'Exvading' Invasive Pediatric Brain Tumors

“外溢”侵袭性小儿脑肿瘤

• 批准号: 8120914
• 负责人: Ravi V. Bellamkonda
• 金额: $ 24.57万
• 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/8120914
• 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）：髓母细胞瘤是小脑的高度侵入性原始神经皮质肿瘤和最常见的儿童恶性脑肿瘤，占小儿脑肿瘤的20-40％。治疗儿童中侵袭性颅内脑肿瘤是一个重大挑战，由于限制空间，并且需要保持尽可能多的非肿瘤，正常组织以避免长期认知功能障碍。在这种情况下，手术是复杂的，化学疗法容易受到重大副作用，因为细胞毒性药物不能差异地杀死被正常细胞包围的入侵肿瘤细胞。 在此Eureka应用程序中，我们为此问题提供了高度创新且非正统的解决方案。我们通过工程性的耐药性来利用小儿髓母细胞瘤的侵入性性质，该路径将肿瘤从小脑移动到被杀死的预定的亚皮拉植物位置。在这种情况下，我们将术语引入术语是指侵袭的相反 - 肿瘤细胞朝着远离原发性肿瘤部位的方向迁移和增殖，而不是侵入更深的大脑，因此被指示迁移到一个更安全的，预先确定的亚折叠区域。 我们的方法利用了肿瘤的侵入性特征将其从主要部位移开，该路径具有特异性设计的路径，以与其自然迁移途径竞争。两个元素促进了髓鞘细胞瘤迁移和侵入沿瘦脑途径的迁移和侵袭：a）沿着卵巢脑脑脑部表达的瘦脑脑化白质图提出的地形提示和b）富含胶原蛋白的细胞外基质。我们为挖掘肿瘤设计的系统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仿地形线索，并用胶原蛋白I涂上这10个薄膜，以模仿瘦脑途径的ECM提示。除了将肿瘤移出外，我们还建议将其引导到诱导的凋亡水凝胶上，该水凝胶将植入相对安全的下部地点。通过将肿瘤细胞迁移和侵袭到外侧水槽中，我们将向药物输送肿瘤细胞，而不是将药物输送到肿瘤的当前策略，这是由于不规则的血管系统和肿瘤组织的扩散性不良而有问题的。 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临床实践，梵天教授。我们建议拟议的研究具有很高的创新性，有可能为颅内的实体瘤处理新的途径，并代表了非常非正统的研究，而从一支值得尤里卡支持的高素质团队中获得了相当高的成功机会。 公共卫生相关性：髓母细胞瘤是小脑的高度侵入性原始神经皮质肿瘤（PNET）和最常见的儿童脑肿瘤，占所有儿科脑肿瘤的20-40％。目前，尚无有效的疗法可以安全地管理或治疗儿童中侵入性的髓母细胞瘤。该应用旨在利用肿瘤的侵入性，以将肿瘤从大脑中驱逐出境。而且，如果成功的话，它将为诊断出患有这些侵袭性肿瘤的患者大大增强治疗选择。