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Novel microtubule-targeting agents for the treatment of glioblastoma multiform

用于治疗多形性胶质母细胞瘤的新型微管靶向药物

基本信息

批准号：
9755531
负责人：
Nephi Stella
金额：
$ 22.46万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2018-08-15 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9755531
关键词：
Apoptosis Applications Grants Binding Biological Models Blood - brain barrier anatomy Brain Cell membrane Cells Chromosomal Instability Colchicine Data Development Diagnosis Dose Drug Kinetics Exhibits Foundations Glioblastoma Goals Grant In Vitro Laboratories Malignant Neoplasms Malignant neoplasm of brain Measures Microtubules Molecular Mechanisms of Action Mus Patients Penetration Peripheral Pharmaceutical Chemistry Pharmacodynamics Pre-Clinical Model Property Regimen Research Safety Series Site Solid Survival Rate Testing Therapeutic Therapeutic Studies Time Treatment Efficacy Tubulin Universities Washington Work Xenograft Model brain endothelial cell cancer type design experimental study fluorescence imaging imaging approach in vivo mouse model nanomolar novel novel therapeutics outcome forecast pre-clinical standard of care targeted agent tumor uptake

项目摘要

Microtubule targeting agents (MTAs) are commonly prescribed to successfully treat many types of cancers; yet their use for the treatment of brain cancers, such as GBM, has been hindered by their inability to penetrate the brain in therapeutically-relevant doses. Recent evidence shows that GBMs are particularly sensitive to disruptions of microtubule (MT) functions and die by apoptosis, providing a rational to develop brain-penetrant MTAs. The laboratory of Dr. Nephi Stella at the University of Washington developed a new series of MTAs (ST compounds) and showed that these compounds destabilize MT through a different MOA from currently known MTAs. These MTAs kill GBM cells by triggering apoptosis both in vitro and in vivo. The work outline in this R21 grant proposal will provide foundational results on the novel MOA of ST compounds, as well as proof-of- concept in vivo efficacy results in preclinical model systems of PD-PGM, both of which will help develop this therapeutic approach for the treatment of GBM. Our aims are Aim 1: Determine the MOA of ST compounds on tubulin and MT dynamics, as well as their ability to cross cell membranes Aim 2: Determine the therapeutic efficacy and mechanism of ST compounds in PD-GBM xenograft model Our long-term goal is to help better understand and develop novel therapeutics to treat devastating cancers such as GBM.

微管靶向剂 (MTA) 通常用于成功治疗多种类型的癌症；然而它们用于治疗脑癌（例如 GBM）的用途因无法渗透到脑组织而受到阻碍。治疗相关剂量的大脑。最近的证据表明 GBM 对微管（MT）功能的破坏并因细胞凋亡而死亡，为开发脑渗透剂提供了合理的理由 MTA。华盛顿大学 Nephi Stella 博士的实验室开发了一系列新的 MTA（ST 化合物），并表明这些化合物通过与目前已知的不同的 MOA 来破坏 MT 的稳定性 MTA。这些 MTA 通过在体外和体内触发细胞凋亡来杀死 GBM 细胞。 R21中的工作大纲拨款提案将提供 ST 化合物的新型 MOA 的基础结果，以及证明- PD-PGM 的临床前模型系统产生了体内功效概念，这两者都将有助于开发这一技术 GBM 的治疗方法。我们的目标是目标 1：确定 ST 化合物对微管蛋白和 MT 动力学的 MOA，以及它们的能力跨细胞膜目标2：确定ST化合物在PD-GBM异种移植物中的治疗功效和机制模型我们的长期目标是帮助更好地理解和开发治疗毁灭性癌症的新疗法例如GBM。