Transcriptional activation of LAMC1 as a resistance mechanism in recurrent PFA Ependymoma

LAMC1 的转录激活作为复发性 PFA 室管膜瘤的耐药机制

• 批准号: 10762310
• 负责人: Lukas Chavez
• 金额: $ 19.59万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10762310
• 关键词: Transcriptional; activation; LAMC1; resistance; mechanism

Brain and other tumors of the central-nervous system (CNS) are the most common cancers in children aged 0- 14 years in the USA. Ependymoma (EPN) is the third most common pediatric brain tumor and a leading cause of death in childhood cancer patients. The most common and aggressive subgroup, posterior fossa ependymoma group A (PFA), occurs mainly in young children and frequently leads to recurrences. Despite extensive DNA sequencing studies, the only molecular marker associated with particularly poor survival is gain of the chromosome arm 1q. The overall objective of this proposal is to identify the molecular mechanisms that cause the poor survival of 1q+ PFA EPN patients. To approach this objective, we have analyzed the 3D conformation of 1q+ PFA EPN tumor genomes using HiC. As a result, we identify complex inter-chromosomal structural variants (SVs) that result in the formation of new topologically associated domains (‘neo-TADs’) leading to transcriptional activation of LAMC1. Based on these results, we now hypothesize that the transcriptional activation of LAMC1 by the formation of SV-induced neo-TADs is a common resistance mechanism in recurrent 1q+ PFA EPN tumors. Thus, strategies that target LAMC1 may reveal new vulnerabilities and overcome resistance to therapy in the treatment of PFA EPN relapse patients. The rationale for this project is that resolving SVs in a larger cohort of available PFA EPN relapse samples using HiC and functional inhibition experiments against LAMC1 in relapse PFA EPN models are likely to provide a strong scientific framework in which basic mechanisms of epigenetically linked activation of proliferation and new therapeutic opportunities can be identified. The central hypothesis will be tested by pursuing to answer two specific aims: First, we aim to determine the frequency of SVs in a larger cohort of 1q+ PFA ependymomas and their impact on regulatory domains (Aim 1). Second, we aim to determine the therapeutic potential of targeting LAMC1 in patient-derived models of relapse PFA ependymomas (Aim 2). Ultimately, our studies have the potential to improve our understanding of the epigenetic regulation that drives the acquisition of stemness and resistance to therapy and to advance the treatment of PFA EPN patients. The research proposed in this application is innovative, in the applicant’s opinion, because it interrogates a new molecular mechanism of transcriptional LAMC1 activation in recently derived faithful models of PFA EPN. The proposed research is significant, because it is expected to provide new therapeutic opportunities for a pediatric brain tumor type that is a leading cause of death in childhood cancer patients. Ultimately, our studies have the potential to improve our understanding of the epigenetic regulation that drives the acquisition of stemness and to advance the treatment of diseases.

脑肿瘤和中枢神经系统 (CNS) 的其他肿瘤是 0 岁至儿童中最常见的癌症 来美国14年。室管膜瘤 (EPN) 是第三大常见的儿童脑肿瘤，也是一个主要原因 儿童癌症患者的死亡。最常见和最具攻击性的亚群，后颅窝 A 型室管膜瘤 (PFA) 主要发生于幼儿，经常导致复发。尽管 广泛的 DNA 测序研究表明，与生存特别差相关的唯一分子标记是增益 染色体臂1q。该提案的总体目标是确定分子机制 导致 1q+ PFA EPN 患者生存率低。为了实现这一目标，我们分析了 3D 使用 HiC 分析 1q+ PFA EPN 肿瘤基因组的构象。结果，我们识别出复杂的染色体间 导致形成新的拓扑相关域（“neo-TAD”）的结构变体（SV） LAMC1 的转录激活。基于这些结果，我们现在假设转录 通过形成 SV 诱导的 neo-TAD 来激活 LAMC1 是复发性乳腺癌的常见耐药机制 1q+ PFA EPN 肿瘤。因此，针对 LAMC1 的策略可能会揭示新的漏洞并克服 PFA EPN 复发患者治疗中的耐药性。该项目的基本原理是解决 使用 HiC 和功能抑制实验在更大的可用 PFA EPN 复发样本队列中观察 SV 在复发性 PFA EPN 模型中针对 LAMC1 的研究可能会提供一个强大的科学框架，其中基本 表观遗传相关的增殖激活机制和新的治疗机会可以 确定。将通过追求回答两个具体目标来检验中心假设：首先，我们的目标是 确定更大的 1q+ PFA 室管膜瘤队列中 SV 的频率及其对监管的影响 域（目标 1）。其次，我们的目标是确定靶向 LAMC1 在患者来源的治疗中的治疗潜力 复发性 PFA 室管膜瘤模型（目标 2）。最终，我们的研究有潜力提高我们的能力 了解驱动获得干性和治疗耐药性的表观遗传调控 推进 PFA EPN 患者的治疗。本申请提出的研究具有创新性， 申请人的意见，因为它询问了转录 LAMC1 激活的新分子机制 最近导出了 PFA EPN 的忠实模型。拟议的研究意义重大，因为预计 为儿童脑肿瘤类型提供新的治疗机会，该肿瘤是儿童死亡的主要原因 癌症患者。最终，我们的研究有可能提高我们对表观遗传的理解 驱动获得干性并推进疾病治疗的调节。