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: 10018957
• 负责人: DAVID J ROBBINS
• 金额: $ 34万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018957
• 关键词: Address; Apoptosis; Arginine; Attenuated; Basal cell carcinoma; Binding Proteins; Bioinformatics; Biological Assay; Biological Availability; Biological Markers; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cells; Childhood Malignant Brain Tumor; Clinic; Clinical; Data; Databases; Development; Engineering; FDA approved; Family; Family member; GLI Family Protein; Genomics; Goals; Growth; Histopathology; Human; Implant; In Vitro; Kinesin; Malignant Neoplasms; Methylation; Methyltransferase; Mining; Modeling; Mus; Mutation; Patients; Pharmaceutical Preparations; Play; Proteins; Proteomics; Recurrence; Regulation; Relapse; Resistance; Resources; Role; SHH gene; Series; Site; Small Interfering RNA; Structure; Subgroup; Testing; Tissues; Toxic effect; Transferase; Tumor Cell Line; Tumor Volume; Work; base; experience; in vivo; inhibitor/antagonist; innovation; medulloblastoma; mouse model; mutant; new therapeutic target; novel; prevent; research clinical testing; single cell sequencing; small molecule; small molecule inhibitor; smoothened signaling pathway; targeted treatment; transcription factor; tumor; ubiquitin ligase

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) 信号通路在大量人类基因的发生中发挥着关键作用 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 针对关键的上游激活剂 Smoothened (SMO)，它调节 GLI 转录因子家族。其中两种化合物，包括 vismodegib，已获得 FDA 批准用于 转移性基底细胞癌患者，目前正在 MB 患者中进行临床评估。然而， 由于 SMO 下游突变或肿瘤快速复发而产生的固有耐药性已经被 在接受 vismodegib 治疗的 MB 患者中经常观察到。此外，复发的 vismodegib 的基因组分析 耐药性基底细胞癌揭示了与结构多样的 SMO 类似的交叉耐药机制 抑制剂。这些数据凸显了迫切需要具有不同作用机制的靶向治疗， 用于治疗患有 SHH 驱动的癌症的患者并预防肿瘤复发。此举的目标 建议是识别和表征一组新颖的此类调节剂（目标 1 和 2），并验证它们的体内作用 使用 MB 的小鼠和人类原位小鼠模型发挥作用（目标 3）。本文提出的工作将解决 SHH 驱动的癌症中对新型药物靶点的巨大临床需求。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至关重要的 成功完成拟议目标。