Targeting Go and Grow in Glioblastoma

项目描述 胶质母细胞瘤以无法控制的方式增殖并在正常大脑内广泛扩散的能力 定义恶性表型并使这种疾病一致致命。有效治疗胶质母细胞瘤 因此需要找到驱动恶性表型的这两个组成部分的靶标。我们有 确定了一个这样的目标——分子马达的肌球蛋白 II 家族。我们证明肌球蛋白 II 家族成员 可以用一种中枢神经系统渗透性的无毒小分子抑制剂作为目标，并且该药物可以抑制 胶质母细胞瘤小鼠模型中的肿瘤进展并显着延长生存期。然而我们也发现 以肌球蛋白 II 家族成员为目标会导致多种增殖的补偿性上调 刺激信号通路，当肌球蛋白 II 发挥作用时，抑制这些通路在综合上是致命的 被阻止。在本提案中，我们将制定策略以增强肌球蛋白 II 靶向策略的功效 以我们的新发现为基础来治疗胶质母细胞瘤。这些转化研究的结果对于 我们不断努力开发有效的治疗方法，阻止胶质母细胞瘤侵袭和 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.