'Exvading' Invasive Pediatric Brain Tumors

“外溢”侵袭性小儿脑肿瘤

• 批准号: 8267563
• 负责人: Ravi V. Bellamkonda
• 金额: $ 24.58万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-04 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267563
• 关键词: Accounting; Adverse effects; Apoptosis; Area; Biomedical Engineering; Brain; Brain Neoplasms; Cerebellar Neoplasms; Cerebellum; Child; Childhood; Childhood Brain Neoplasm; Childhood Medulloblastomas; Collagen; Confined Spaces; Cues; Cytotoxic agent; Diagnosis; Diffuse; Drug Delivery Systems; Elements; Engineering; Extracellular Matrix; Extracellular Matrix Proteins; Film; Healthcare; Hydrogels; Impaired cognition; Implant; Invaded; Location; Malignant neoplasm of brain; Nature; Neoplasm Metastasis; Neurosurgeon; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pediatric Oncology; Pharmaceutical Preparations; Primary Neoplasm; Primitive Neuroectodermal Tumor; Proliferating; Qualifying; Refractory; Research; Resistance; Site; Solid Neoplasm; Solutions; System; Therapeutic; Tissues; Tumor Cell Invasion; Tumor Tissue; base; brahma; chemotherapy; clinical practice; cognitive function; design; effective therapy; innovation; killings; medical schools; medulloblastoma; migration; nanofiber; neoplastic cell; oncology program; public health relevance; success; tumor; white matter

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.

描述（由申请人提供）：髓母细胞瘤是一种高度侵袭性的小脑原始神经外胚肿瘤，也是最常见的儿童恶性脑肿瘤，占儿科脑肿瘤的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正常组织，以避免长期认知功能障碍，因此进一步复杂化。在这种情况下，手术是复杂的，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。 在尤里卡的应用中，我们提出了一个高度创新和非正统的解决方案。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，将肿瘤从小脑移动到预先确定的硬膜下位置，在那里它们被杀死。在这种情况下，我们引入术语“侵袭”来表示与“侵袭”相反的意思-肿瘤细胞在远离原发肿瘤部位的方向上迁移和增殖，而不是侵入大脑更深处，因此被引导迁移到更安全的预定硬膜下区域以被杀死。 我们的方法利用了肿瘤的侵袭性，通过提供一条阻力最小的路径，将其从原发部位移开，该路径专门设计用于与其自然迁移途径竞争。成神经管细胞瘤沿着软脑膜途径的迁移和侵袭由两个因素促进：a）由软脑膜白色束呈现的地形线索，和B）沿着软脑膜束表达的富含胶原的细胞外基质。我们设计肿瘤挖掘系统的设计标准包含了这两个元素;我们建议使用对齐的基于纳米纤维的聚合物薄膜来模拟地形线索，并在这10微米薄膜上涂上胶原蛋白I来模拟软脑膜的细胞外基质线索。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骨质疏松的水凝胶中，该水凝胶将被植入相对安全的硬膜下位置。通过将肿瘤细胞迁移和侵袭引导至外部汇，我们将肿瘤细胞递送至药物，而不是目前的将药物递送至肿瘤的策略，由于肿瘤组织的不规则脉管系统和差的扩散性，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/肿瘤药物递送专家Bellamkonda教授（PI），埃默里医学院儿科肿瘤学项目主任和亚特兰大儿童保健（CHOA），Macdonald教授和埃默里/CHOA的执业儿科神经外科医生组成，他在临床实践中治疗髓母细胞瘤儿童，Brahma教授。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，并代表了显著的非正统研究，值得尤里卡支持的高素质团队的成功机会相当高。 公共卫生相关性：髓母细胞瘤是小脑的高度侵袭性原始神经外胚层肿瘤（PNIPs），也是儿童最常见的恶性脑肿瘤，占所有儿童脑肿瘤的20-40%。目前，还没有有效的治疗方法来安全地管理或治疗儿童侵袭性髓母细胞瘤。该应用旨在利用肿瘤的侵袭性将肿瘤从大脑中排出;如果成功的话，它将大大增加诊断患有这些侵袭性肿瘤的患者的治疗选择。