Differential response of glioblastomas to microtubule targeting agents

胶质母细胞瘤对微管靶向剂的差异反应

• 批准号: 10650168
• 负责人: Nephi Stella
• 金额: $ 34.86万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-02 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650168
• 关键词: Address; Apoptosis; Behavior; Binding; Biological Assay; Biological Models; Blood - brain barrier anatomy; Brain; Cancer cell line; Carbazoles; Cell Culture Techniques; Cell Cycle; Cell Survival; Cell division; Cells; Chromosomal Instability; Colchicine; Collaborations; Coupled; DNA Damage; Data; Development; Diagnosis; Exhibits; Faith; Foundations; Genetic; Glioblastoma; Goals; Grant; Growth; Hematologic Neoplasms; Image; Laboratories; Link; Malignant - descriptor; Measures; Microscopy; Microtubules; Mitosis; Modeling; Molecular; Mus; Non-Malignant; Oncogenic; Patients; Penetrance; Platelet-Derived Growth Factor; Property; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Reporting; Research Project Grants; Series; Site; Solid; TP53 gene; Testing; Therapeutic; Time; Treatment Efficacy; Tubulin; Work; Xenograft procedure; blood-brain barrier crossing; cancer cell; cancer type; cell motility; experimental study; genetic approach; in vivo; in vivo Model; innovative technologies; insight; learning algorithm; live cell imaging; live cell microscopy; migration; mouse model; novel; novel therapeutics; pharmacologic; pre-clinical; response; side effect; standard care; standard of care; synergism; targeted agent; temozolomide; treatment response; tumor; tumorigenesis

Microtubule targeting agents (MTAs) are commonly prescribed to treat many types of cancers; yet their use for the treatment of glioblastomas (GBM) is limited by their poor brain penetrance. We developed a new series of MTAs (ST-compounds) that destabilize microtubules (MT) and kill GBM through a novel mechanism of action (MOA). Our recent results show that ST-compounds pass the blood brain barrier (BBB) and exhibits in vivo therapeutic efficacy in a preclinical mouse model of GBM. This new R01 uses complementary expertise and approaches to study how the novel MOA of ST- compounds differs from known MTAs and its therapeutic efficacy in several preclinical mouse model of GBM. Specifically, it leverages several innovative technologies, including live-cell imaging and artificial learning algorithms, to better understand why GBM are particularly sensitive to the antitumor activity of ST-compounds. Experiments will be performed on patient-derived GBM (PD-GBM) in culture and include measure of real-time changes in GBM cell migration, cell division and cell cycle fate as fundamental readouts of tumorigenesis. In vivo experiments will be done on both genetic orthotopic mouse models of GBM and orthotopic mouse model of PD-GBM. Our aims are: 1: Differential impact of MTAs on the migration and mitosis of GBM in culture. 2: Differential impact of MTAs on the viability and fate of GBM in culture. 3: Therapeutic efficacy and mechanism of ST-401 in GBM models in vivo. Our immediate goal is to increase our understanding of the precise MOA by which MTAs regulate GBM tumorigenesis and how this interacts with standard care treatments. This work will help set a solid foundation for the development of a new class of MTAs for the safe treatment of patients diagnosed with GBM.

通常规定了微管靶向剂（MTA）以治疗多种类型的癌症。然而他们的用途 胶质母细胞瘤（GBM）的治疗受到其脑部渗透不良的限制。我们开发了一系列新的 MTA（ST-COMPOUNDS）通过新颖的作用机理杀死微管（MT）并杀死GBM （MOA）。我们最近的结果表明，St-Compound通过血液脑屏障（BBB）并在体内展示 GBM的临床前小鼠模型中的治疗功效。 这种新的R01使用补充专业知识和方法来研究ST-的新型MOA如何 化合物与已知的MTA及其治疗功效有所不同。 具体而言，它利用了几种创新技术，包括实时成像和人工学习 算法，以更好地理解为什么GBM对St-Compounds的抗肿瘤活性特别敏感。 实验将在培养物中对患者来源的GBM（PD-GBM）进行，并包括实时的测量 GBM细胞迁移，细胞分裂和细胞周期命运的变化是肿瘤发生的基本读数。在 体内实验将在GBM的遗传原位小鼠模型和原位小鼠模型上进行 PD-GBM。我们的目标是： 1：MTA对GBM培养中GBM迁移和有丝分裂的差异影响。 2：MTA对GBM培养中的生存能力和命运的差异影响。 3：在体内GBM模型中ST-401的治疗功效和机制。 我们的直接目标是增加我们对MTA调节GBM的确切MOA的理解 肿瘤发生及其如何与标准护理治疗相互作用。这项工作将有助于为坚实的基础树立稳固的基础 为了开发新的MTA类，用于安全治疗被诊断为GBM的患者。

项目成果

Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells.

• DOI: 10.1016/j.ejmech.2018.09.026
• 发表时间: 2018-11-05
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Diaz P;Horne E;Xu C;Hamel E;Wagenbach M;Petrov RR;Uhlenbruck B;Haas B;Hothi P;Wordeman L;Gussio R;Stella N
• 通讯作者: Stella N

A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis.

• DOI: 10.1093/noajnl/vdaa165
• 发表时间: 2021-01
• 期刊: Neuro-oncology advances
• 作者: Horne EA;Diaz P;Cimino PJ;Jung E;Xu C;Hamel E;Wagenbach M;Kumasaka D;Wageling NB;Azorín DD;Winkler F;Wordeman LG;Holland EC;Stella N
• 通讯作者: Stella N