Targeting Go and Grow in Glioblastoma

项目说明 胶质母细胞瘤以无法控制的方式增殖并广泛弥散在正常脑内的能力 定义恶性表型，并使这种疾病一致致死。有效治疗胶质母细胞瘤 因此，需要找到驱动这两种恶性表型成分的靶点。我们有 发现了一个这样的靶点--肌球蛋白II分子马达家族。我们发现肌球蛋白II家族成员 可以被一种无毒的小分子抑制剂靶向，这是中枢神经系统的意思，这种药物抑制 在胶质母细胞瘤小鼠模型中，肿瘤进展并显著延长生存期。然而，我们也发现 以肌球蛋白II家族成员为靶标导致多种增殖的代偿性上调- 刺激信号通路，当肌球蛋白II发挥作用时，抑制这些通路是合成致命的 是被屏蔽的。在这项提案中，我们将制定策略来增强肌球蛋白II靶向策略的有效性。 在我们新发现的基础上治疗胶质母细胞瘤。这些翻译研究的结果将对 我们正在努力开发有效的治疗方法，以阻止胶质母细胞瘤的侵袭和 扩散。

PROJECT DESCRIPTION The ability of glioblastomas to proliferate in an uncontrollable manner and disperse widely within normal brain define the malignant phenotype and make this disease uniformly lethal. Effectively treating glioblastoma therefore requires finding targets that drive these two components of the malignant phenotype. We have identified one such target—the myosin II family of molecular motors. We show that myosin II family members can be targeted with a non-toxic small molecule inhibitor that is CNS permeant, and that this drug suppresses tumor progression and significantly prolongs survival in murine models of glioblastoma. However, we also find that targeting myosin II family members leads to a compensatory upregulation of a variety of proliferation- stimulating signaling pathways, and that inhibiting these pathways is synthetically lethal when myosin II function is blocked. In this proposal, we will develop strategies to enhance the efficacy of a myosin II targeting strategy in treating glioblastoma that build on our novel findings. Results from these translational studies will be vital to our ongoing efforts to develop effective treatment approaches that block both glioblastoma invasion and proliferation.