Targeting Leptomeningeal Metastasis in Medulloblastoma

靶向髓母细胞瘤的软脑膜转移

• 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
• 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

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)是儿童最常见的恶性脑肿瘤。即使进行了积极的治疗， 许多病人仍然死于他们的疾病。此外，幸存者由于以下原因遭受严重的长期副作用 治疗，被认为在很大程度上是由于辐射对发育中的神经造成的损害 系统。与其他通过脑实质渗透的脑瘤不同，MB通常会扩散 通过环绕大脑和脊髓的脑膜，一种称为软脑膜的现象 转移(LM)。我们最近进行了一次高通量药物筛选以鉴定多肽抗生素。 放线菌素作为一种治疗MB感兴趣的化合物。我们开发了方法来封装 放线菌素在可生物降解和生物相容的聚合物纳米粒中。我们还确定了一个 能够靶向脊髓血管和患者上调的受体的多肽配体 派生的MB。我们的初步数据表明，由纳米粒输送的放线菌素显著 在治疗颅内MB时，静脉给药比免费药物更有效。此外，我们 证明直接将纳米颗粒注射到脑脊液(CSF)可定位于恶性肿瘤 细胞，以减缓LM的生长。在这项工作中，我们将评估传递策略(靶向配体的存在， 管理途径)，以优化这些甲基溴的新方法。纳米粒子将被“条形码”标记为荧光 在不同的波长中，使得对照和靶向纳米颗粒的细胞水平分布 可以在单个受试者内对配方进行评估，以直接评估纳米颗粒的命运和药物作用 细胞水平。我们将在患者衍生和基因工程的MB模型中测试这些系统 展示了光镜。我们假设，改进的、有针对性的纳米颗粒传递将增加对 将转移细胞转化为药物，以提高治疗效果和降低辐射剂量所需的实现 彻底的肿瘤治疗。为了验证这一假设，我们将(1)跟踪靶向纳米颗粒的传递 (2)评估放线菌素的释放、活性和毒性；以及(3) 靶向治疗联合放射治疗的疗效测试。我们的实验方法已经设计好 循序渐进地改进载药纳米粒的设计，通过直接 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 脊髓靶向给药的策略将与其他播散性癌症或 影响脊髓的神经系统疾病。