Targeting oncogenic dopamine receptor signaling in glioblastoma

靶向胶质母细胞瘤中的致癌多巴胺受体信号传导

• 批准号: 10062485
• 负责人: Jeongwu Lee
• 金额: $ 48.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062485
• 关键词: Agonist; Anabolism; Antipsychotic Agents; Binding; Bioinformatics; Biological; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Cell Death; Cell Maintenance; Cells; Chemotherapy and/or radiation; Clinic; DNA Sequence Alteration; Data; Development; Dopamine; Dopamine Receptor; Drug Delivery Systems; Drug Targeting; Enzymes; Excision; FDA approved; GTP-Binding Proteins; Genetic; Glioblastoma; Goals; Growth; Heterogeneity; Human; Libraries; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Analysis; Molecular Target; Mus; Neurotransmitters; Nonsense Mutation; Oncogenic; Operative Surgical Procedures; Organoids; Pathologic; Pathway interactions; Patients; Pattern; Peptide Receptor; Pharmacology; Phenotype; Prediction of Response to Therapy; Primary Brain Neoplasms; Radiation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; Specimen; Stratification; System; Testing; Therapeutic; Translations; Treatment Efficacy; Tumor-Derived; Validation; antitumor effect; base; brain cell; chemotherapy; curative treatments; disorder subtype; dopamine transporter; drug sensitivity; genomic data; in vivo; inhibitor/antagonist; irradiation; knock-down; neoplastic cell; novel; novel strategies; pre-clinical; predictive marker; radiation resistance; receptor; resistance mechanism; response; self-renewal; standard care; stem; systemic toxicity; targeted agent; temozolomide; therapeutically effective; therapy resistant; tool; tumor; tumor growth; tumorigenic; validation studies

Glioblastoma (GBM) is the most common and the most lethal brain cancer. The challenges inherent in developing effective GBM therapeutics include resistance to standard treatments such as radiation and chemotherapy, limited drug delivery into the tumor due to the Blood-Brain-Barrier (BBB), genetic and molecular heterogeneity, and a subpopulation of stem-like GBM cells (GSCs). Here, we propose a novel strategy that may overcome the above hurdles. Our recent studies have discovered that dopamine receptor subtype 2 (DRD2), a key receptor for dopamine signaling in the brain, promoted GBM growth and survival. Mechanistically, oncogenic DRD2 signaling in GBM activates c-MET receptor, a key regulator for cancer stem phenotype and GBM therapeutic resistance, via direct interaction between DRD2 and c-MET. Importantly, DRD2 inhibition via an FDA-approved DRD2 antagonist, which can freely pass the BBB, potently inactivated oncogenic signaling pathways, diminished clonogenic growth of GSCs, and impeded GBM growth. Based on these findings, we propose three Aims to validate the DRD2 targeting as new concept for the treatment of human GBM: 1) The mechanistic Aim will explore how the DRD2 targeting leads to tumor cell death and how inactivation of this axis can be reliably achieved in GBM. 2) The stratification Aim will identify disease subtypes and groups of patients that may be most responsive to the DRD2 targeting based on our finding that a subset of GBM tumors produces dopamine and these tumors are more addicted to oncogenic DRD2 signaling. 3) The goal of therapeutic Aim is the development and preclinical validation of DRD2 antagonists using mouse avatars bearing patient-derived GBM tumors.

胶质母细胞瘤(GBM)是最常见和最致命的脑癌。面临的内在挑战 开发有效的GBM疗法包括抵抗标准治疗，如辐射和 化疗，由于血脑屏障(BBB)、遗传和分子方面的原因，对肿瘤的药物输送有限 异质性，以及干细胞样基底膜细胞(GSCs)亚群。在这里，我们提出了一种新的战略， 可能会克服上述障碍。我们最近的研究发现，多巴胺受体亚型2 DRD2是大脑中多巴胺信号的关键受体，它促进了GBM的生长和存活。 从机制上讲，GBM中致癌的DRD2信号激活c-met受体，c-met受体是肿瘤干细胞的关键调节因子 通过DRD2和c-Met之间的直接相互作用，表型和GBM治疗耐药。重要的是 通过FDA批准的DRD2拮抗剂抑制DRD2，该拮抗剂可以自由通过BBB，有效地灭活 致癌信号通路，抑制GSCs的克隆生长，阻碍GBM的生长。基于 这些发现，我们提出了三个目的，以验证DRD2靶向作为治疗肺癌的新概念 人类GBM：1)机制目标将探索DRD2靶向如何导致肿瘤细胞死亡和 如何在GBM中可靠地实现此轴的停用。2)分层的目的是识别疾病 根据我们的发现，对DRD2靶向最敏感的患者亚型和群体 GBM肿瘤的一个亚群产生多巴胺，这些肿瘤更容易对致癌的DRD2上瘾 发信号。3)治疗的目标是开发和临床前验证DRD2拮抗剂。 使用携带患者来源的GBM肿瘤的小鼠头像。