Lentiviral-Induced Swine Model of Spinal Cord Glioma

项目总结 高级别脊髓胶质瘤(SCG)是一种孤儿疾病，导致显著 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，这代表了一种难以治愈的疾病的恶性本质。 护理的标准。另一方面，这提出了一个问题，即 现有的临床前动物模型，特别是从外科角度--可广泛扩展的 SCG的大型动物模型以前是不可用的。为此，布利斯和卡诺尔 实验室合作开始解决这一领域的空白，开发了一种微型猪SCG 模特。通过慢病毒靶向RTK/RAS/PI3K和P53通路，我们的 初步数据表明，高级别星形细胞瘤的诱导与组织病理学， 对100%的小型猪进行放射学和转录特征分析。因此，我们假设 这个模型系统的下一步进展是调节肿瘤表型和 在可直接翻译的外科应用中展示其实用性。在所附的建议书中，我们 将首先评估SCG的诱导作用，方法是针对与 人类疾病包括PDGFB、P53、CDKN2A、EGFR和PTEN(AIM 1)。这代表了 有机会生产高度特征化的SCG病变用于治疗测试 免疫活性，更具解剖学相关性的大型动物模型。同时，我们将应用我们的 现有小型猪SCG模型(AIM 2)首次实现肿瘤内对流增强 SCG在大型动物体内的分娩(CED)研究。鼠类对化疗药物CED的研究 SCG已经报道了抑制肿瘤生长和改善神经功能障碍的研究。然而， 由于啮齿动物系统的解剖学限制，这些数据不能很容易地缩放以进行翻译。 尽管在SCG中正在进行CED的I期人体试验，但药物分布和CED参数 人们对此了解甚少。事实上，CED在治疗颅内胶质瘤的人体试验中的失败可能是 归因于药物分配不力和单一治疗。因此，我们的研究将采用 用于延长肿瘤内CED的植入式泵。我们将研究参数(流速、 输液体积)以评估最佳读数(分布体积、回流、安全性、放射学 VS化疗分配)。这些数据将对目前产生直接的翻译影响 以及未来的审判。

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.