Targeting Go and Grow in Glioblastoma

靶向胶质母细胞瘤的 Go and Grow

基本信息

批准号：
10053146
负责人：
Peter Canoll
金额：
$ 57.38万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10053146
关键词：
Address Apoptosis Automobile Driving Brain Categories Cells Complex Development Disease Dose Environment Epidermal Growth Factor Receptor Family Family member Genetic Genetically Engineered Mouse Glioblastoma Goals Growth Human Impairment In Vitro Invaded Knock-out Measures Mechanics Methods Molecular Motors Monitor Mus Myosin Type II Newly Diagnosed Nonmuscle Myosin Type IIA Paralysed Pathway interactions Permeability Pharmaceutical Preparations Phenotype Polyploidy Population Proliferating Protein Isoforms Radiation Radiosensitization Resistance Rest Signal Pathway Signal Transduction Slice Testing Therapeutic Thick Tissues Toxic effect Translating Up-Regulation effective therapy falls in vivo inhibitor/antagonist malignant phenotype mouse model non-muscle myosin novel phosphoproteomics response single-cell RNA sequencing small hairpin RNA small molecule inhibitor transcriptome sequencing translational study tumor tumor growth tumor progression

项目摘要

PROJECT DESCRIPTION The ability of glioblastomas to proliferate in an uncontrollable manner and disperse widely within normal brain define the malignant phenotype and make this disease uniformly lethal. Effectively treating glioblastoma therefore requires finding targets that drive these two components of the malignant phenotype. We have identified one such target—the myosin II family of molecular motors. We show that myosin II family members can be targeted with a non-toxic small molecule inhibitor that is CNS permeant, and that this drug suppresses tumor progression and significantly prolongs survival in murine models of glioblastoma. However, we also find that targeting myosin II family members leads to a compensatory upregulation of a variety of proliferation- stimulating signaling pathways, and that inhibiting these pathways is synthetically lethal when myosin II function is blocked. In this proposal, we will develop strategies to enhance the efficacy of a myosin II targeting strategy in treating glioblastoma that build on our novel findings. Results from these translational studies will be vital to our ongoing efforts to develop effective treatment approaches that block both glioblastoma invasion and proliferation.

项目描述胶质母细胞瘤以无法控制的方式增殖并广泛分散在正常大脑中的能力定义恶性表型，并使这种疾病统一致命。有效治疗胶质母细胞瘤因此，需要查找驱动恶性表型的这两个组成部分的目标。我们有确定了一个这样的靶标 - 肌球蛋白II分子电机家族。我们证明肌球蛋白II家庭成员可以用无毒的小分子抑制剂（CNS Pereant）靶向，并且该药物抑制肿瘤进展并显着延长胶质母细胞瘤鼠模型的存活。但是，我们也发现针对肌球蛋白II家族成员的那个导致各种扩散的补偿性上调刺激信号通路，抑制这些途径在肌球蛋白II功能时综合致死被阻止。在此提案中，我们将制定策略来提高肌球蛋白II靶向策略的效率在治疗基于我们的新发现的胶质母细胞瘤时。这些翻译研究的结果对于我们正在进行的努力开发有效的治疗方法，以阻止胶质母细胞瘤侵袭和增殖。