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 手术、放疗和大剂量化疗相结合，提高了存活率，许多 MB患者仍然死于这种疾病。此外，存活的患者会遭受严重的长期副作用。 作为治疗结果的影响。因此，开发更有效、毒性更低的产品至关重要。 治疗。最具侵袭性的MB亚型包括表现出 MYC癌基因。MYC扩增MB患者的肿瘤转移到 整个大脑和脊髓，经常经历治疗抵抗，并具有极差的 预见书。在这个应用中，我们建议使用新的小鼠MYC驱动的MB和患者来源的MB 异种移植模型研究少突胶质细胞系转录因子2的作用 MYC扩增的MB在肿瘤发生、发展和转移中的作用我们将使用这些老鼠模型 评估一种新的靶向治疗方法。为此，我们将：(1)评估是否 切除寡核苷酸肿瘤细胞可以防止肿瘤的形成、进展和转移，(2)确定 2基因缺失是否能阻止肿瘤的进展和转移，以及(3)检测 预测靶向小分子抑制剂的寡核苷酸可以抑制生长和预防 人MYC扩增的MB PDX模型中的转移。如果这些研究成功，它们将有所帮助。 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.