Tumor 'tractor beam' for diffuse cancers

项目总结 目前，治疗弥漫性癌症的选择很少。这是一个特别的挑战 对于发生在敏感组织(即不能切除)的弥漫性癌症，在 哪些药物扩散是有限的，或者是在典型干预措施导致无法接受的患者中 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(使它们不那么扩散)，或 或者，将这些单元格移动到不太重要的位置。作为我们方法的基础，我们将使用 弥漫性桥脑胶质瘤是儿童脑肿瘤中最具侵袭性的形式之一 (DIPG)，这是治疗弥漫性癌症固有挑战的象征。需要 治疗DIPG的新方法尤其关键，因为它发生在脑桥--一个拥有关键 呼吸、咀嚼、心跳和吞咽的中心-并导致令人沮丧的中位存活率 时间为9个月，99%以上的患者是致命的。 我们建议利用转录和药物抑制技术来量化潜在的 趋电肿瘤细胞反应的机制。这将揭示电致药物靶点和 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， 不同电极蒙太奇对DIPG细胞形态和方向的影响 大脑皮质和脑桥。为了支持我们的方法，我们将计算方法应用于迭代 模拟和设计模拟蒙太奇以响应田后观察到的生长模式 申请。这些研究将提供一种新的方法来解决普遍存在的 扩散癌症，以便他们可以变得更容易接受标准护理治疗。

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.