Molecular Motors and Glioma Dispersion

描述（由申请人提供）：恶性胶质瘤在正常脑内分散的能力最终使我们目前对这种肿瘤的所有治疗无效。这种侵袭性倾向进一步受到抗血管生成药物的刺激，抗血管生成药物已进入胶质瘤治疗的主流。不幸的是，旨在阻断这种侵袭性表型的治疗方法不会产生普遍或持久的反应，这强调了需要找到新的方法来靶向这种肿瘤的脑分散。在我们之前的工作中，我们确定了分子马达非肌肉肌球蛋白II（NMMII）是胶质瘤侵袭装置的重要组成部分。在本申请中，我们将研究NMMII在驱动胶质瘤侵袭中的作用，以及靶向NMMII在一组现实和稳健的胶质母细胞瘤临床前模型中阻断恶性胶质瘤侵袭表型的功效。这些转化研究的结果将与我们的临床前模型中的联合治疗研究相结合，以确定NMMII抑制剂与抗血管生成和放射治疗之间的潜在协同作用。 公共卫生相关性：神经胶质瘤侵袭大脑的能力限制了目前对这种疾病的所有治疗，这突出了开发新方法来阻断脑肿瘤侵袭的必要性。在本申请中，我们提出，分子马达NMMII代表这样的目标。在这项研究中，我们将严格检查NMMII如何驱动胶质瘤分散，以及如何特异性和有效地靶向它。

DESCRIPTION (provided by applicant): The ability of malignant gliomas to disperse within normal brain ultimately renders ineffective all of our current therapies for this tumor. This invasive propensity is further stimulated by antiangiogenics, which have entered the mainstream of glioma therapeutics. Unfortunately, treatments designed to block this invasive phenotype do not produce universal or durable response, which underscores the need to find new ways of targeting brain dispersion by this tumor. In our prior work, we established that the molecular motor non-muscle myosin II (NMMII) is an essential component of the glioma invasion apparatus. In this application, we will examine the roles of NMMII in driving glioma invasion and the efficacy of targeting NMMII in blocking the invasive phenotype of malignant gliomas in a set of realistic and robust preclinical models of glioblastoma. Results from these translational studies will be combined with combination therapy studies in our pre-clinical models in order to identify potential synergy between NMMII inhibitors and anti-angiogenic and radiation therapy. PUBLIC HEALTH RELEVANCE: The ability of gliomas to invade brain limits all the current therapies for this disease, and this highlights the need to develop new methods to block brain tumor invasion. In this application, we propose that the molecular motor NMMII represents such a target. In this study, we will critically examine how NMMII drives glioma dispersion and how it can be specifically and effectively targeted.