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：
10829143
负责人：
Rachael W Sirianni
金额：
$ 48.59万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10829143
关键词：
Address Affect Angiopoietin-2 Antibiotics Attention Bar Codes Blood Brain Brain Neoplasms Cell Culture Techniques Cells Central Nervous System Neoplasms 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 Metastatic Neoplasm to the Spine Methods Modeling Modification Molecular Movement Mus Neoplasm Metastasis Nervous System Operative Surgical Procedures Outcome Study Patients Pediatric Neoplasm Peptides Pharmaceutical Preparations 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 intravenous administration medulloblastoma nanoparticle nanoparticle delivery nanopolymer 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

PROJECT SUMMARY / ABSTRACT 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.

项目摘要 /摘要髓母细胞瘤（MB）是最常见的恶性儿童脑肿瘤。即使进行了积极的治疗，许多患者仍然死于疾病。此外，幸存者由于治疗，认为这很大程度导致辐射引起的对发育神经的损害系统。与其他脑肿瘤通过脑实质浸润的其他脑肿瘤通常会传播通过围绕大脑和脊髓的脑膜，这种现象称为瘦脑转移（LM）。我们最近进行了高通量药物筛查以识别多肽抗生素放线霉素作为治疗MB的兴趣化合物。我们开发了封装的方法放线霉素在可生物降解和生物相容性聚合物纳米颗粒中。我们还确定了肽配体能够靶向脊髓脉管系统和患者上调的受体派生的MB。我们的初步数据表明，从纳米颗粒传递的放线菌素显着静脉内给药时，在治疗颅内MB方面更有效。此外，我们证明直接施用到脑脊液（CSF）的纳米颗粒与恶性定位细胞减慢LM的生长。在这项工作中，我们将评估交付策略（靶向配体的存在，管理途径）以优化MB中的这些新方法。纳米颗粒将被“条形码”到荧光在不同的波长中，使对照和靶向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MB的患者衍生和基因工程模型中测试这些系统展示LM。我们假设改进的，有针对性的纳米颗粒输送将增强转移到药物的转移性细胞，以提高治疗功效并减少实现所需的辐射剂量完整的肿瘤疗法。为了检验这一假设，我们将（1）跟踪目标纳米颗粒到大脑和脊髓中的恶性细胞；（2）评估放线霉素的分娩，活性和毒性；（3）靶向疗法与辐射结合的测试功效。我们的实验方法已设计依次完善载有药物的纳米颗粒的设计，以直接通过将LM作为一种独特的疾病负担。我们期望这些研究的结果也将产生新的脊髓靶向药物输送的策略，该策略将与其他散布的癌症或影响脊髓的神经疾病。