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: 10308691
• 负责人: Lukas Chavez
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308691
• 关键词: Brain; Cancer Patient; Cause of Death; Cell Line; Central Nervous System Neoplasms; Child; Childhood Brain Neoplasm; Chromatin; Chromosome Arm; Chromosomes; Complex; DNA sequencing; Data; Diagnosis; Disease; Ependymoma; Epigenetic Process; Event; Extracellular Matrix Proteins; Fossa; Frequencies; Genes; Genetic; Genetic Transcription; Laminin; Lead; Link; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Mission; Modeling; Molecular; Molecular Conformation; Neoplasm Metastasis; Oncogenes; Oncogenic; Patients; Phenotype; Posterior Fossa; Prevalence; Prevention; Public Health; Recurrence; Relapse; Research; Sampling; Series; Specimen; Subgroup; Technology; Testing; Therapeutic; Three-dimensional analysis; Transcriptional Activation; Tumor Cell Invasion; United States National Institutes of Health; Variant; aged; base; cancer genome; cohort; epigenetic regulation; experimental study; genome sequencing; genome-wide; human disease; improved; innovation; molecular marker; novel therapeutics; patient derived xenograft model; relapse patients; resistance mechanism; stemness; therapy resistant; tumor; tumor progression; whole genome

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- 0岁儿童最常见的癌症