他滨获得临床批准，瓜地他滨（SGI- 110）正在进行临床试验，我们的临床合作者在其中一项试验中担任 PI（John Glod，NCI 儿科分会），这笔资助旨在进一步确定 DNMT1 抑制剂在 MYCN- 中的敏感性放大的NB。目标：我们的目标是检验 DNMT1 抑制剂对扩增产物具有合成致死性的假设 NB 中的 MYCN，扩增的 MYCN 驱动 DNMT1 表达，导致全局甲基化，包括关键部位抑癌基因座，以及 GD2 关键合酶基因的抑制。作为GD2合酶表达随着 DNMT1 抑制剂的增加，DNMT1 抑制剂迅速增加，我们建议 DNMT1 抑制剂可以与 DNMT1 抑制剂合理组合。抗 GD2 抑制剂 dinutuximab，常规用于 MYCN 扩增 NB 的维持阶段。具体目标：具体目标 1. 表征 MYCN 扩增的 DNMT1 抑制的敏感性和机制成神经细胞瘤具体目标 2：确定 DNMT1 抑制剂在 MYCN- 不同小鼠模型中的功效和耐受性扩增神经母细胞瘤，单独或与标准维持治疗相结合研究设计：我们发现 DNMT1 抑制对 MYCN 扩增的 NB 有效。我们将进一步使用细胞培养模型来表征扩增的 MYCN 在 DNMT1 抑制剂敏感性中的作用，我们将在其中操纵 MYCN 表达，并验证我们在化学和生物学上看到的活性是否不同事实上，通过 DNMT1 基因研究，DNMT1 抑制剂能够达到目标。我们将进行 ChIP 和其他研究探讨 MYCN 是否直接调节 DNMT1 来影响基因组的甲基化。我们将确定更接近 MYCN 扩增的 NB 中的关键 DNMT1 靶点。此外，我们将询问收集 MYCN 扩增的小鼠模型，包括 GEMMS 和 PDX，以确定两者的活性地西他滨和瓜地西他滨。最后，我们发现 DNMT1 抑制会影响 GD2 合成和关键视黄酸酸（RA）抗性基因，我们将确定 DNMT1 抑制剂是否对抗 GD2 抗体敏感 dinutuximab 和体内 RA，两者均用于 MYCN 扩增 NB 的维持治疗。