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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不可控制的方式增殖并在正常脑内广泛分散的能力定义恶性表型并使这种疾病一致致命。有效治疗胶质母细胞瘤因此，需要找到驱动恶性表型的这两种组分的靶点。我们有确定了一个这样的目标-肌球蛋白II家族的分子马达。我们发现肌球蛋白II家族成员可以用一种无毒的小分子抑制剂靶向，这种抑制剂是CNS渗透性的，在胶质母细胞瘤小鼠模型中的肿瘤进展和显著延长的存活率。然而，我们也发现，靶向肌球蛋白II家族成员导致多种增殖的补偿性上调，刺激信号通路，当肌球蛋白II发挥作用时，抑制这些通路是合成致死的被挡.在本提案中，我们将制定策略，以提高肌球蛋白II靶向策略的有效性在治疗胶质母细胞瘤方面的新发现。这些转化研究的结果将是至关重要的，我们正在努力开发有效的治疗方法，阻止胶质母细胞瘤的侵袭，增殖