Sema3C Signaling as an Alternative Activator of Canonical Wnt Signaling in Glioblastoma

Sema3C 信号转导作为胶质母细胞瘤中典型 Wnt 信号转导的替代激活剂

• 批准号: 10676655
• 负责人: Jennifer S Yu
• 金额: $ 40.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676655
• 关键词: Binding; Blood Vessels; Bypass; Cell Nucleus; Clinical Trials; Complex; Cues; Data; Development; Dissection; Dose; Gene Expression; Genes; Genetic; Genetic Transcription; Glioblastoma; Glioma; Guanosine Triphosphate; Human; Hypoxia; Impairment; Ligand Binding; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of prostate; Modeling; Molecular; Monomeric GTP-Binding Proteins; NRP1 gene; Normal tissue morphology; Nuclear; Nuclear Translocation; PTK2B gene; Pathway interactions; Patient-Focused Outcomes; Phosphotransferases; Primary Brain Neoplasms; Recurrent disease; Regulation; Resistance; Role; Semaphorins; Signal Transduction; Therapeutic; Toxic effect; Tumor Promotion; Tumorigenicity; WNT Signaling Pathway; Work; Xenograft Model; axon guidance; beta catenin; clinically significant; experimental study; improved; improved outcome; inhibitor; malignant breast neoplasm; mouse model; neuronal guidance; novel; novel therapeutic intervention; overexpression; pharmacologic; preclinical study; programs; receptor; receptor binding; resistance mechanism; self-renewal; stem-like cell; therapeutic target; therapy resistant; tumor; tumor initiation; tumor progression; tumorigenic

PROJECT SUMMARY The Wnt pathway is frequently dysregulated in many cancers, underscoring it as a therapeutic target. Although Wnt inhibitors appear promising in many preclinical studies, they have failed uniformly in clinical trials. Molecular mechanisms of resistance are poorly defined. Further dissection of the precise mechanisms of WNT pathway activation in specific tumor types is needed to develop new WNT pathway inhibitors with less toxicity. The axonal guidance program Sema3C/PlxnD1 promotes the self-renewal and tumorigenicity of glioma stem-like cells (GSCs), but the underlying mechanisms are unclear. Our data now suggest that Sema3C/PlxnD1 signaling functions as an alternative activator of canonical Wnt signaling. Importantly, Sema3C-driven Wnt signaling occurred despite suppression of Wnt ligand secretion, suggesting that Sema3C may drive canonical Wnt signaling independent of Wnt binding to its receptors. As Sema3C/PlxnD1 signaling is used in over 85% of GBM, it may represent an important mechanism of resistance to upstream Wnt pathway inhibitors. Our data support that Sema3C/PlxnD1 signaling regulates two critical aspects Wnt signaling: beta-catenin stability and nuclear translocation. In this proposal, we aim to identify molecular mechanisms by which Sema3C/PlxnD1 regulate canonical Wnt signaling. Additionally, we aim to assess the therapeutic impact of targeting Sema3C signaling to improve sensitivity to upstream Wnt inhibitors in mouse models of GBM. These studies will provide a novel therapeutic strategy to achieve clinically significant Wnt pathway inhibition in GSCs potentially without the toxicity of currently available WNT inhibitors. These studies may be applied to other cancers including breast and prostate cancers that utilize both Sema3C and Wnt signaling.

项目摘要 Wnt通路在许多癌症中经常失调，强调它作为一种治疗方法， 目标尽管Wnt抑制剂在许多临床前研究中看起来很有希望，但它们已经失败了。 在临床试验中一致。耐药的分子机制定义不清。进一步 对特定肿瘤类型中WNT通路激活的精确机制的剖析， 需要开发新的毒性更小的WNT通路抑制剂。轴突引导程序 Sema 3C/PlxnD 1促进胶质瘤干细胞样细胞（GSC）的自我更新和致瘤性， 但其潜在机制尚不清楚。我们的数据现在表明Sema 3C/PlxnD 1信号传导 作为经典Wnt信号传导的替代激活剂发挥作用。Sema 3C驱动的Wnt 尽管Wnt配体分泌受到抑制，但信号传导仍然发生，这表明Sema 3C可能 独立于Wnt与其受体的结合而驱动典型的Wnt信号传导。作为Sema 3C/PlxnD 1 信号转导在超过85%的GBM中使用，它可能代表了对GBM的抗性的重要机制。 上游Wnt途径抑制剂。我们的数据支持Sema 3C/PlxnD 1信号调节两个 关键方面Wnt信号传导：β-连环蛋白稳定性和核转位。在这项提案中， 我们的目标是确定Sema 3C/PlxnD 1调节经典Wnt的分子机制， 信号此外，我们的目标是评估靶向Sema 3C信号传导的治疗作用， 改善GBM小鼠模型对上游Wnt抑制剂的敏感性。这些研究将 提供了一种新的治疗策略，以实现临床上显著的Wnt途径抑制， GSC可能没有目前可用的WNT抑制剂的毒性。这些研究可能是 适用于其他癌症，包括利用Sema 3C和Wnt的乳腺癌和前列腺癌 信号