The role of Olig2 in the tumorigenesis, progression and metastasis in MYC-amplified medulloblastoma

项目摘要 髓母细胞瘤是儿童最常见的恶性脑肿瘤。虽然治疗 结合手术、放疗和大剂量化疗， MB患者仍然死于这种疾病。此外，存活的患者遭受严重的长期副作用， 作为治疗的结果。因此，开发更有效、毒性更小的药物至关重要。 治疗MB的最具侵袭性的亚型由表现出扩增的肿瘤组成。 MYC癌基因。MYC扩增MB患者表现出高频率的肿瘤播散， 整个大脑和脊髓，经常经历治疗抵抗， 两杯在本申请中，我们提出使用新的小鼠MYC驱动的MB和患者来源的 异种移植（PDX）模型，以研究少突胶质细胞谱系转录因子2（Olig2）的作用 MYC扩增MB的肿瘤发生、进展和转移。我们将使用这些小鼠模型 评估一种新的靶向治疗方法。为此，我们将：（1）评估是否 消融Olig2+肿瘤细胞可以防止肿瘤的形成、进展和转移，（2）确定 寡聚体2基因的缺失是否阻止肿瘤进展和转移，以及（3）测试寡聚体2基因的缺失是否阻止肿瘤进展和转移。 预测用小分子抑制剂靶向Olig2可以抑制生长并预防 在人MYC扩增的MB PDX模型中的转移。如果这些研究成功， 确定可有效治疗MYC扩增MB患者的新靶向疗法。

Project Summary Medulloblastoma (MB) is the most common malignant brain tumor in children. Although treatment combining surgery, radiation and high-dose chemotherapy has led to increased survival rates, many MB patients still die from the disease. Moreover, surviving patients suffer severe long-term side effects as a consequence of treatment. It is therefore crucial to develop more effective and less toxic therapies. The most aggressive subtype of MB consists of tumors that exhibit amplification of the MYC oncogene. Patients with MYC-amplified MB exhibit a high frequency of tumor dissemination to the entire brain and spinal cord, often experience treatment resistance and have extremely poor prognoses. In this application, we propose to use novel mouse MYC-driven MB and patient-derived xenograft (PDX) models to investigate the role of oligodendrocyte lineage transcription factor 2 (Olig2) in tumorigenesis, progression and metastasis of MYC-amplified MB. We will use these mouse models to evaluate a novel targeted approach to treatment. To accomplish this we will: (1) evaluate whether ablation of Olig2+ tumor cells can prevent tumor formation, progression and metastasis, (2) determine whether deletion of the Olig2 gene prevents tumor progression and metastasis, and (3) test the prediction that targeting Olig2 with a small molecule inhibitor can inhibit growth and prevent metastasis in a human MYC-amplified MB PDX model. If these studies are successful, they will help identify new targeted therapies that can be effective in treating patients with MYC-amplified MB.