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

项目摘要 脑膜瘤是最常见的原发性颅内肿瘤。虽然许多这些 肿瘤是良性的，表现为WHO I级病变，可以用标准治疗方法治愈。 手术切除和放射治疗的治疗干预，复发仍然是 相对常见。在一线治疗失败后，不幸的是没有有效的治疗方法 为患有进行性复发脑膜瘤的患者提供持久，长期 在这种情况下，疾病控制一直是一个挑战。需要新的治疗方法 对于这些案件。 现代基因组学技术已经允许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的突变。最近的工作（我们的团队和其他人） 在主要由WHO I级和未经治疗的脑膜瘤组成的大型队列中， SMO、AKT1、KLF4、BAP1、TRAF7和TERT启动子突变在这些基因的特定亚群中 肿瘤，除了已确立的NF2失活，这是其特征， 肿瘤。为了进一步描述我们可以得出最大临床 受益于这些改变的治疗靶向，我们已经聚集了一个大的队列， 脑膜瘤患者，与先前发现的队列不同， 来自复发性、治疗后和WHO分级进展肿瘤的标本。 因此，我们提出的基因组分析将侧重于了解分子生物学。 这种疾病的临床谱的改变，更重要的是，有可能 确定驱动脑膜瘤复发或发生恶性肿瘤的遗传因素， 转化，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提供重要的信息，以促进设计和 正在进行的复发性进行性脑膜瘤临床试验的解释。

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.