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）