Novel microtubule-targeting agents for the treatment of glioblastoma multiform

微管靶向剂（MTA）通常用于成功治疗许多类型的癌症;然而， 它们用于治疗脑癌如GBM的用途受到了阻碍，因为它们不能穿透肿瘤细胞。 治疗相关剂量的大脑。最近的证据表明，GBM对 微管（MT）功能的破坏并通过凋亡而死亡，为开发脑渗透剂提供了理论依据。 MTA。 华盛顿大学的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使MT不稳定 MTA。这些MTA通过在体外和体内触发细胞凋亡来杀死GBM细胞。本R21中的工作大纲 赠款提案将提供ST化合物的新型MOA的基础性结果，以及 概念体内功效导致PD-PGM的临床前模型系统，这两者都将有助于开发这一 治疗GBM的方法。我们的目标是 目的1：确定ST化合物对微管蛋白和MT动力学的MOA，以及它们对微管蛋白和MT动力学的影响的能力。 穿过细胞膜 目的2：确定ST化合物在PD-GBM异种移植物中的治疗效果和机制 模型 我们的长期目标是帮助更好地理解和开发新的疗法来治疗毁灭性的癌症 例如GBM。

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.