Neuro-oncology of Familial Neoplasia Syndromes

家族性肿瘤综合征的神经肿瘤学

• 批准号: 10018690
• 负责人: Richard James Youle
• 金额: $ 79.14万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10018690
• 关键词: Adolescent; Adrenal Glands; Adult; Affect; Antihypertensive Agents; Apoptosis; Biochemical; Cataract; Cell Extracts; Cells; Central Nervous System Neoplasms; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 3; Clinical; Clinical Data; Clinical Research; Cranial Nerves; Cutaneous T-cell lymphoma; Cyst; Data; Development; Enrollment; Ependymoma; Erythropoietin; Evolution; Excision; Extravasation; Future; Gene Mutation; Genetic; Germ-Line Mutation; Glioma; Growth; HDAC4 gene; Hamartoma; Histone Deacetylase Inhibitor; In Vitro; Kidney; Knowledge; Laboratories; Lesion; Measures; Molecular; Morbidity - disease rate; Natural History; Nature; Neoplasms; Nerve; Nervous System Neoplasms; Nervous system structure; Neuraxis; Neurilemmoma; Neurofibromatosis 2; Neurologic Deficit; Neurology; Operative Surgical Procedures; Ophthalmology; Oral; Organ; Pancreas; Pathology; Patients; Pattern; Peripheral Nerves; Peripheral Nervous System Neoplasms; Permeability; Pharmaceutical Preparations; Plant Roots; Plasma; Play; Propranolol; Proteins; Publishing; Refractory; Renal Cell Carcinoma; Retinal; Role; Specimen; Spinal nerve structure; Stuttering; Symptoms; Syndrome; Syringes; Therapeutic Clinical Trial; Time; Tissue Banks; Tumor Biology; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; VHL mutation; VHL protein; Vascular Endothelial Growth Factors; Vestibular Nerve; Visceral; Von Hippel-Lindau Syndrome; Vorinostat; base; bilateral vestibular Schwannoma; body system; endolymphatic sac; hemangioblastoma; in vivo; insight; member; meningioma; mutant; neuro-oncology; novel therapeutics; prospective; reproductive; treatment risk; tumor; tumor growth; tumor progression; tumor xenograft

von Hippel-Lindau Disease (VHL) We are continuing to follow VHL patients in a natural history study of 250 VHL patients (Lonser et al. 2014) to gain further insights into the natural history of VHL-associated central nervous system (CNS) hemangioblastomas. So far, our findings confirm that most hemangioblastomas grow in a saltatory pattern characterized by periods of growth and quiescence. Quiescent tumors do not need treatment. Hemangioblastomas are more likely to cause symptoms and need surgical treatment if they are associated with enlarging tumor cysts. Plasma extravasation through permeable tumor vessels underlies the formation of peritumoral cysts and syringes. Embryologic hemangioblasts are the cells of origin of VHL-associated CNS hemangioblastomas. New, noninvasive treatments for VHL-associated CNS hemangioblastoma are needed. Our laboratory has documented that mutant VHL protein expressed by a germline missense VHL gene mutation retains some biochemical function, but this function is lost through accelerated breakdown of the mutant protein. Vorinostat, a histone deacetylase inhibitor approved for the treatment of refractory cutaneous T-cell lymphoma (CTCL), experimentally slows the intracellular breakdown of the mutant VHL protein. An intramural clinical study (14-N-0067) is ongoing in which Vorinostat is given for 1 week to adult patients with known germline missense VHL gene mutation who require surgical resection of a hemangioblastoma. The study examines the presence and quantity of mutant VHL protein tumor in tumor specimens from surgery. The level of mutant VHL protein from Vorinostat-treated patients is compared to levels of mutant VHL protein in tissue banked from previous surgical resections. To date, a total of 5 subjects have enrolled in the study, received the study drug, and proceeded to surgery. Of the 5 treated subjects, 4 subjects had tumor specimens obtained during surgery. These specimens are currently being analyzed to determine whether Vorinostat reduces degradation of mutant VHL protein. One subject did not have a confirmed hemangioblastoma resection on pathology, so does not have an associated tumor specimen for analysis. Genetic expression of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in tumor is also measured. This yet unpublished study will provide preliminary data that may support a subsequent therapeutic clinical trial of Vorinostat in patients with missense VHL mutations. This year Surgical Neurology Branch members continued to publish articles about VHL. One article confirmed that propranolol, a commonly used oral anti-hypertensive, had anti-tumor activity against VHL related hemangioblastoma (HB) cells extracted from patient tumor tissue. Propranolol decreased VHL-HB and VHL-related renal cell carcinoma (RCC) viability in vitro likely by modulation of VEGF expression and by inducing apoptosis. Propranolol abrogated 786-O xenograft tumor progression in vivo, and retrospective clinical data suggested that propranolol curtailed HB growth. These results suggest that propranolol may play a role in the treatment of VHL-related tumors. Neurofibromatosis Type 2 (NF2) The protean nature of central nervous system tumors in NF2 and incomplete understanding of their natural history and underlying mechanisms of symptom formation have resulted in treatment being delayed until after the development of neurologic deficits. Based on this treatment paradigm, tumors at the time of treatment are typically large and associated with irreversible neurologic deficits and increased risk of treatment-induced morbidity. Subsequently, knowledge of the natural history of tumors associated with NF2 is critical for predicting the future growth of a tumor and deciding on the best treatment of affected patients. To gain clinical and molecular insights into the effects of NF2 gene mutations on tumor development/progression and to identify features associated with symptom evolution in NF2-associated tumors, we are performing an ongoing natural history study of 269 NF2 patients. Analysis of this study data will allow us to gain a better understanding of the natural history of CNS tumors in NF2. So far, variable patterns of tumor growth, including a stuttering pattern, have been observed in many subjects. Preliminary studies suggest that genetic factors beyond the NF2 gene mutation are associated with increased meningioma aggressiveness in patients with NF2. This prospective natural history study should be useful in identifying the factors that affect tumor biology, symptom formation and, optimal timing of treatment in NF2.

