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;然而它们用于治疗癌症的用途是不确定的。 胶质母细胞瘤（GBM）的治疗受限于其较差的脑渗透率。我们开发了一系列新的 MTA（ST-化合物）通过一种新的作用机制破坏微管（MT）稳定并杀死GBM （MOA）。我们最近的研究结果表明，ST-化合物通过血脑屏障（BBB），并在体内表现出 在GBM的临床前小鼠模型中的治疗功效。 这一新的R 01使用互补的专业知识和方法来研究ST的新型MOA- 化合物不同于已知的MTA，并且其在几种GBM临床前小鼠模型中的治疗功效不同。 具体来说，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。 实验将在培养的患者源性GBM（PD-GBM）上进行，包括实时测量 GBM细胞迁移、细胞分裂和细胞周期命运的变化作为肿瘤发生的基本读数。在 将在GBM的遗传原位小鼠模型和原位小鼠模型上进行体内实验。 关于PD-GBM我们的目标是： 1：MTA对培养物中GBM的迁移和有丝分裂的不同影响。 2：MTA对培养物中GBM的活力和命运的不同影响。 3：ST-401在体内对GBM模型的治疗效果和机制。 我们的直接目标是增加我们对MTA调节GBM的精确MOA的理解 肿瘤发生以及它如何与标准护理治疗相互作用。这项工作将有助于奠定坚实的基础 开发一种新的MTA，用于安全治疗诊断为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.