(PQ6) Molecular Mechanisms of Dormancy in MYC-Driven Medulloblastoma

描述（由申请人提供）：髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤。尽管手术、放疗和大剂量化疗提高了生存率，但许多MB患者仍死于该病，部分原因是 肿瘤复发率高。因此，MB的新的和更有效的疗法是至关重要的。最具侵袭性的MB亚型由表现出MYC癌基因过表达或扩增的肿瘤组成。MYC驱动的MB患者最初对治疗有反应，但数月或数年后复发，这表明一些肿瘤细胞可以持续存在，并在治疗后长时间保持休眠状态。然而，这种休眠的分子基础以及导致肿瘤复发的事件仍然不清楚。我们最近开发了一种独特的MYC驱动MB模型，使我们能够诱导休眠，识别和分离休眠肿瘤细胞（DTC），并将这些细胞与它们产生的正常干细胞进行比较。利用该模型，我们提出：（1）确定DTC是否在表型和功能上类似于干细胞，（2）通过比较DTC、干细胞和恶性肿瘤细胞的基因表达谱来确定肿瘤细胞休眠的分子机制，以及（3）筛选促进休眠肿瘤细胞分化但对正常干细胞无毒的小分子。如果这些研究成功，它们将有助于确定预防MYC驱动的MB和其他恶性肿瘤复发的新方法。!

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant brain tumor in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival rates, many MB patients still die from their disease, in part due to the high incidence of tumor recurrence. Thus, novel and more effective therapies for MB are critically important. The most aggressive subtype of MB consists of tumors that exhibit overexpression or amplification of the MYC oncogene. Patients with MYC-driven MB initially to respond to therapy, but then relapse months or years later, suggesting that some tumor cells can persist, and remain dormant for prolonged periods after treatment. However, the molecular basis of this dormancy, and the events that lead to tumor recurrence, remain unclear. We recently developed a unique model of MYC-driven MB that allows us to induce dormancy, to identify and isolate dormant tumor cells (DTCs), and to compare these cells to the normal stem cells from which they arise. Using this model, we propose to: (1) Determine whether DTCs resemble stem cells phenotypically and functionally, (2) Identify the molecular mechanisms of tumor cell dormancy by comparing the gene expression profiles of DTCs, stem cells and malignant tumor cells, and (3) Screen for small molecules that promote differentiation of dormant tumor cells, but are not toxic to normal stem cells. If these studies are successful, they will help identify novel approaches to preventing tumor relapse in MYC-driven MB and other malignancies. !