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- 10岁儿童中最常见的癌症。 在美国14年。室管膜瘤（EPN）是第三大常见的小儿脑肿瘤， 儿童癌症患者的死亡率。最常见和最具侵略性的亚组，后颅窝 A组室管膜瘤（PFA）主要发生在幼儿中，经常导致复发。尽管 广泛的DNA测序研究表明，与特别差的生存率相关的唯一分子标记是增益。 染色体臂1 q。这项建议的总体目标是确定分子机制， 导致1 q + 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的1 q + PFA EPN肿瘤基因组的构象。结果，我们发现了复杂的染色体间 结构变体（SV），其导致新的拓扑相关结构域（“neo-TADs”）的形成， LAMC 1的转录激活。基于这些结果，我们现在假设， 通过形成SV诱导的neo-TADs激活LAMC 1是复发性结肠癌中常见的耐药机制。 1 q + PFA EPN肿瘤。因此，针对LAMC 1的策略可以揭示新的漏洞并克服 PFA EPN复发患者的治疗耐药。该项目的基本原理是，解决 使用HiC和功能抑制实验的较大队列可用PFA EPN复发样本中的SV 在复发PFA EPN模型中针对LAMC 1的研究可能提供了一个强大的科学框架，其中基本的 表观遗传学相关的增殖激活机制和新的治疗机会可以 鉴定中心假设将通过追求回答两个具体目标来检验：首先，我们的目标是 确定1 q + PFA室管膜瘤的较大队列中SV的频率及其对调节的影响 域（目标1）。第二，我们的目标是确定靶向LAMC 1在患者源性肿瘤中的治疗潜力。 复发PFA室管膜瘤模型（目的2）。最终，我们的研究有可能改善我们的 了解表观遗传调控，推动获得干性和耐药性治疗， 促进PFA EPN患者的治疗。本申请中提出的研究是创新的， 这是本申请人的观点，因为它询问了一种新的转录LAMC 1激活的分子机制， 最近衍生的PFA EPN的忠实模型。这项研究意义重大，因为它有望 为儿童脑肿瘤类型提供新的治疗机会，这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。 调节，推动获得干性和推进疾病的治疗。