Differential response of glioblastomas to microtubule targeting agents

微管靶向剂(MTA)通常用于治疗许多类型的癌症；然而，它们的用途 胶质母细胞瘤(GBM)的治疗因其较差的脑穿透性而受到限制。我们开发了一系列新的 通过一种新的作用机制破坏微管(MT)和杀死GBM的MTA(ST-化合物) (MOA)。我们最近的结果表明，ST-化合物可以通过血脑屏障(BBB)，并在体内表现出来 临床前脑脊髓炎小鼠模型的治疗效果。 新的R01使用互补的专业知识和方法来研究ST-MOA的新MOA- 化合物与已知的MTA不同，在几种临床前小鼠GBM模型上的治疗效果不同。 具体地说，它利用了几项创新技术，包括活细胞成像和人工学习 算法，以更好地理解为什么GBM对ST-化合物的抗肿瘤活性特别敏感。 实验将在患者来源的GBM(PD-GBM)的培养中进行，并包括实时测量 基底膜细胞迁移、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……里面 体内实验将在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对培养的GBM迁移和有丝分裂的不同影响。 2：MTA对培养的GBM的活性和命运的不同影响。 3、ST-401对大鼠GBM模型的治疗作用及其机制。 我们的直接目标是增加我们对MTA监管GBM的确切MOA的理解 肿瘤的发生及其与标准护理治疗的相互作用。这项工作将有助于奠定坚实的基础 用于开发一类新的MTA，用于安全治疗被诊断为GBM的患者。

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.