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

Olig2在MYC扩增性髓母细胞瘤发生、进展和转移中的作用

基本信息

批准号：
10470023
负责人：
Yanxin Pei
金额：
$ 39.81万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-07 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470023
关键词：
Ablation Address Aftercare Blood - brain barrier anatomy Brain Cells Childhood Brain Neoplasm Childhood Malignant Brain Tumor Clinical Research Combined Modality Therapy Development Diagnosis Disease Distant Metastasis Exhibits Frequencies Ganciclovir Genes Genomics Growth High Dose Chemotherapy Human In Vitro Incidence Knock-in Knowledge MYC gene Malignant neoplasm of brain Mitotic Modeling Molecular Molecular Target Mus Neoplasm Metastasis Operative Surgical Procedures Patients Pediatric Neoplasm Pharmaceutical Preparations Prognosis Prosencephalon Radiation Radiation therapy Recurrent tumor Relapse Resistance Role SHH gene Simplexvirus Spinal Cord Subgroup Survival Rate Tamoxifen Testing Thymidine Kinase Time Tumor stage antagonist base cell growth cell suicide chemotherapy conditional knockout effective therapy efficacy testing experience improved in vivo medulloblastoma mouse model neoplastic cell new therapeutic target novel novel therapeutic intervention oligodendrocyte lineage patient derived xenograft model preclinical evaluation prevent side effect small molecular inhibitor small molecule inhibitor suicide gene therapy resistant transcription factor tumor tumor growth tumor progression tumorigenesis

项目摘要

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.

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。