Novel regulators of Gli-driven medulloblastoma

Gli 驱动的髓母细胞瘤的新型调节因子

• 批准号: 10651875
• 负责人: DAVID J ROBBINS
• 金额: $ 35.4万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651875
• 关键词: medulloblastoma; novel

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 The combined experience of our team, our extensive unpublished findings, and the unique resources we bring to this project will prove pivotal in successful completion of the proposed Aims.

项目摘要 Sonic Hedgehog（SHH）信号通路在许多人类肿瘤的发生中起着重要作用。 癌症，包括髓母细胞瘤。迄今为止，大多数阻断SHH信号传导的小分子抑制剂 已经针对关键的上游激活剂Smoothened（SMO），它调节细胞的水平和活性， GLI转录因子家族。这些化合物中的两种，包括维莫德吉，是FDA批准用于 转移性基底细胞癌患者，目前正在MB患者中进行临床评价。然而，在这方面， 由于SMO下游突变或快速肿瘤复发而产生的固有耐药性已经被 在接受维莫德吉治疗的MB患者中经常观察到。此外，复发性维莫德吉的基因组分析 耐药的基底细胞癌揭示了对结构多样的SMO交叉耐药的相似机制 抑制剂的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， 其用于治疗患有SHH驱动的癌症的患者并防止其肿瘤复发。这个目标 一项建议是鉴定和表征一组新的此类调节剂（目标1和2），并在体内验证其活性。 使用MB的小鼠和人原位小鼠模型（Aim 3），本文件提出的工作将涉及 在SHH驱动的癌症中对新的可药用靶点的大量临床需求。结合我们的经验， 团队，我们广泛的未发表的研究结果，以及我们为这个项目带来的独特资源将证明是至关重要的， 圆满完成了提出的目标。