Elucidating the drivers of medulloblastoma initiation and recurrence

 描述（由申请人提供）：髓母细胞瘤（MB）是最常见的儿童恶性脑癌。虽然大部分患者对多模式治疗有反应，但显著的治疗诱导的发病率和复发（几乎总是导致死亡）仍然是这些患者临床管理的显著障碍。因此，已经做出了重大努力来确定这种癌症的新靶向疗法，既缩小了原发性肿瘤又防止复发。这些化合物之一，vismodegib，FDA批准用于转移性基底细胞癌患者，已在MB患者的hedgehog（HH）亚组的各种临床试验中显示出希望。我们未发表的结果，沿着Dirks组最近发表的数据，表明HH驱动的MB中的MB癌症干细胞（CSC）群体对维莫德吉难治，这一观察结果可能导致接受该SMO抑制剂治疗的患者的MB复发。因此，这类抑制剂可能仅靶向肿瘤块，而不触及可能导致肿瘤复发的癌症干细胞库。我们的工作重点是在MB的HH亚组中寻找SMO根除CSC的替代靶点。将在Ptch 1、p53-/-CSC培养物上离体筛选MB靶向CSC储库的新候选治疗（目标1）。选择的治疗方法将与维莫德吉在MB的ND 2：SmoA 1鼠模型上组合，以研究Aim 2中的无肿瘤生存期。我们在小鼠MB模型中发现的相关性将在PTCH 1驱动的人MB模型中进一步验证（目的3）。我们的长期目标是开发一种缩小原发性肿瘤并靶向CSC储库的治疗策略。

 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 Our unpublished results, along with recently published data from the Dirks group, suggests that a population of MB cancer stem cells (CSC) in HH driven MB is refractory to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.