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.

von Hippel-Lindau病（VHL） 在250名VHL患者的自然史研究中，我们将继续关注VHL患者（Lonser等人，2014年），以进一步了解与VHL相关的中枢神经系统（CNS）Hemangioblastomas的自然历史。 到目前为止，我们的发现证实，大多数血管群都以盐的形式生长，其特征在于生长和静止的时期。 静止的肿瘤不需要治疗。 血管母细胞瘤更可能引起症状，如果与肿瘤囊肿肿大有关，则需要手术治疗。通过可渗透的肿瘤血管进行的血浆渗出是周围囊肿和注射器形成的基础。 胚胎血管细胞是与VHL相关的CNS血管母细胞瘤起源细胞。需要针对VHL相关的CNS血管母细胞瘤的新的无创治疗。我们的实验室已经证明，通过种系错义VHL基因突变表达的突变VHL蛋白保留了一定的生化功能，但是由于突变蛋白的加速分解而丧失了该功能。 Vorinostat是一种组蛋白脱乙酰基酶抑制剂，批准治疗难治性皮肤T细胞淋巴瘤（CTCL），实验性地减慢了突变体VHL蛋白的细胞内分解。一项正在进行的壁内临床研究（14-N-0067）正在进行中，其中伏诺替纳斯塔特为需要手术切除血管母细胞瘤的已知种系错线VHL基因突变的成年患者1周。该研究检查了手术中肿瘤标本中突变体VHL蛋白肿瘤的存在和数量。 将经过vorinostat处理的患者的突变VHL蛋白水平与以前手术切除术结合的组织中的突变体VHL蛋白水平进行了比较。迄今为止，总共有5名受试者参加了研究，接受了研究药物并进行了手术。在这5名治疗受试者中，有4名受试者在手术期间获得了肿瘤标本。目前正在分析这些标本，以确定伏诺替纳斯特是否会减少突变体VHL蛋白的降解。一个受试者没有确认的关于病理学的血管母细胞瘤切除术，因此没有相关的肿瘤标本进行分析。 还测量了肿瘤中血管内皮生长因子（VEGF）和红细胞生成素（EPO）的遗传表达。这项尚未发表的研究将提供初步数据，以支持伏诺诺替氏伏洛诺尼替氏vhl突变患者的随后的治疗临床试验。 今年的外科神经病学分支机构成员继续发表有关VHL的文章。 一篇文章证实，普遍是一种常用的口服抗高血压，具有抗肿瘤活性，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。 普萘洛尔降低了VHL-HB和VHL相关的肾细胞癌（RCC）的生存能力，可能通过调节VEGF表达和诱导凋亡而进行体外。普萘洛尔废除了体内786-O异种移植肿瘤的进展，回顾性临床数据表明普萘洛尔减少了HB的生长。这些结果表明普萘洛尔可能在治疗与VHL相关肿瘤的治疗中起作用。 2型神经纤维瘤病（NF2） NF2中枢神经系统肿瘤的蛋白质性质以及对其自然历史和症状形成的潜在机制的不完全理解，导致治疗被延迟到神经系统缺陷的发展后。基于此治疗范式，治疗时的肿瘤通常很大，并且与不可逆的神经系统缺陷和治疗引起的发病率的风险增加有关。随后，对与NF2相关的肿瘤的自然历史的了解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。 为了获得对NF2基因突变对肿瘤发育/进展的影响的临床和分子见解，并确定与NF2相关肿瘤中症状演化相关的特征，我们正在对269名NF2患者进行一项持续的自然史研究。 对本研究数据的分析将使我们能够更好地了解NF2中CNS肿瘤的自然史。到目前为止，在许多受试者中都观察到了肿瘤生长的可变模式，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患者的脑膜瘤侵袭性增加有关。 这项前瞻性自然史研究应有助于确定影响NF2中肿瘤生物学，症状形成和最佳治疗时机的因素。