Tumor 'tractor beam' for diffuse cancers

项目摘要 目前，治疗弥漫性癌症的选择很少。这是一个特殊的挑战 对于在敏感组织中出现的扩散性癌症（即，不适合切除）， 药物扩散有限的患者，或典型干预措施不可接受的患者 后遗症（例如，儿科患者）。 在这里，我们研究了一种新的方法：用电场（趋电性）引导细胞， 将扩散的癌细胞合并到一个或几个位置（使其扩散性降低），或 或者将这些细胞移到不太重要的位置。作为我们方法的基础，我们将使用 弥漫性内在脑桥胶质瘤是小儿脑肿瘤中最具侵袭性的一种 （DIPG），其象征治疗弥漫性癌症中固有的挑战。需要 DIPG的新治疗方法尤其重要，因为它出现在pons-一个关键的宿主部位 呼吸、咀嚼、心跳和吞咽的中枢， 9个月，超过99%的患者死亡。 我们建议使用转录组学和药理学抑制来量化， 趋电肿瘤细胞反应的机制。这将揭示趋电药物靶点， 提供控制以操纵/增强进一步的趋电性。我们将在体内进行研究， 各种电极蒙太奇的影响，以形成和引导浸润性DIPG细胞在这两个 皮质和脑桥。为了支持我们的方法，我们将应用计算方法迭代地 模拟和设计刺激蒙太奇，以响应野外后观察到的生长模式 应用程序.这些研究将提供一种新的方法来解决一个普遍的问题， 扩散性癌症，使他们可以变得更适合标准的护理疗法。

PROJECT SUMMARY Currently, there are few options for treating diffuse cancers. This is a particular challenge for diffuse cancers that arise in sensitive tissues (i.e., not amenable to resection), in tissues in which drug diffusion is limited, or in patients for whom typical interventions incur unacceptable sequelae (e.g., pediatric patients). Here, we investigate a novel approach: guiding cells with electrical fields (electrotaxis) to consolidate the diffuse cancer cells to one or few locations (making them less diffuse), or alternately, move these cells to a less critical location. As a basis for our approach, we will use one of the most aggressive forms of pediatric brain tumor, Diffuse Intrinsic Pontine Glioma (DIPG), which is emblematic of the challenges inherent in treating diffuse cancers. The need for new treatments for DIPG is particularly critical, as it arises in the pons–a site that hosts critical centers for breathing, chewing, heartbeat and swallowing–and incurs a dismal median survival time of 9 months and is fatal in more than 99% of patients. We propose to quantify, using transcriptomics and pharmacological inhibition, underlying mechanisms of electrotactic tumor cell response. This will reveal electrotactic drug targets and provide controls to manipulate/enhance further electrotaxis. We will investigate in vivo, the effects of various electrode montages to shape and steer infiltrative DIPG cells in both the cortex and pons. To support our approach, we will apply computational methods to iteratively model and design stimulation montages in response to observed patterns of growth after field application. These studies will provide a novel approach to addressing the general problem of a diffuse cancer so that they can become more amenable to standard-of-care therapies.