Targeting leptomeningeal metastasis in medulloblastoma

靶向髓母细胞瘤的软脑膜转移

基本信息

批准号：
10595323
负责人：
Rachael W Sirianni
金额：
$ 5.77万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10595323
关键词：
Address Affect Angiopoietin-2 Antibiotics Attention Bar Codes Blood Brain Brain Neoplasms Cell Culture Techniques Cells Cerebellum Cerebrospinal Fluid Childhood Malignant Brain Tumor Clinical Data Diagnosis Disease Drug Delivery Systems Drug Design Drug Targeting Encapsulated Ensure Excision Exhibits Formulation Genetic Engineering Growth Human Characteristics In Vitro Individual Infiltration Injections Intravenous Ligands Low Dose Radiation Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Meninges Metastatic Neoplasm to the Leptomeninges Methods Modeling Modification Molecular Movement Mus Neoplasm Metastasis Nervous system structure Neuraxis Operative Surgical Procedures Outcome Study Patients Pediatric Neoplasm Peptides Pharmaceutical Preparations Polymers Primary Neoplasm Prognosis Radiation Radiation Dose Unit Radiation induced damage Resolution Route Site Spinal Cord Subarachnoid Space Surface Survivors System Testing Therapeutic Time Tissues Toxic effect Treatment Efficacy Treatment Side Effects Work actinomycin aggressive therapy biocompatible polymer biodegradable polymer brain parenchyma burden of illness cancer cell chemotherapy cisterna magna clinical translation design drug action drug discovery drug efficacy effective therapy efficacy testing ethylene glycol expectation high throughput screening high-throughput drug screening human disease improved in vivo innovation interest medulloblastoma nanoparticle nanoparticle delivery nanoparticle drug nervous system disorder novel strategies poly(lactic acid)polypeptide receptor side effect small molecule targeted delivery targeted treatment therapeutic candidate therapy outcome tool treatment response tumor tumor growth

项目摘要

Medulloblastoma (MB) is the most common malignant childhood brain tumor. Even with aggressive therapy, many patients still die of their disease. Moreover, survivors suffer severe long-term side effects as a result of treatment, which are thought to result in large part from radiation-induced damage to the developing nervous system. Unlike other brain tumors, which infiltrate through the brain parenchyma, MB commonly spreads through the meninges that surround the brain and spinal cord, a phenomenon termed leptomeningeal metastasis (LM). We recently performed a high throughput drug screen to identify the polypeptide antibiotic actinomycin as a compound of interest for the treatment of MB. We developed methods to encapsulate actinomycin within biodegradable and biocompatible polymeric nanoparticles. We have also identified a peptide ligand capable of targeting receptors that are upregulated on both spinal cord vasculature and patient derived MB. Our preliminary data demonstrate that actinomycin delivered from nanoparticles is significantly more effective at treating intracranial MB than free drug when administered intravenously. Further, we demonstrate that nanoparticles administered directly to the cerebrospinal fluid (CSF) localize with malignant cells to slow the growth of LM. In this work, we will evaluate delivery strategies (presence of targeting ligand, route of administration) to optimize these new approaches in MB. Nanoparticles will be "barcoded" to fluoresce in distinct wavelengths, such that the cellular level distribution of both control and targeted nanoparticle formulations can be evaluated within a single subject to directly assess nanoparticle fate and drug action at the cellular level. We will test test these systems in patient derived and genetically engineered models of MB exhibiting LM. We hypothesize that improved, targeted nanoparticle delivery will enhance exposure of metastatic cells to drug, to improve therapeutic efficacy and reduce the radiation dose needed to achieve complete tumor therapy. To test this hypothesis, we will (1) track delivery of targeted nanoparticles to malignant cells in the brain and spinal cord; (2) evaluate delivery, activity, and toxicity of actinomycin; and (3) test efficacy of targeted therapies in combination with radiation. Our experimental approach has been designed to sequentially refine the design of drug-loaded nanoparticles to yield a better treatment for MB by directly addressing LM as a unique disease burden. We expect that the outcome of these studies will also yield new strategies for spinal cord targeted drug delivery that will be relevant to other disseminated cancers or neurological diseases affecting the spinal cord.

髓母细胞瘤（MB）是最常见的恶性儿童脑肿瘤。即使采用积极的治疗，许多患者仍然死于疾病。此外，幸存者还因以下原因遭受严重的长期副作用：治疗，据认为这在很大程度上是由于辐射对发育中的神经造成的损伤造成的系统。与其他浸润脑实质的脑肿瘤不同，MB 通常会扩散通过围绕大脑和脊髓的脑膜，这种现象称为软脑膜转移（LM）。我们最近进行了高通量药物筛选来鉴定多肽抗生素放线菌素作为治疗 MB 的感兴趣的化合物。我们开发了封装方法可生物降解和生物相容性聚合物纳米粒子中的放线菌素。我们还确定了一个能够靶向脊髓血管系统和患者上调的受体的肽配体衍生MB。我们的初步数据表明，纳米粒子释放的放线菌素显着静脉内给药时，治疗颅内 MB 比游离药物更有效。此外，我们证明直接给予脑脊液（CSF）的纳米颗粒可定位恶性细胞细胞以减缓 LM 的生长。在这项工作中，我们将评估递送策略（靶向配体的存在，给药途径）来优化 MB 中的这些新方法。纳米粒子将被“条形码”以发出荧光在不同的波长下，使得对照和目标纳米颗粒的细胞水平分布可以在单个受试者中评估制剂，以直接评估纳米颗粒的命运和药物作用细胞水平。我们将在患者衍生的 MB 基因工程模型中测试这些系统展出LM。我们假设改进的、有针对性的纳米颗粒递送将增强转移细胞转向药物，以提高治疗效果并减少实现所需的放射剂量完整的肿瘤治疗。为了检验这一假设，我们将 (1) 跟踪靶向纳米颗粒的递送脑和脊髓中的恶性细胞； (2)评价放线菌素的递送、活性和毒性；和（3）测试靶向治疗与放射治疗相结合的疗效。我们的实验方法已经设计好依次改进载药纳米粒子的设计，通过直接直接产生更好的 MB 治疗将LM视为一种独特的疾病负担。我们预计这些研究的结果也将产生新的成果与其他播散性癌症相关的脊髓靶向药物输送策略或影响脊髓的神经系统疾病。