'Exvading' Invasive Pediatric Brain Tumors

描述(申请人提供)：髓母细胞瘤是高侵袭性的原始小脑神经外胚层肿瘤，是最常见的儿童恶性脑肿瘤，占儿童脑肿瘤的20%-40%。治疗儿童侵袭性颅内肿瘤是一个巨大的挑战，由于空间有限，而且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，这一挑战变得更加复杂。在这种情况下，手术很复杂，化疗容易产生重大副作用，因为细胞毒药物不能有区别地杀死被正常细胞包围的侵袭性肿瘤细胞。在这个Eureka应用程序中，我们为这个问题提供了一个高度创新和非正统的解决方案。我们利用儿童髓母细胞瘤的侵袭性，设计了一条阻力最小的路径，将肿瘤从小脑移动到预定的硬膜下位置，在那里它们被杀死。在这种情况下，我们引入术语外溢意味着侵袭的对立面--肿瘤细胞向远离原发肿瘤部位的方向迁移和增殖，而不是向脑内更深的部位侵袭，从而被引导到更安全的、预先确定的硬膜下区域被杀死。我们的方法利用肿瘤S的侵袭性特征，通过提供一条阻力最小的路径来将其移出原发部位，该路径专门设计成与其自然迁移路径竞争。髓母细胞瘤沿软脑膜通路的迁移和侵袭是由两个因素促成的：a)软脑膜白质束所呈现的地形线索；b)沿软脑膜通路表达的富含胶原的细胞外基质。我们设计一个挖掘肿瘤的系统的设计标准结合了这两个元素；我们建议使用定向的纳米纤维聚合物薄膜来模拟地形线索，并在这10微米的薄膜上涂上I型胶原，以模拟软脑膜通路的ECM线索。除了将肿瘤移出外，我们还建议将它们引导到一种工程化的诱导细胞凋亡的水凝胶中，该凝胶将被植入相对安全的硬膜下位置。通过将肿瘤细胞的迁移和侵袭引导到外部下沉，我们将把肿瘤细胞输送到药物，而不是目前的将药物输送到肿瘤的策略，后者由于肿瘤组织的血管不规则和扩散能力差而存在问题。我们组建了一支高素质的跨学科团队，成员包括生物工程师/肿瘤药物输送专家Bellamkonda教授(PI)、亚特兰大埃默里医学院和儿童S医疗保健儿科肿瘤项目主任(CHEA)、Macdonald教授和Emory/Choa儿科神经外科执业医生Brahma教授。我们认为，这项拟议的研究具有很高的创新性，有可能为治疗位于颅内的实体肿瘤开辟一条新的途径，并代表着来自值得尤里卡支持的高资质团队的相当高的成功机会的重大非正统研究。

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.