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Ink4a/ARF/Ink4b locus in Neurofibromatosis Type 1

1 型神经纤维瘤病中的 Ink4a/ARF/Ink4b 位点

基本信息

批准号：
10453098
负责人：
Benjamin Will Darbro
金额：
$ 56.86万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453098
关键词：
Age Agreement Animal Model Antineoplastic Agents Automobile Driving Benign Biological Biological Assay Biology CDK4 gene CDKN2A gene Cause of Death Cell model Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Conflict (Psychology)Development Diagnostic Disease Drug Targeting Drug resistance Early Diagnosis Event Frequencies Future Genes Genetic Histologic Human Hyperactivity In Vitro Intervention Lead Lesion Link Literature MEKs Malignant - descriptor Malignant Neoplasms Mediator of activation protein Modeling Molecular Mus NF1 gene Neoplasms Neurofibromatosis 1 Neurofibrosarcoma Oncogenic Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacology Physiological Plasma Plexiform Neurofibroma Prevention Proteomics Reporting Resistance Role Sampling Specimen Testing Tumor Biology Tumor Markers Tumor Suppressor Proteins Up-Regulation Work base cell transformation chemotherapy clinically significant drug-sensitive genetic analysis genomic locus human model improved in vivo in vivo Model individualized medicine inhibitor inhibitor therapy innovation insight liquid biopsy mouse model neurofibroma new combination therapies overexpression pre-clinical preclinical study predictive test preemptive intervention premalignant prevent prognostic assays prognostic value reconstitution targeted treatment therapy resistant transcriptome sequencing tumor tumor DNA tumor progression

项目摘要

Summary/Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis-1 (NF1). MPNSTs arise in NF1 patients from benign plexiform neurofibromas (PNFs) but it is unclear why only ~30% of PNFs transform into MPNSTs. Recent studies suggest that inactivation of the INK4a/ARF/INK4b locus (called CDKN2A for INK4a and ARF; CDKN2B for INK4b) generates a pre-malignant lesion called an atypical neurofibromatous neoplasm of uncertain biology (ANNUBP). ANNUBPs are the newly recognized precursor to MPNSTs, but mechanisms that drive and classify this transitional intermediate are poorly defined. INK4a/ARF/INK4b disruption is the main alteration currently linked to ANNUBPs, besides NF1 loss and RABL6A upregulation. In MPNSTs, the locus is altered at one, two or all three genes, with worse patient survival associated with loss of all three. Each gene (INK4a, ARF, and INK4b) encodes a tumor suppressor, but their separate contributions and cooperativity with other factors in driving cancer remain incompletely understood. Given their prominent role, a better understanding of INK4a, ARF, and INK4b in MPNST development is needed, as drugs targeting the locus are either approved or showing promise in other cancers. Our central hypothesis is p16Ink4a, ARF and p15Ink4b act cooperatively in multiple pathways to suppress the transformation of benign PNFs and ANNUBPs to MPNSTs. Aim 1 will define significant genetic and proteomic events coinciding with INK4a, ARF and INK4b inactivation in human ANNUBPs and MPNSTs by genetic, molecular and histologic analyses. Results will be correlated to clinical variables such as survival. The prognostic value of a newly developed liquid biopsy assay evaluating locus status and other tumor markers will be determined in NF1 patients. Aim 2 employs CRISPR editing of p16Ink4a, ARF and/or p15Ink4b in human PNF-derived cells to determine their roles in PNF-ANNUBP-MPNST transformation. Directed analyses of suspected MPNST driver genes in cells and mouse models will identify genes that selectively cooperate with INK4a, ARF, or INK4b loss to drive ANNUBP-MPNST transformation in vitro and in vivo. Aim 3 establishes the biological significance of drugs targeting Ink4a/Arf/Ink4b relevant pathways in PNF-ANNUBP-MPNST therapy and prevention. Predicted mediators of acquired resistance to therapy will be verified using molecular and pharmacologic approaches. Studies will determine the value of targeted therapy against pre-MPNST models to prevent malignant progression. Impact: Studies will provide new insights into INK4a/ARF/INK4b, one of the most frequently inactivated loci in human cancers. Innovative animal models of PNF-ANNUBP-MPNST progression will be generated and mechanisms of transformation leading to MPNST will be defined. Preclinical studies will assess a new combination therapy targeting Ink4a/Arf/Ink4b pathways in preventing malignant progression. Results will advance our understanding of events driving MPNST development, facilitating earlier diagnosis and pre-emptive interventions targeting ANNUBPs.

摘要/摘要恶性周围神经鞘瘤（MPNST）是恶性周围神经鞘瘤患者死亡的主要原因。神经纤维瘤病-1（NF 1）。MPNST发生于NF 1患者的良性丛状神经纤维瘤（PNF），但它是不清楚为什么只有约30%的PNF转化为MPNST。最近的研究表明， INK 4a/ARF/INK 4 b基因座（INK 4a和ARF称为CDKN 2A; INK 4 b称为CDKN 2B）产生癌前病变。这种病变称为生物学不确定的非典型神经纤维瘤肿瘤（ANNUBP）。ANNUBP是新的 MPNSTs的前体，但驱动和分类这种过渡中间体的机制很差定义了INK 4a/ARF/INK 4 b中断是目前与ANNUBP有关的主要变化，此外还有NF 1损失， RABL 6A上调。在MPNST中，基因座在一个、两个或所有三个基因上发生改变，患者生存率更差与失去这三个人有关每个基因（INK 4a，ARF和INK 4 b）编码一个肿瘤抑制因子，但它们的基因编码的肿瘤抑制因子的基因。单独的贡献和协同性与其他因素在驱动癌症仍然没有完全理解。鉴于其突出的作用，需要更好地了解INK 4a，ARF和INK 4 b在MPNST开发中的作用，因为靶向该基因座的药物要么已被批准，要么在其他癌症中显示出希望。我们的中心假设是p16 Ink 4a，ARF和p15 Ink 4 b在多个途径中协同作用，抑制良性PNF和ANNUBP向MPNST的转化。目标1将定义显著遗传和蛋白质组学事件与人ANNUBP和MPNST中INK 4a、ARF和INK 4 b失活一致，遗传、分子和组织学分析。结果将与生存率等临床变量相关。的一种新开发的评估基因座状态和其他肿瘤标志物的液体活检检测的预后价值将在NF 1患者中确定。目的2在人类中使用p16 Ink 4a、ARF和/或p15 Ink 4 b的CRISPR编辑 PNF衍生的细胞，以确定它们在PNF-ANNUBP-MPNST转化中的作用。定向分析细胞和小鼠模型中的疑似MPNST驱动基因将鉴定出选择性与MPNST协同作用的基因。 INK 4a、ARF或INK 4 b损失以驱动体外和体内ANNUBP-MPNST转化。目标3确立了靶向Ink 4a/Arf/Ink 4 b通路药物在PNF-ANNUBP-MPNST治疗中的生物学意义和预防获得性耐药的预测介质将使用分子和药理学方法。研究将确定针对MPNST前模型的靶向治疗的价值，防止恶性进展。影响：研究将为INK 4a/ARF/INK 4 b提供新的见解，在人类癌症中经常失活的基因座。PNF-ANNUBP-MPNST进展的创新动物模型将产生和转换机制导致MPNST将被定义。临床前研究将评估靶向Ink 4a/Arf/Ink 4 b通路的新联合疗法预防恶性进展。结果将促进我们对MPNST发展的事件的理解，促进早期诊断，针对非洲国家土著人民方案采取先发制人的干预措施。