Investigating and targeting pathways of malignant peripheral nerve sheath tumor (MPNST)

恶性周围神经鞘瘤（MPNST）的研究和靶向途径

• 批准号: 10215635
• 负责人: YUAN ZHU
• 金额: $ 58.6万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215635
• 关键词: Affect; Alleles; Allografting; Apoptotic; Benign; Biological Markers; CDKN2A gene; Cause of Death; Cell Cycle Arrest; Cell Line; Cessation of life; Characteristics; Clinical; Clinical Trials; Combined Modality Therapy; Death Rate; Deletion Mutation; Development; Drug Screening; Drug Targeting; Excision; Exhibits; Genetic study; Genetically Engineered Mouse; Growth; Hematology; Human; Imaging technology; Individual; Inferior; Inherited; Lesion; Location; MDM2 gene; MEK inhibition; MEKs; Magnetic Resonance Imaging; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; NF1 gene; Neurofibromatosis 1; Neurofibrosarcoma; Operative Surgical Procedures; Outcome Measure; PI3K/AKT; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral Nerve Sheath Neoplasm; Play; Plexiform Neurofibroma; Polycomb; Pre-Clinical Model; Radiation; Repressor Proteins; Risk; Role; Series; Signal Pathway; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Translations; Treatment Efficacy; Tumor Suppressor Genes; Tumor-Derived; Work; Xenograft Model; drug repurposing; effective therapy; fluorodeoxyglucose positron emission tomography; genome-wide analysis; imaging modality; in vivo; inhibitor/antagonist; loss of function mutation; mouse model; neoplastic cell; nervous system disorder; neurofibroma; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; ras GTPase-Activating Proteins; response; sarcoma; screening; stem cells; success; therapeutic target; therapy design

Project Abstract Malignant peripheral nerve sheath tumors (MPNST) cause one of the highest rates of sarcoma-specific death. Nearly half of MPNSTs arise from individuals with neurofibromatosis type 1 (NF1), representing a leading cause of death in these patients. NF1 patients carry germline heterozygous inactivating mutations in the NF1 tumor suppressor gene. NF1 encodes a RAS-GTPase Activating Protein (RAS-GAP), a negative regulator of RAS-mediated signaling pathways including RAF/MEK/ERK and PI3K/AKT/mTORC signaling pathways. Inactivation of the remaining NF1 wild-type alleles drives the formation of a critical benign precursor lesion of MPNST, plexiform neurofibroma (PNF) that is observed in 30%-50% of NF1 patients. Genetic studies have shown that the progression of PNF-to-MPNST requires inactivation of additional pathways including (1) inactivation of the p53 pathway, either by mutations/deletions of TP53 or CDKN2A that encodes tumor suppressor genes INK4A and ARF, and (2) loss of the Polycomb repressor complex 2 (PRC2), by targeting SUZ12 or EED. Despite the absence of PNFs, most non-NF1-associated sporadic and radiation-induced MPNSTs also carry genetic alterations in these three pathways, and hence are considered as MPNST core pathways. Despite recent progress in understanding the mechanism underlying MPNST pathogenesis, no effective therapy is currently available except for complete surgical resection of MPNST, which is often not feasible due to its deep location and invasive growth pattern. Thus, the development of new therapies for MPNSTs is urgently needed. The main objective of this proposal is to investigate and target these three MPNST core pathways as a strategy to develop novel therapies for this incurable human cancer. In Aim 1, we will test the hypothesis that therapeutic strategies enhancing p53-mediated apoptotic responses by MEK inhibition will present an effective therapy for CDKN2A-deficient MPNSTs with wild-type TP53. We will establish the mechanistic basis and therapeutic efficacy of two clinically ready drugs that target these two MPNST core pathways in a series of preclinical models of MPNSTs including low-passage cell lines, allograft and GEM models, as well as human MPNST-derived cell lines and xenograft models. In Aim 2, we will identify molecular mechanisms underlying PRC2 loss in the initiation, progression and therapeutic vulnerability of MPNSTs. We will investigate a series of novel MPNST models inactivating all three MPNST core pathways and establish the molecular basis of acquiring stem-cell characteristics by PRC2 loss-induced reprogramming or de-differentiation during the PNF-to-MPNST transition. Our work focuses on developing therapeutic strategies specifically for PRC2-proficient and PRC2-deficient MPNSTs.

项目摘要 恶性周围神经鞘瘤(MPNST)是肉瘤特异性死亡率最高的疾病之一。 近一半的MPNST来自1型神经纤维瘤病(NF1)患者，这是主要原因 这些病人死亡的可能性。NF1患者携带NF1基因的种系杂合失活突变 肿瘤抑制基因。NF1编码一种Ras-GTP酶激活蛋白(RAS-GAP)，它是一种负调控因子 RAS介导的信号通路包括RAF/MEK/ERK和PI3K/AKT/mTORC信号通路。 剩余的NF1野生型等位基因失活导致严重的良性前驱病变的形成 在MPNST中，网状神经纤维瘤(PNF)出现在30%-50%的NF1患者中。基因研究已经 研究表明，从PNF到MPNST的进展需要其他途径的失活，包括(1) 通过编码肿瘤的TP53或CDKN2A的突变/缺失使P53途径失活 抑制基因Ink4a和arf，以及(2)通过靶向丢失多梳抑制物复合体2(PRC2) SuZ12或EED。尽管没有PNF，但大多数非NF1相关的零星和辐射诱导 MPNST也在这三条途径中携带基因改变，因此被认为是MPNST的核心 小路。尽管最近在理解MPNST发病机制方面取得了进展，但没有 目前有有效的治疗方法，除了完全手术切除MPNST外，这通常不是 由于其深部的地理位置和侵入性的生长模式，因此是可行的。因此，新的治疗方法的开发 迫切需要MPNSTs。这项提议的主要目标是调查和打击这三个人 MPNST核心路径作为一种策略来开发这种无法治愈的人类癌症的新疗法。在目标1中， 我们将验证这样一种假设，即治疗策略通过MEK增强P53介导的细胞凋亡反应 抑制野生型TP53将为CDKN2A缺陷的MPNSTs提供一种有效的治疗方法。我们将建立 针对这两种MPNST的两种临床现成药物的作用机制和疗效 一系列MPNSTs临床前模型的核心通路，包括低传代细胞系、同种异体移植和 GEM模型，以及人MPNST来源的细胞系和异种移植模型。在目标2中，我们将确定 前列腺癌发生、发展及治疗易感性中PRC2缺失的分子机制 MPNSTs。我们将研究一系列新的MPNST模型，使所有三个MPNST核心通路失活，并 建立通过PRC2丢失诱导重编程获得干细胞特征的分子基础或 PnF向MPNST转变过程中的去分化。我们的工作重点是开发治疗策略 特别适用于精通PRC2和缺乏PRC2的MPNST。