Lentiviral-Induced Swine Model of Spinal Cord Glioma

慢病毒诱导的猪脊髓胶质瘤模型

• 批准号: 10630906
• 负责人: NICHOLAS M BOULIS
• 金额: $ 52.24万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630906
• 关键词: Address; Anatomy; Animal Model; Animals; Astrocytoma; Behavioral; Biological Models; Biopsy; CDKN2A gene; Canis familiaris; Characteristics; Chemoresistance; Clinical; Contrast Media; Convection; Data; Development; Device or Instrument Development; Disease; Drug Delivery Systems; Epidermal Growth Factor Receptor; Evaluation; Excision; Failure; Family suidae; Future; Gadolinium; Gene Transfer; Genes; Genetic; Glioma; Gliomagenesis; Goals; Growth; High Pressure Liquid Chromatography; Histopathology; Human; Immunocompetent; Implantable Pump; Individual; Indolent; Infusion procedures; Knowledge; Laboratories; Lesion; Magnetic Resonance Imaging; Malignant - descriptor; Measures; Mediating; Miniature Swine; Modeling; Molecular; Monitor; Morbidity - disease rate; Nature; Neurologic Deficit; Oncogenes; Operative Surgical Procedures; Outcome; PDGFB gene; PIK3CG gene; PTEN gene; Pathway interactions; Patients; Phase; Phenotype; Platelet-Derived Growth Factor; Process; Radiology Specialty; Rare Diseases; Recurrence; Reflux; Refractory; Reporting; Rodent; Rodent Model; Safety; Serial Magnetic Resonance Imaging; Spinal Cord; Spinal Cord Neoplasms; Study models; Surgical Models; Surgical margins; Survival Rate; System; TP53 gene; Testing; Therapeutic; Transgenes; Translations; Tumor Suppression; clinically relevant; design; drug distribution; effective therapy; experience; experimental group; human disease; improved; knock-down; mortality; neurosurgery; phase I trial; porcine model; pre-clinical; radiation resistance; small hairpin RNA; standard of care; therapeutic evaluation; transcriptomics; transgene delivery; translational impact; translational study; tumor; tumor growth; vector

PROJECT SUMMARY High-grade Spinal Cord Glioma (SCG) is an orphan disease that results in significant morbidity and mortality, with no effective treatment options available. Despite significant advances in our knowledge of the disease process, there have unfortunately been limited changes to the clinical outcomes. In part, this represents the malignant nature of a disease that is refractory to the standard of care. On the other hand, this raises the question of the translational value of existing preclinical animal models, especially from a surgical standpoint – where widely scalable large animal models of SCG were previously unavailable. To this end, the Boulis and Canoll laboratories partnered to begin addressing this gap in the field by developing a minipig SCG model. Through lentiviral targeting of the well implicated RTK/RAS/PI3K and p53 pathways, our preliminary data demonstrates the induction of high-grade astrocytoma with histopathologic, radiologic, and transcriptomic characterization in 100% of minipigs. Consequently, we posit that the next steps to advancement of this model system are to modulate tumor phenotype and to demonstrate its utility in a directly translatable surgical application. In the enclosed proposal, we will begin by evaluating the induction of SCG by targeting common genetic lesions implicated in the human disease including PDGFB, P53, CDKN2A, EGFR, and PTEN (AIM 1). This represents the opportunity to produce highly characterized SCG lesions for therapeutic testing in an immunocompetent, more anatomically relevant, large animal model. In parallel, we will apply our existing minipig SCG model (AIM 2) to perform the first intra-tumoral convection enhanced delivery (CED) study for SCG in a large animal. Rodent studies of chemotherapeutic CED for SCG have reported suppression of tumor growth and amelioration of neurologic deficits. However, these data cannot be readily scaled for translation due to anatomic limitations of rodent systems. Despite an ongoing Phase I human trial for CED in SCG, drug distribution and CED parameters are poorly understood. Indeed, failures of CED in human trials for intracranial glioma can be attributed to both ineffective drug distribution and single treatments. As such, our study will employ implanted pumps for prolonged intratumoral CED. We will investigate parameters (flow rate, volume of infusion) to evaluate optimal readouts (volume of distribution, reflux, safety, radiologic vs chemotherapeutic distribution). These data will have immediate translational impact on present and future trials.

项目摘要 高级别脊髓胶质瘤（SCG）是一种罕见疾病， 发病率和死亡率，没有有效的治疗选择。尽管取得了重大进展 在我们对疾病过程的了解中，不幸的是， 临床结果。在某种程度上，这代表了一种疾病的恶性本质， 护理标准。另一方面，这也提出了翻译价值的问题。 现有的临床前动物模型，特别是从手术角度来看-可广泛扩展 SCG的大型动物模型以前是不可用的。为此，布利斯和卡诺尔夫妇 实验室合作，开始通过开发小型猪SCG来解决该领域的这一差距 模型通过慢病毒靶向与RTK/RAS/PI 3 K和p53通路密切相关的细胞， 初步数据表明诱导高级别星形细胞瘤具有组织病理学， 100%小型猪的放射学和转录组学表征。因此，我们认为， 进一步发展该模型系统的下一步是调节肿瘤表型， 证明其在可直接平移的外科应用中的效用。在所附提案中，我们 将开始通过评估SCG的诱导作用， 人类疾病包括PDGFB、P53、CDKN 2A、EGFR和PTEN（AIM 1）。这代表 有机会产生高度特征化的SCG病变，用于治疗试验， 免疫活性、解剖学相关性更高的大型动物模型。与此同时，我们将应用我们的 现有的小型猪SCG模型（AIM 2）进行第一次肿瘤内对流增强 在大型动物中进行SCG的CED递送研究。化疗CED用于啮齿动物的研究 SCG已报道抑制肿瘤生长和改善神经功能缺损。然而，在这方面， 由于啮齿类动物系统的解剖学限制，这些数据不能容易地按比例换算。 尽管正在进行的SCG中CED的I期人体试验，但药物分布和CED参数 我们对此知之甚少。事实上，CED在颅内胶质瘤人体试验中的失败可能是 这是由于无效的药物分配和单一治疗。因此，我们的研究将采用 植入泵以延长肿瘤内CED。我们将研究参数（流速， 输注量），以评估最佳读数（分布容积、反流、安全性、放射学 相对于化疗剂分布）。这些数据将对目前的翻译产生直接影响。 和未来的审判。