'Exvading' Invasive Pediatric Brain Tumors

描述（申请人提供）：髓母细胞瘤是小脑高度侵袭性的原始神经外胚层肿瘤，是儿童最常见的恶性脑肿瘤，占儿童脑肿瘤的20-40%。治疗儿童侵袭性颅内脑肿瘤是一项重大挑战，由于空间有限，需要尽可能多地保留非肿瘤的正常组织，以避免长期的认知功能障碍，这一挑战进一步复杂化。在这种情况下，手术很复杂，化疗容易产生严重的副作用，因为细胞毒性药物不能区别地杀死被正常细胞包围的入侵肿瘤细胞。在这个EUREKA应用程序中，我们提出了一个高度创新和非正统的解决方案来解决这个问题。我们利用小儿髓母细胞瘤的侵袭性，设计了一条阻力最小的路径，将肿瘤从小脑转移到预先确定的硬脑膜下位置，在那里它们被杀死。在这种情况下，我们引入术语“侵袭”来表示侵袭的对立面——肿瘤细胞向远离原发肿瘤部位的方向迁移和增殖，而不是向大脑深处侵入，因此被引导迁移到更安全、预先确定的硬脑膜下区域进行杀伤。我们的方法利用肿瘤的侵袭性，通过提供一种最小阻力的途径，与肿瘤的自然迁移途径竞争，将其移出原发部位。髓母细胞瘤沿轻脑膜途径的迁移和侵袭受到两个因素的促进：a)由轻脑膜白质束提供的地形线索，b)沿轻脑膜束表达的富含胶原蛋白的细胞外基质。我们的设计标准是设计一个系统来挖掘肿瘤，包括这两个元素；我们建议使用排列整齐的纳米纤维聚合物薄膜来模拟地形线索，并在这些10微米的薄膜上涂上胶原蛋白I来模拟脑膜轻脑膜通路的ECM线索。除了将肿瘤移出外，我们建议将它们导入一种诱导细胞凋亡的工程水凝胶，将其植入相对安全的硬膜下位置。通过引导肿瘤细胞迁移和侵袭到一个外部sink，我们将把肿瘤细胞递送到药物中，而不是目前的将药物递送到肿瘤中的策略，由于肿瘤组织的血管系统不规则和扩散性差，这是有问题的。我们组建了一支高素质的跨学科团队，由生物工程师/肿瘤药物输送专家Bellamkonda教授（PI）、Emory医学院和亚特兰大儿童保健学院（CHOA）儿科肿瘤学项目主任Macdonald教授和Emory/CHOA的执业儿科神经外科医生Brahma教授组成，他在临床实践中治疗髓母细胞瘤儿童。我们认为，拟议的研究具有高度创新性，有可能为颅内实体瘤的治疗开辟一条新的途径，并且代表了一个非常非正统的研究，值得EUREKA支持的高素质团队有相当高的成功机会。

DESCRIPTION (provided by applicant): Medulloblastomas are highly invasive primitive neuroectodermal tumors of the cerebellum and the most common childhood malignant brain tumor, constituting 20-40% of pediatric brain tumors. Treating invasive intracranial brain tumors in children represents a significant challenge that is complicated further due to confined space and the need to preserve as much non-tumor, normal tissue as possible to avoid long-term cognitive dysfunction. In such cases, surgery is complicated and chemotherapy is prone to major side effects because cytotoxic drugs cannot differentially kill invading tumor cells surrounded by normal cells. In this EUREKA application, we present a highly innovative and unorthodox solution to this problem. We exploit the invasive nature of pediatric medulloblastomas by engineering a path of least resistance that moves tumors from the cerebellum to a pre-determined sub-dural location where they are killed. In this context, we introduce the term exvasion to mean the opposite of invasion - the tumor cells migrate and proliferate in a direction away from the primary tumor site, instead of invading deeper into the brain, and are thus directed to migrate to a safer , pre-determined sub-dural region to be killed. Our approach exploits the tumor s invasive character to move it away from the primary site by offering a path of least resistance specifically engineered to compete with its natural migratory pathway. Medulloblastoma migration and invasion along the leptomeningial pathway is facilitated by two elements: a) topographical cues presented by leptomeningial white matter tracts, and b) collagen rich extracellular matrix expressed along the leptomeningeal tract. Our design criteria to engineer a system to excavate tumors incorporates both of these elements; we propose to use aligned nanofiber-based polymeric thin films to mimic the topographical cues, and we coat these 10 micron-thin films with collagen I to mimic the ECM cues of the leptomeningial pathway. In addition to moving tumors out we propose to direct them to an engineered apoptosis-inducing hydrogel that will be implanted in a relatively safe sub-dural location. By directing tumor cell migration and invasion to an external sink, we will deliver tumor cells to the drug, rather than the current strategy of delivering the drug to the tumor, which is problematic due to the irregular vasculature and poor diffusivity of the tumor tissue. We have assembled a highly qualified, inter-disciplinary team consisting of a bioengineer/tumor drug delivery expert, Prof. Bellamkonda (PI), the Director of the Pediatric Oncology program at Emory School of Medicine and Children s Healthcare of Atlanta (CHOA), Prof. Macdonald, and a practicing pediatric neurosurgeon at Emory/CHOA who treats children with Medulloblastoma in his clinical practice, Prof. Brahma. We suggest that the proposed research is highly innovative, has the potential to open a new avenue for the treatment of solid tumors located intracranially, and represents significantly unorthodox research with a reasonably high chance of success from a highly qualified team worthy of EUREKA support. PUBLIC HEALTH RELEVANCE: Medulloblastomas are highly invasive primitive neuroectodermal tumors (PNETs) of the cerebellum and the most common malignant brain tumor of childhood, constituting 20-40% of all pediatric brain tumors. Currently, there exist no effective therapies to safely manage or treat invasive medulloblastomas in children. This application aims to exploit the invasive nature of tumors to exvade tumors out of the brain; and, if successful, it will dramatically enhance therapeutic options for patients diagnosed with these aggressive tumors.