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Tumor-Selective Delivery Approaches for Medulloblastoma

髓母细胞瘤的肿瘤选择性递送方法

基本信息

批准号：
10543087
负责人：
Daniel Alan Heller
金额：
$ 60.3万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543087
关键词：
Address Adult Affinity Antineoplastic Agents Biochemical Biodistribution Biological Availability Blood - brain barrier anatomy Brain Brain Neoplasms Cancer Etiology Central Nervous System Cephalic Cerebellar Neoplasms Cessation of life Child Childhood Brain Neoplasm Childhood Malignant Brain Tumor Clinical Common Neoplasm Compensation Dependence Diagnosis Disease Distant Dose Drug Delivery Systems Drug Kinetics Drug Modulation Drug Targeting Drug toxicity Endothelial Cells Endothelium Excision Extravasation Genetic Genomics Goals Immunofluorescence Immunologic Inflammation Investigation Ionizing radiation Knowledge Leptomeninges Measurement Mediating Metastatic Neoplasm to the Leptomeninges Modeling Molecular Molecular Biology Morbidity - disease rate Multiple Sclerosis Mus Neoplasm Metastasis Neurocognitive Deficit Operative Surgical Procedures Outcome P-Selectin Pathway interactions Patients Pediatric Neoplasm Pharmaceutical Preparations Pharmacodynamics Physiological Pre-Clinical Model Precision therapeutics Primary Brain Neoplasms Primary Neoplasm Radiation Radiation Dose Unit Radiation therapy Research Personnel Resistance Role Route SHH gene Sonic Hedgehog Pathway Stroke Technology Therapeutic Therapeutic Agents Therapeutic Index Toxic effect Treatment Efficacy Treatment-related toxicity Tumor Tissue Vertebral column Vincristine Work aggressive therapy bone brain tissue cancer cell chemotherapy childhood cancer mortality clinical application conventional therapy effective therapy efficacy evaluation imaging modality improved improved outcome in vivo inhibitor irradiation knowledge translation medulloblastoma microCT molecular targeted therapies mouse model multiphoton microscopy nanoparticle nanoparticle delivery nanoparticle drug neoplastic cell nervous system disorder neuroinflammation novel novel strategies novel therapeutic intervention novel therapeutics precision drugs precision medicine primary endpoint side effect standard of care synergism systemic toxicity targeted treatment therapy resistant treatment strategy tumor uptake

项目摘要

The majority of primary brain tumors result in high morbidity and very poor survival. Brain tumors are now unfortunately the leading cause of cancer-related death in children. Medulloblastoma is the most common malignant pediatric brain tumor resulting in the death of nearly one-third of afflicted children despite very aggressive therapies that include surgical resection, whole brain and spine radiation therapy, and systemic chemotherapy. Furthermore, the vast majority of surviving children have poor outcomes and significant neurocognitive deficits due to the toxicity of these therapies. A major barrier to improving outcomes for primary brain tumor patients is the relative ineffective delivery of therapeutic agents across the blood-brain barrier (BBB) specifically to brain tumor cells while sparing normal surrounding brain tissue. Heretofore, researchers have found few mechanisms to target therapies specifically to primary brain tumors, to avoid systemic toxicities. We seek to address this problem to improve drug therapeutic indices by proposing a strategy to target therapies specifically to brain tumor vasculature utilizing a novel nanoparticle- based drug delivery system that has high affinity to P-selectin on endothelial cells within tumors. Our preliminary studies show selective nanoparticle extravasation and targeting to tumors across the blood-brain barrier in a novel autochthonous GEM medulloblastoma model. Our team proposes a strategy to localize both conventional and precision drugs to brain tumor tissue by targeting therapies to P-selectin on tumor vasculature. We will employ a physiologically and genetically-relevant mouse model of Sonic hedgehog-driven medulloblastoma to identify synergy with radiation therapy in enhancing tumor-selective nanoparticle drug delivery, and will pursue the following specific aims: 1) To evaluate the P-selectin-mediated targeting, role of radiation, and mechanism of extravasation across the blood-brain barrier in medulloblastoma, 2) To assess the efficacy and toxicity of P-selectin-targeted chemotherapy/SHH pathway inhibition in Sonic hedgehog-driven medulloblastoma, and 3) To assess the effects of focal radiation therapy of primary medulloblastoma tumors on P-selectin and nanoparticle drug delivery to distant leptomeningeal brain tumor metastases within the central nervous system in vivo. We will utilize biochemical and imaging methods including intravital multiphoton microscopy, confocal immunofluorescence and immuno-EM, micro-CT for bone analysis, pharmacokinetic and biodistribution measurements, and molecular biology approaches to assess nanoparticle delivery mechanisms, treatment efficacy, and toxicity. Our primary endpoint is to identify tumor-selective strategies that synergize with current standard of care therapies for medulloblastoma. Should our results prove favorable, we envision clinical applicability to patients with medulloblastoma and other primary brain tumors as well as neurological diseases that have been shown to have endothelial inflammation including multiple sclerosis and stroke.

大多数原发脑肿瘤的发病率很高，存活率很低。脑瘤是现在不幸的是，这是儿童癌症相关死亡的主要原因。髓母细胞瘤是最常见的儿童恶性脑瘤导致近三分之一的儿童死亡，尽管积极的治疗，包括手术切除，全脑和脊柱放射治疗，以及全身化疗。此外，绝大多数幸存儿童的结局很差，而且由于这些疗法的毒性而导致的神经认知障碍。改善初选结果的主要障碍脑肿瘤患者是相对无效的跨血脑屏障的治疗药物 (Bbb)特异性地作用于脑瘤细胞，同时保留正常的周围脑组织。到目前为止，研究人员几乎没有发现针对初级大脑的治疗机制。肿瘤，以避免全身毒性。我们试图通过以下方式解决这个问题，以提高药物治疗指数提出了一种策略，利用一种新的纳米颗粒，专门针对脑瘤血管系统进行治疗- 基于与肿瘤内皮细胞上的P-选择素具有高亲和力的药物输送系统。我们的初步研究显示有选择性的纳米颗粒外渗和靶向肿瘤穿过血脑一种新的自体宝石髓母细胞瘤模型中的屏障。我们的团队提出了一项将两者本地化的战略 P-选择素靶向治疗脑瘤组织的常规药物和精密药物脉管系统。我们将使用一种生理和遗传相关的Sonic Hedgehog驱动的小鼠模型髓母细胞瘤与放射治疗在增强肿瘤选择性纳米药物方面的协同作用并将追求以下具体目标：1)评估P-选择素介导的靶向，作用髓母细胞瘤的辐射和血脑屏障外渗机制，2)评估 P-选择素靶向化疗/SHH通路抑制对超音速刺猬的疗效和毒性 3)评价原发髓母细胞瘤的放射治疗效果。 P-选择素和纳米粒给药治疗远端脑转移瘤的研究体内的中枢神经系统。我们将利用生化和成像方法，包括活体内多光子显微镜，共聚焦免疫荧光和免疫-EM，骨分析的微型CT，药代动力学和生物分布测量，以及评估纳米颗粒输送机制的分子生物学方法，治疗效果好，毒性大。我们的主要目标是确定协同作用的肿瘤选择性策略目前髓母细胞瘤的护理治疗标准。如果我们的结果被证明是有利的，我们设想髓母细胞瘤和其他原发脑肿瘤以及神经科患者的临床适用性已被证明具有内皮炎症的疾病，包括多发性硬化症和中风。