Novel regulators of Gli-driven medulloblastoma

项目摘要 Sonic Hedgehog(SHH)信号通路在大量人类疾病的发生中起着关键作用 癌症，包括髓母细胞瘤。到目前为止，大多数阻断SHH信号的小分子抑制剂 已经瞄准了关键的上游激活剂Smoothens(SMO)，它调控着 Gli转录因子家族。其中两种化合物，包括vismodegib，是FDA批准用于 转移性基底细胞癌患者，目前正在接受MB患者的临床评估。然而， 由于SMO下游突变或肿瘤快速复发所致的固有耐药性已经出现 常见于接受Vismodegib治疗的MB患者。此外，对复发的vismodegib进行基因组分析 耐药的基底细胞癌对结构不同的SMO表现出类似的交叉耐药机制 抑制剂。这些数据突出了对具有不同作用机制的靶向治疗的迫切需要， 用于治疗患有SHH驱动的癌症的患者，并防止肿瘤复发。这样做的目的是 建议是确定和表征一组新的这样的调节子(目标1和2)，并在体内验证它们 使用小鼠和人类原位小鼠MB模型的作用(目标3)。在此提出的工作将解决 SHH驱动的癌症对新的可用药靶点的实质性临床需求。我们的综合经验 团队，我们广泛的未发表的发现，以及我们为该项目带来的独特资源，将被证明是 圆满完成拟议目标。

Project Abstract The Sonic Hedgehog (SHH) signaling pathway plays critical roles in the genesis of a large number of human cancers, including medulloblastoma. To date, the majority of small molecule inhibitors that block SHH signaling have targeted the pivotal upstream activator Smoothened (SMO), which regulates the levels and activity of the GLI family of transcription factors. Two of these compounds, including vismodegib, are FDA-approved for metastatic basal cell carcinoma patients, and are now undergoing clinical evaluation in MB patients. However, inherent resistance due to mutations downstream of SMO, or rapid tumor recurrence, has already been frequently observed in MB patients treated with vismodegib. Further, genomic analysis of relapsed, vismodegib resistant basal cell carcinomas has revealed similar mechanisms of cross-resistance to structurally diverse SMO inhibitors. Such data highlight the urgent need for targeted therapies with distinct mechanisms of action, with which to treat patients harboring SHH-driven cancers and to prevent their tumor recurrence. The goal of this proposal is to identify and characterize a novel set of such regulators (Aims 1 & 2), and to validate their in vivo roles using mouse and human orthotopic mouse models of MB (Aim 3). The work proposed herein will address the substantial clinical need for novel druggable targets in SHH-driven cancers. The combined experience of our team, our extensive unpublished findings, and the unique resources we bring to this project will prove pivotal in successful completion of the proposed Aims.