Ink4a/ARF/Ink4b locus in Neurofibromatosis Type 1

1 型神经纤维瘤病中的 Ink4a/ARF/Ink4b 位点

• 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
• 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

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 恶性周围神经鞘肿瘤（MPNST）是患者的主要死亡原因 神经纤维瘤病1（NF1）。 MPNST在来自良性丛状神经纤维瘤（PNF）的NF1患者中出现 尚不清楚为什么只有约30％的PNF转变为MPNST。最近的研究表明，失活 ink4a/arf/ink4b locus（用于ink4a和arf; cdkn2b for ink4b的CDKN2A）生成预防剂 病变称为不确定生物学（Annubp）的非典型神经纤维瘤肿瘤。 Annubps是新的 公认的MPNST前体，但是驱动和分类此过渡中间体的机制很差 定义。 Ink4a/arf/ink4b中断是当前与Annubps相关的主要更改，除了NF1损失和 Rabl6a上调。在MPNST中，该基因座以一个，两个或全部三个基因改变，患者生存较差 与所有三个损失有关。每个基因（Ink4a，arf和ink4b）编码肿瘤抑制剂，但它们 与驱动癌症的其他因素的单独贡献和合作性尚未完全理解。 鉴于它们的重要作用，需要在MPNST开发中更好地了解Ink4a，ARF和Ink4b， 由于针对基因座的药物要么被批准，要么在其他癌症中表现出承诺。 我们的中心假设是p16ink4a，arf和p15ink4b在多种途径中合作 抑制良性PNF和Annubps向MPNST的转化。 AIM 1将定义重要的遗传 和蛋白质组学事件与Ink4a，ARF和Ink4b在人类annubps和mpnst中灭活一致 遗传，分子和组织学分析。结果将与临床变量（例如生存）相关。这 新开发的液体活检测定法评估基因座状态和其他肿瘤标记的预后价值将 在NF1患者中确定。 AIM 2在人类中使用P16INK4A，ARF和/或P15INK4B的CRISPR编辑 PNF衍生的细胞确定它们在PNF-Annubp-MPNST转换中的作用。定向分析 可疑的细胞和小鼠模型中的MPNST驱动基因将识别与选择性合作的基因 Ink4a，ARF或Ink4b损失以驱动体外和体内转换Annubp-MPNST。 AIM 3建立 PNF-ANNUBP-MPNST疗法中靶向Ink4a/arf/ink4b的药物的生物学意义 和预防。将使用分子和 药理方法。研究将确定目标治疗对MPNST模型的价值 防止恶性进展。影响：研究将为Ink4a/arf/ink4b提供新的见解，这是最多的 在人类癌症中经常灭活基因座。 PNF-Annubp-MPNST进展的创新动物模型 将生成，将定义导致MPNST的转换机制。临床前研究将 评估针对INK4A/ARF/INK4B途径的新组合疗法，以防止恶性进展。 结果将提高我们对推动MPNST开发事件的理解，促进早期诊断和 针对安努布普斯的预取用干预措施。