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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：
10159228
负责人：
Anthony Charles Faber
金额：
$ 35.51万
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/10159228
关键词：
Affect Age Antibodies Biological 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/antagonist 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驱动这种危险的NB子集，目前还没有间接或直接的MYCN抑制剂临床证明，因此，对MYCN扩增的NB的新疗法仍然是儿科癌症治疗。在目前的方案中，我们证明了DNA(胞嘧啶-5)- 甲基转移酶1(DNMT1)的抑制对MYCN扩增的NBS具有人工致死作用。此外，我们还有发现DNMT1抑制剂作为MYCN抑制剂，产生了可以利用的反馈从药学上讲。作为DNMT1抑制剂，地西他滨已被临床批准，而吉西他滨(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)，这项拨款旨在进一步确定DNMT1抑制剂在MYCN中的敏感性- 扩增的Nb。目的：我们的目标是验证DNMT1抑制剂对扩增的合成致死的假设。 Nb中的MYCN，扩增的MYCN驱动DNMT1的表达，导致包括at Key在内的全局甲基化肿瘤抑制基因，以及GD2的关键合成酶基因的抑制。AS GD2合成酶的表达随着DNMT1抑制剂的迅速增加，我们建议DNMT1抑制剂可以合理地与抗GD2抑制剂迪努昔单抗，在MYCN扩增的NBS的维护阶段常规使用。具体目标：特异性目的1.研究MYCN扩增产物对DNMT1抑制的敏感性及其机制神经母细胞瘤具体目标2：确定DNMT1抑制剂在不同MYCN-1小鼠模型中的疗效和耐受性扩增的神经母细胞瘤，单独和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是有效的。我们将进一步使用细胞培养模型表征扩增的MYCN在DNMT1抑制剂敏感性中的作用操纵MYCN的表达，并验证我们在化学和生物上看到的活性是不同的通过对DNMT1基因的研究，DNMT1抑制剂实际上达到了靶点。我们将进行芯片和其他研究探讨MYCN是否直接调节DNMT1以影响基因组甲基化。我们将决定更接近于MYCN扩增的NB中的关键DNMT1靶标是什么。此外，我们还将审问一名收集MYCN扩增的小鼠模型，包括GEMM和PDX，以确定两者的活性地西他滨和吉西他滨。最后，我们发现DNMT1的抑制会影响GD2的合成和关键的维甲酸耐酸(RA)基因，我们将确定DNMT1抑制剂是否对抗GD2抗体敏感地诺昔单抗和体内对RA的作用，这两种药物都用于MYCN扩增的NB的维持治疗。