希佩尔-林道病 (VHL) 我们正在对 250 名 VHL 患者进行自然史研究（Lonser et al. 2014），继续追踪 VHL 患者，以进一步了解 VHL 相关中枢神经系统 (CNS) 血管母细胞瘤的自然史。 到目前为止，我们的研究结果证实，大多数血管母细胞瘤以跳跃模式生长，其特征是生长和静止期。 静止的肿瘤不需要治疗。 如果血管母细胞瘤与增大的肿瘤囊肿相关，则更有可能引起症状并需要手术治疗。血浆通过可渗透的肿瘤血管外渗是形成瘤周囊肿和注射器的基础。 胚胎成血管细胞是 VHL 相关中枢神经系统成血管细胞瘤的起源细胞。 VHL 相关中枢神经系统血管母细胞瘤需要新的非侵入性治疗方法。我们的实验室已经证明，由种系错义VHL基因突变表达的突变VHL蛋白保留了一些生化功能，但该功能由于突变蛋白的加速分解而丧失。 Vorinostat 是一种组蛋白脱乙酰酶抑制剂，被批准用于治疗难治性皮肤 T 细胞淋巴瘤 (CTCL)，在实验上可减缓突变 VHL 蛋白的细胞内分解。一项壁内临床研究 (14-N-0067) 正在进行中，其中对已知种系错义 VHL 基因突变、需要手术切除血管母细胞瘤的成年患者给予伏立诺他 1 周。该研究检查了手术肿瘤标本中突变 VHL 蛋白肿瘤的存在和数量。 将伏立诺他治疗患者的突变 VHL 蛋白水平与之前手术切除组织中的突变 VHL 蛋白水平进行比较。迄今为止，共有 5 名受试者参加了该研究，接受了研究药物，并进行了手术。在 5 名接受治疗的受试者中，有 4 名受试者在手术期间获得了肿瘤标本。目前正在对这些样本进行分析，以确定伏立诺他是否会减少突变型 VHL 蛋白的降解。一名受试者在病理学上没有确认血管母细胞瘤切除，因此没有相关的肿瘤标本用于分析。 还测量了肿瘤中血管内皮生长因子（VEGF）和促红细胞生成素（EPO）的基因表达。这项尚未发表的研究将提供初步数据，可能支持随后对 VHL 错义突变患者进行伏立诺他治疗临床试验。 今年，外科神经病学分会成员继续发表有关 VHL 的文章。 一篇文章证实普萘洛尔（一种常用的口服抗高血压药）对从患者肿瘤组织中提取的 VHL 相关血管母细胞瘤 (HB) 细胞具有抗肿瘤活性。 普萘洛尔可能通过调节 VEGF 表达和诱导细胞凋亡来降低 VHL-HB 和 VHL 相关肾细胞癌 (RCC) 的体外活力。普萘洛尔在体内消除了 786-O 异种移植肿瘤的进展，回顾性临床数据表明普萘洛尔可抑制 HB 生长。这些结果表明普萘洛尔可能在治疗 VHL 相关肿瘤中发挥作用。 2 型神经纤维瘤病 (NF2) NF2 中枢神经系统肿瘤的千变万化的性质以及对其自然史和症状形成的潜在机制的不完全了解导致治疗被推迟到出现神经功能缺损之后。基于这种治疗模式，治疗时的肿瘤通常很大，并且与不可逆的神经功能缺损和治疗引起的发病风险增加相关。随后，了解与 NF2 相关的肿瘤的自然史对于预测肿瘤的未来生长和决定受影响患者的最佳治疗至关重要。 为了深入了解 NF2 基因突变对肿瘤发生/进展的影响，并确定与 NF2 相关肿瘤症状演变相关的特征，我们正在对 269 名 NF2 患者进行一项持续的自然史研究。 对这项研究数据的分析将使我们更好地了解 NF2 中 CNS 肿瘤的自然史。到目前为止，在许多受试者中观察到了不同的肿瘤生长模式，包括口吃模式。初步研究表明，NF2 基因突变以外的遗传因素与 NF2 患者脑膜瘤侵袭性增加有关。 这项前瞻性自然史研究应该有助于确定影响 NF2 肿瘤生物学、症状形成和最佳治疗时机的因素。