Elucidating the drivers of medulloblastoma initiation and recurrence

 描述(申请人提供)：髓母细胞瘤(MB)是最常见的儿童恶性脑癌。虽然大多数患者对多模式治疗有反应，但大量治疗导致的发病率和复发(几乎总是导致死亡)仍然是这些患者临床管理中的重大障碍。因此，人们在寻找既能缩小原发肿瘤又能防止复发的新型靶向治疗方面付出了很大努力。其中一种化合物vismodegib已被FDA批准用于转移性基底细胞癌患者，在针对MB患者Hedgehog(HH)亚群的各种临床试验中显示出良好的前景。我们未发表的结果，以及Dirks小组最近发表的数据表明，在HH驱动的MB中，MB癌症干细胞(CSC)群体对vismodegib无效，这一观察结果可能会导致使用这种SMO抑制剂治疗的MB复发。因此，这类抑制剂可能只针对肿瘤块状组织，而对可能导致肿瘤复发的癌症干细胞储存库保持不变。我们的工作重点是寻找SMO的替代目标，以根除甲基溴HH亚群内的CSCs。靶向CSC储存库的MB的新候选治疗方法将在ptch1、p53-/-CSCs培养上进行体外筛选(目标1)。选定的治疗方法将在ND2：SmoA1 MB小鼠模型上与vismodegib相结合，以研究AIM 2中的无瘤生存率。我们在MB小鼠模型中的相关性将在ptch1驱动的人类MB模型(Aim 3)中进一步验证。我们的长期目标是开发一种治疗策略，缩小原发肿瘤并针对CSC储存库。

 DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant pediatric brain cancer. While the bulk of patients respond to multimodal therapy, significant treatment induced morbidity, and relapse (which almost always results in death) remain significant barriers in the clinical management of these patients. Thus, significant effort has gone into identifying novel targeted therapies for this cancer that both shrink the primary tumor and prevent relapse. One of these compounds, vismodegib, which is FDA-approved for metastatic basal cell carcinoma patients, has shown promise in various clinical trials for hedgehog (HH) subgroup of MB patients. Our unpublished results, along with recently published data from the Dirks group, suggests that a population of MB cancer stem cells (CSC) in HH driven MB is refractory to vismodegib, an observation likely to lead to MB recurrence in patients treated with this SMO inhibitor. Thus, this class of inhibitors may only target the tumor bulk whil leaving the cancer stem cell reservoir, which is likely responsible for tumor relapse, untouched. We focus our work in finding alternative targets to SMO for CSCs eradication within HH subgroup of MB. New candidate treatments for MB targeting CSC reservoir will be screened ex vivo on Ptch1, p53-/- CSCs cultures (Aim 1). Selected therapeutic approach will be combined with vismodegib on the ND2:SmoA1 murine model of MB to study tumor-free survival in Aim 2. Relevance of our findings in murine models of MB will be further validated in a PTCH1 driven human MB model (Aim 3). Our long-term goal is to develop a therapeutic strategy that shrinks primary tumor and targets CSC reservoir.