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MYC activation in tumor progression of neuroblastoma

MYC 激活在神经母细胞瘤肿瘤进展中的作用

基本信息

批准号：
10555259
负责人：
Min Hee Kang
金额：
$ 36.56万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10555259
关键词：
Antibodies Antineoplastic Agents Binding Binding Sites Biological Markers Biopsy Cell Line Cephalic Child Clinical Clinical Treatment Collaborations DNA-PKcs DNA-dependent protein kinase Data Diagnosis Differentiation Inducer Disease model Drug resistance Enhancers Gene Amplification Genetic Transcription Genomics Goals Immunotherapy Isotretinoin MAPKAPK2 gene MYCN gene Maintenance Therapy Malignant Childhood Neoplasm Malignant Neoplasms Messenger RNA Modeling Molecular Monoclonal Antibody Ch14.18 Neuroblastoma Oncogenes Outcome PRKDC gene Patients Pediatric Neoplasm Pediatric Oncology Group Pharmaceutical Preparations Phosphorylation Phosphorylation Site Phosphotransferases Play Pre-Clinical Model Progressive Disease Proteins Proto-Oncogene Proteins c-myc Recurrence Recurrent disease Regulation Resistance Resistance development Role Sampling Solid Neoplasm Sympathetic Nervous System Transactivation Transcriptional Activation Treatment Protocols Vitamin A Xenograft procedure c-myc Genes cancer cell chemotherapy cytokine druggable target established cell line high risk improved in vivo inhibitor knock-down neuroblastoma cell new therapeutic target novel optimal treatments overexpression patient derived xenograft model patient subsets pharmacologic potential biomarker protein expression response small molecule standard of care therapeutic target transcription factor tumor tumor progression

项目摘要

Post-consolidation maintenance therapy with 13-cis retinoic acid (13-cisRA) and the chimeric anti-GD2 antibody dinutuximab (Unituxin®) improves the survival of high-risk neuroblastoma (NB) patients. Despite currently available optimal therapy > 40% of children still develop recurrent disease, which is fatal for most. In the current proposal we seek to identify molecular mechanisms of progressive disease in NB patients. Although MYC genomic amplification is seen in 1% of NB patients, c-MYC protein is overexpressed in 11% of patients at diagnosis. Our preliminary data show that high c-MYC protein expression is far more frequent in progressive disease relative to diagnosis using patient-derived cell lines established from clinical samples at progressive disease and at diagnosis. In searching the mechanisms of MYC transcriptional activation, we demonstrated that transcription factors, OCT4 and TCF 3 were elevated in a cell line model selected to express high c-MYC in replicating the clinical treatment schedule of maintenance therapy (13-cisRA) in high-risk neuroblastoma. When OCT4 was knocked-down, the expression of c-MYC was decreased and the sensitivity to 13-cisRA was restored. Subsequently, we identified two kinases, MAPKAPK2 (MK2) and DNAPK, which are predicted to bind and phosphorylate OCT4. The MK2-OCT4-c-MYC axis was confirmed in another progressive disease model of neuroblastoma with high c-MYC expression. Based on our preliminary data, we hypothesize 1) that kinase(s) phosphorylate OCT4 and the phosphorylated OCT4-induces transcriptional activation of c-MYC and that those kinases can be targeted to inhibit the activation of OCT4-induced c-MYC overexpression, and thus the expression of the kinase(s) could be biomarkers and therapeutic targets for patients with progressive disease with high c-MYC. Our goals are: 1) to employ our extensive panel of NB cell lines and patient-derived xenografts (PDXs) to define the specific roles of OCT4 and its phosphorylation regulation by MK2 and DNA-PKcs kinases in a c-MYC overexpression state that causes resistance to one of the maintenance therapy in NB, 2) to validate them as potential markers of poor outcome in collaboration with the Children's Oncology Group (COG) in patient tumor samples, and 3) to demonstrate the feasibility of inhibiting key kinase(s) to modulate OCT4/c-MYC axis to enhance activity of chemotherapy in NB cell lines and patient-derived xenografts (PDXs). The ultimate goal of the proposed study is to validate regulation of c-MYC as a novel mechanism of tumor progression in neuroblastoma and to identify a druggable target(s) for drug-resistant recurrent neuroblastoma.

使用 13-cis 视黄酸 (13-cisRA) 和嵌合抗 GD2 进行巩固后维持治疗抗体 dinutuximab (Unituxin®) 可提高高危神经母细胞瘤 (NB) 患者的生存率。尽管目前可用的最佳治疗，> 40% 的儿童仍然会出现复发性疾病，这是对大多数人来说是致命的。在当前的提案中，我们寻求确定进行性疾病的分子机制在 NB 患者中。尽管 1% 的 NB 患者出现 MYC 基因组扩增，但 c-MYC 蛋白诊断时 11% 的患者过度表达。我们的初步数据表明，高c-MYC蛋白相对于使用患者来源的细胞进行诊断，表达在进行性疾病中更为频繁根据疾病进展和诊断时的临床样本建立的系。在搜索中为了了解 MYC 转录激活的机制，我们证明了转录因子 OCT4 和在复制临床试验中选择表达高 c-MYC 的细胞系模型中，TCF 3 升高高危神经母细胞瘤维持治疗（13-cisRA）的治疗方案。当 OCT4 是敲低后，c-MYC 的表达降低，对 13-cisRA 的敏感性恢复。随后，我们鉴定了两种激酶，MAPKAPK2 (MK2) 和 DNAPK，预计它们会结合并使 OCT4 磷酸化。 MK2-OCT4-c-MYC 轴在另一种进展性疾病中得到证实高c-MYC表达的神经母细胞瘤模型。根据我们的初步数据，我们假设 1) 激酶磷酸化 OCT4 并且磷酸化的 OCT4 诱导转录激活 c-MYC 并且这些激酶可以靶向抑制 OCT4 诱导的 c-MYC 的激活过度表达，因此激酶的表达可以作为生物标志物和治疗靶点具有高 c-MYC 的进展性疾病患者。我们的目标是：1）利用我们广泛的专家小组 NB 细胞系和患者来源的异种移植物 (PDX) 来定义 OCT4 及其特定作用 c-MYC 过表达状态下 MK2 和 DNA-PKcs 激酶的磷酸化调节导致对 NB 中的一种维持治疗产生耐药性，2) 验证它们作为潜在标志物与儿童肿瘤学组 (COG) 合作在患者肿瘤样本中结果不佳，以及 3) 证明抑制关键激酶调节OCT4/c-MYC轴以增强的可行性 NB 细胞系和患者来源的异种移植物 (PDX) 中的化疗活性。最终目标是拟议的研究旨在验证 c-MYC 的调节作为肿瘤进展的新机制神经母细胞瘤并确定耐药性复发性神经母细胞瘤的药物靶点。