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: 10531922
• 负责人: Jeongwu Lee
• 金额: $ 47.17万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531922
• 关键词: Agonist; Anabolism; Antipsychotic Agents; Binding; Bioinformatics; Biological; Biological Assay; Blood - brain barrier anatomy; Brain; Cell Death; 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; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mediating; Mediator; Modeling; Molecular; Molecular Analysis; Molecular Target; Mus; Neurotransmitters; Nonsense Mutation; Oncogenic; Operative Surgical Procedures; Organoids; Pathologic; Pathway interactions; Patients; Pattern; Peptides; 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 Promotion; Tumor-Derived; Validation; antagonist; antitumor effect; biomarker identification; blood-brain barrier crossing; brain cell; chemotherapy; curative treatments; disorder subtype; dopamine transporter; drug sensitivity; genomic data; in vivo; inhibitor; irradiation; knock-down; neoplastic cell; novel; novel strategies; pharmacologic; pre-clinical; 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。所固有的挑战 开发有效的GBM治疗剂包括对标准治疗如放射的抗性， 化疗，由于血脑屏障（BBB），遗传和分子生物学， 异质性和干细胞样GBM细胞（GSC）亚群。在这里，我们提出了一种新的策略， 可以克服上述障碍。我们最近的研究发现多巴胺受体亚型2 DRD 2是大脑中多巴胺信号传导的关键受体，它促进了GBM的生长和存活。 从机制上讲，GBM中的致癌DRD 2信号转导激活c-MET受体，这是癌症干细胞的关键调节因子。 表型和GBM治疗抗性，通过DRD 2和c-MET之间的直接相互作用。重要的是， 通过FDA批准的DRD 2拮抗剂抑制DRD 2，可自由通过BBB，有效灭活 致癌信号传导途径，减少GSC的克隆生长，并阻碍GBM生长。基于 根据这些发现，我们提出了三个目标来验证DRD 2靶向作为治疗糖尿病的新概念。 人GBM：1）机制目标将探索DRD 2靶向如何导致肿瘤细胞死亡， 如何在GBM中可靠地实现该轴的失活。2)分层目标将识别疾病 根据我们的发现， GBM肿瘤的一个子集产生多巴胺，这些肿瘤更依赖于致癌DRD 2 发信号。3)治疗目的的目标是DRD 2拮抗剂的开发和临床前验证 使用携带患者来源的GBM肿瘤的小鼠化身。

项目成果

Tissue factor links inflammation, thrombosis, and senescence in COVID-19.

• DOI: 10.1038/s41598-022-23950-y
• 发表时间: 2022-11-18
• 期刊: Scientific reports
• 影响因子: 4.6

Dopamine receptor D2 regulates glioblastoma survival and death through MET and death receptor 4/5.

• DOI: 10.1016/j.neo.2023.100894
• 发表时间: 2023-03
• 期刊: Neoplasia
• 影响因子: 4.8
• 作者: Hye-Min Jeon;Young-Taek Oh;Y. Shin;Nakho Chang;Donggeun Kim;Donghun Woo;Yoon Yeup;K. Joo;H. Jo;Heekyoung Yang;Jin-Ku Lee;Wonyoung Kang;J. Sa;Won Jun Lee;J. Hale;J. Lathia;B. Purow;Myung-Jin Park;J. B. Park;D. Nam;Jeongwu Lee

The semaphorin 3A/neuropilin-1 pathway promotes clonogenic growth of glioblastoma via activation of TGF-β signaling.

• DOI: 10.1172/jci.insight.167049
• 发表时间: 2023-11-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Jeon, Hye-Min;Shin, Yong Jae;Lee, Jaehyun;Chang, Nakho;Woo, Dong-Hun;Lee, Won Jun;Nguyen, Dayna;Kang, Wonyoung;Cho, Hee Jin;Yang, Heekyoung;Lee, Jin-Ku;Sa, Jason K.;Lee, Yeri;Kim, Dong Geon;Purow, Benjamin W.;Yoon, Yeup;Nam, Do-Hyun;Lee, Jeongwu
• 通讯作者: Lee, Jeongwu