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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

基本信息

批准号：
10316212
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
项目类别：
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/10316212
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 antagonist antitumor effect base brain cell chemotherapy curative treatments disorder subtype dopamine transporter drug sensitivity genomic data in vivo inhibitor 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

项目摘要

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。固有的挑战