Impact of genetic alterations in meningioma on natural history and therapeutic response

脑膜瘤遗传改变对自然史和治疗反应的影响

• 批准号: 9227547
• 负责人: Priscilla Kaliopi Brastianos
• 金额: $ 26.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227547
• 关键词: AKT1 gene; Address; Adjuvant; Aftercare; Anterior; Appearance; Automobile Driving; BAP1 gene; Behavior; Benign; Brain imaging; Categories; Characteristics; Classification; Clinical; Clinical Trials; Collaborations; Common Neoplasm; DNA Sequence Alteration; Data; Development; Disease; Event; Excision; Failure; Foundations; Frequencies; Future; Gene Mutation; Genes; Genetic; Genomics; Genotype; Goals; Histologic; Intracranial Neoplasms; Knowledge; Lead; Lesion; Letters; Malignant - descriptor; Malignant Neoplasms; Mission; Molecular; Molecular Analysis; Molecular Genetics; Mutation; NF2 Gene Inactivation; Natural History; Neoplasms; Oncogenic; Operative Surgical Procedures; Outcome; Patients; Phenotype; Principal Investigator; Protocols documentation; Public Health; Radiation therapy; Radiosurgery; Recurrence; Relapse; Research Personnel; Secure; Specimen; Systemic Therapy; Technology; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Intervention; Therapeutic Trials; Treatment-Associated Neoplasms; United States National Institutes of Health; Work; base; clinical decision-making; clinical phenotype; clinically significant; cohort; design; disorder control; effective therapy; inhibitor/antagonist; meningioma; mutant; neoplastic cell; next generation sequencing; novel; novel therapeutic intervention; phase 2 study; promoter; response; screening; secondary outcome; skull base; standard care; targeted treatment; therapeutic target; tool; treatment response; tumor

PROJECT SUMMARY Meningiomas are the most common primary intracranial tumor. Although many of these tumors are benign, presenting as WHO grade I lesions that can be cured with the standard therapeutic interventions of surgical resection and radiation therapy, recurrence is nevertheless relatively common. After failure of frontline treatment, there is unfortunately no effective therapy to offer patients who have progressive recurrent meningioma, and securing durable, long-term disease control in this setting has been challenging. New therapeutic approaches are needed for these cases. Modern genomic technologies have allowed for broad characterization of somatic gene mutations found in tumor cells in many different cancers. Recent work (by our team and others) in large cohorts consisting primarily of WHO grade I and untreated meningiomas has identified SMO, AKT1, KLF4, BAP1, TRAF7 and TERT promoter mutations in specific subsets of these tumors, in addition to the well-established NF2 inactivation that is characteristic of this neoplasm. To further characterize the clinical scenarios where we can derive maximal clinical benefit with therapeutic targeting of these alterations, we have assembled a large cohort of meningioma patients, which unlike prior discovery cohorts, are considerably enriched for specimens derived from recurrent, post-treatment and WHO grade-progressive tumors. Our proposed genomic analyses will therefore focus on understanding the molecular alterations across the clinical spectrum of this disease, and more importantly, have the potential to identify the genetic factors that drive meningiomas to relapse or undergo malignant transformation, targets which could be prioritized to maximize clinical impact. Thus, the successful execution of this work will provide important information to facilitate the design and interpretation of ongoing clinical trials for recurrent progressive meningioma.

项目概要 脑膜瘤是最常见的原发性颅内肿瘤。虽然其中许多 肿瘤是良性的，表现为WHO I级病变，可以用标准治愈 手术切除和放射治疗等治疗干预措施，但仍会复发 比较常见。一线治疗失败后，遗憾的是没有有效的治疗方法 为患有进行性复发性脑膜瘤的患者提供持久、长期的治疗 在这种情况下，疾病控制一直具有挑战性。需要新的治疗方法 对于这些情况。 现代基因组技术已经能够对体细胞基因进行广泛的表征 在许多不同癌症的肿瘤细胞中发现了突变。最近的工作（我们的团队和其他人） 在主要由世界卫生组织 I 级和未经治疗的脑膜瘤组成的大型队列中发现 其中特定子集中的 SMO、AKT1、KLF4、BAP1、TRAF7 和 TERT 启动子突变 肿瘤，除了众所周知的 NF2 失活（这是其特征） 肿瘤。为了进一步描述临床场景，我们可以得出最大的临床效果 为了受益于针对这些改变的治疗目标，我们聚集了一大群 与之前的发现群体不同，脑膜瘤患者的脑膜瘤患者的基因丰富程度相当高 来自复发性、治疗后和 WHO 级进展性肿瘤的标本。 因此，我们提出的基因组分析将侧重于了解分子 这种疾病的整个临床范围的改变，更重要的是，有潜力 确定导致脑膜瘤复发或恶性的遗传因素 转型，可以优先考虑的目标，以最大限度地提高临床影响。因此， 这项工作的成功执行将为促进设计和 正在进行的复发性进展性脑膜瘤临床试验的解释。