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：
10577840
负责人：
Benjamin Will Darbro
金额：
$ 54.49万
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/10577840
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 Classification Clinical Clustered Regularly Interspaced Short Palindromic Repeats Development Diagnostic Disease Drug Targeting Drug resistance Early Diagnosis Event Frequencies Future Genes Genetic Histologic Human Hyperactivity In Vitro Learning Lesion Link Literature MEKs Malignant - descriptor Malignant Neoplasms Mediator Modeling Molecular Mus NF1 gene Neoplasms Neurofibromatosis 1 Neurofibrosarcoma Oncogenic Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Physiological Plasma Plexiform Neurofibroma Prevention Proteomics RAS driven tumor Reporting Resistance Role Sampling Specimen Testing Therapeutic Intervention Tumor Biology Tumor Markers Tumor Suppressor Proteins Up-Regulation Work 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 pharmacologic pre-clinical preclinical study 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）是导致患者死亡的主要原因神经纤维瘤病-1 (NF1)。 MPNST 出现于良性丛状神经纤维瘤 (PNF) 的 NF1 患者中，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，失活 INK4a/ARF/INK4b 基因座（对于 INK4a 和 ARF 称为 CDKN2A；对于 INK4b 称为 CDKN2B）产生癌前基因病变称为生物学不确定的非典型神经纤维瘤性肿瘤（ANNUBP）。 ANNUBP 是新的公认的 MPNST 前体，但驱动和分类这种过渡中间体的机制很差定义的。除了 NF1 丢失和 RABL6A 上调。在 MPNST 中，一个、两个或全部三个基因的位点发生改变，患者生存率较差与全部三者的损失有关。每个基因（INK4a、ARF 和 INK4b）都编码一个肿瘤抑制因子，但它们的导致癌症的单独贡献和与其他因素的协同作用仍不完全清楚。鉴于 INK4a、ARF 和 INK4b 在 MPNST 开发中的突出作用，需要更好地了解它们，因为针对该位点的药物要么已获得批准，要么在其他癌症中显示出前景。我们的中心假设是 p16Ink4a、ARF 和 p15Ink4b 在多种途径中协同作用抑制良性 PNF 和 ANNUBP 向 MPNST 的转化。目标 1 将定义显着的遗传以及与人类 ANNUBP 和 MPNST 中 INK4a、ARF 和 INK4b 失活同时发生的蛋白质组事件遗传、分子和组织学分析。结果将与生存率等临床变量相关。这新开发的液体活检评估位点状态和其他肿瘤标志物的预后价值将在 NF1 患者中进行测定。目标 2 采用 CRISPR 编辑人类 p16Ink4a、ARF 和/或 p15Ink4b PNF 衍生细胞确定其在 PNF-ANNUBP-MPNST 转化中的作用。定向分析细胞和小鼠模型中可疑的 MPNST 驱动基因将识别与选择性合作的基因 INK4a、ARF 或 INK4b 损失驱动 ANNUBP-MPNST 体外和体内转化。目标 3 确立了 PNF-ANNUBP-MPNST 治疗中靶向 Ink4a/Arf/Ink4b 相关通路的药物的生物学意义和预防。将使用分子和方法验证获得性治疗耐药性的预测介质药理学方法。研究将确定针对 MPNST 模型的靶向治疗的价值防止恶变进展。影响：研究将为 INK4a/ARF/INK4b 提供新的见解，这是最重要的研究之一人类癌症中经常失活的位点。 PNF-ANNUBP-MPNST 进展的创新动物模型将产生并定义导致 MPNST 的转化机制。临床前研究将评估针对 Ink4a/Arf/Ink4b 通路的新联合疗法在预防恶性进展方面的作用。结果将增进我们对推动 MPNST 发展的事件的理解，促进早期诊断和针对 ANNUBP 的先发制人的干预措施。