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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.

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驱动这种危险的NB亚群，没有MYCN的间接或直接抑制剂已经被发现。临床上已经证明，因此，MYCN扩增NB的新疗法仍然是一个高级别的优先事项，儿科癌症治疗在目前的建议中，我们证明了DNA（胞嘧啶-5）- 甲基转移酶1（DNMT 1）抑制对MYCN扩增的NB是合成致死的。另外我们有发现DNMT 1抑制剂作为MYCN抑制剂，创造一个反馈，可以利用药物学上的由于DNMT 1抑制剂地西他滨在临床上被批准，并且胍地西他滨（SGI-2000）也是如此。 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 儿科分支），该基金旨在进一步确定DNMT 1抑制剂在MYCN中的敏感性- 放大NB 目的：我们的目的是检验DNMT 1抑制剂对扩增的DNA具有合成致死性的假设。 MYCN在NB中的作用，并且扩增的MYCN驱动DNMT 1表达，导致全局甲基化，包括在关键的肿瘤抑制基因座，以及GD 2的关键合酶基因的抑制。As GD 2合酶表达随着DNMT 1抑制剂的迅速增加，我们建议DNMT 1抑制剂可以合理地与抗GD 2抑制剂dinutuximab，常规用于MYCN扩增的NB的维持期。具体目标：具体目标1。在MYCN扩增的细胞中表征对DNMT 1抑制的敏感性和机制。神经母具体目标2：确定DNMT 1抑制剂在不同MYCN小鼠模型中的疗效和耐受性- 扩增的神经母细胞瘤，单独使用和与标准维持治疗联合使用研究设计：我们发现DNMT 1抑制在MYCN扩增的NB中有效。我们将进一步使用细胞培养模型表征扩增的MYCN在DNMT 1抑制剂敏感性中的作用，操纵MYCN表达，并验证我们在化学和生物学上不同的细胞中看到的活性， DNMT 1抑制剂实际上是通过DNMT 1遗传研究靶向的。我们将进行ChIP和其他研究探讨MYCN是否直接调控DNMT 1影响基因组甲基化。我们将确定在MYCN扩增的NB中，DNMT 1的关键靶点是什么。此外，我们将审问一名收集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胍地西他滨。最后，我们发现DNMT 1抑制影响GD 2的合成和关键的维甲酸，酸（RA）抗性基因，我们将确定DNMT 1抑制剂是否对抗GD 2抗体敏感地努妥昔单抗和RA在体内，这两种药物都用于MYCN扩增的NB的维持治疗。