Engineering stem cell therapies to understand and overcome glioblastoma adaption

工程干细胞疗法以了解和克服胶质母细胞瘤适应

• 批准号: 10218274
• 负责人: Shawn Hingtgen
• 金额: $ 31.84万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-26 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218274
• 关键词: Address; Adult; Affect; Aftercare; Animals; Apoptotic; Autologous; Blood - brain barrier anatomy; Brain; Cells; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Diffuse; Disease; Distant; Dose; Drug Carriers; Drug Delivery Systems; Engineering; Event; Excision; Failure; Fibroblasts; Future; Genetic Engineering; Genetically Engineered Mouse; Glioblastoma; Goals; Grant; Home; Homing; Human; Immune; Immune system; Immunocompetent; In Vitro; Infusion procedures; Injections; Luciferases; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Mus; Operative Surgical Procedures; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Process; Proliferating; Recurrence; Resected; Resistance; Seeds; Site; Solid; Somatic Cell; Surgically-Created Resection Cavity; TNFSF10 gene; Technology; Testing; Therapeutic; Tissues; Transplantation; Tumor Stem Cells; Ventricular; Work; Xenograft Model; Xenograft procedure; anti-cancer; anticancer activity; base; bioluminescence imaging; cancer cell; cancer invasiveness; cell killing; cell type; clinically relevant; cytotoxic; defined contribution; engineered stem cells; gene product; improved; migration; mouse model; neoplastic cell; nerve stem cell; novel; patient derived xenograft model; preclinical study; prevent; response; stem cell delivery; stem cell therapy; transcription factor; transdifferentiation; tumor; tumor behavior

Project Summary/Abstract Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer Glioblastoma (GBM). Engineered NSCs have unique tumor-homing capacity that allows them to deliver anti-cancer gene products directly into local and invasive GBM foci. Preclinical studies by our group and others have shown tumoricidal NSCs routinely reduce orthotopic GBM xenografts between 70-90% and significantly extend survival of tumor-bearing mice. Yet, these dramatic initial reductions in GBM volumes are not maintained and treatment durability remains a major challenge for NSC-based therapy. GBM escape occurs after treatment with NSCs carrying different therapeutic payloads and in pre-clinical models of both solid and post-surgical GBM. We recently discovered that novel tumor-homing drug delivery vehicles with robust anti- cancer activity can be developed from “induced neural stem cells” (iNSCs) using cellular reprogramming technology, referred to as transdifferentiation (TD). Tumoricidal iNSC therapy reduced GBM xenografts 230- fold in 4 weeks and more than doubled survival. Similar to wild-type NSC therapy, the tumors were not eradicated and the GBMs re-developed. The events mediating the regrowth of GBMs in response to single- agent NSC/iNSC therapy are unknown. Our results show that transplanted iNSCs drug carriers are cleared from the brain, but repeated intracerebroventricular (ICV) infusion restores carrier levels. We also have evidence that GBM cells become resistant to iNSC-delivered drugs. This allows us to hypothesize that GBM resistance to iNSC therapy can be overcome by repeat administration to address carrier loss and multi-agent iNSC delivery to address tumor resistance. With this grant we propose to test this hypothesis, defining the events that contribute to the dynamic adaption of GBM during NSC treatment and develop strategies to convert the initial tumor kill into sustained GBM suppression. We will investigate carrier clearance, homing, and tumor resistance throughout GBM adaption and recurrence. We will then modulate iNSC therapy through repeated dosing via ICV infusion and delivery of iNSCs carrying multi-drug payloads with the goal of improving treatment durability by overcoming iNSC loss and the emergence of GBM foci that are resistant to single-agent treatments. All testing will be done using our novel surgical resection models of murine-derived GBM cells in immune-competent animals and patient-derived CD133+ human GBM cells to maximize the clinical relevancy of our finding and understand the impact of the immune system on iNSC treatment durability. The results of these studies are essential for creating durable NSC-based tumor therapies capable of producing long-lasting GBM suppression in patient trials.

项目摘要/摘要 基因设计的神经干细胞（NSC）是高度侵略性大脑的承诺疗法 癌症母细胞瘤（GBM）。工程的NSC具有独特的肿瘤能力，使他们能够交付 抗癌基因产物直接进入局部和侵入性GBM焦点。我们小组和其他人的临床前研究 已显示肿瘤NSC通常将原位GBM异种移植物降低在70-90％之间，并显着降低 延长承重肿瘤小鼠的存活率。然而，这些GBM量的这些显着初始减少不是 维持和治疗耐用性仍然是基于NSC的治疗的主要挑战。 GBM逃生发生 用携带不同治疗有效载荷的NSC进行处理后，以及在固体和固体和固体模型中 手术后的GBM。我们最近发现，具有强大抗抗药性的新型肿瘤供应车辆 可以使用细胞重编程从“诱导的神经干细胞”（INSC）开发癌症活性 技术，称为转分化（TD）。肿瘤性INSC治疗降低了GBM Xenographictic 230- 在4周内折叠，生存率翻了一番。与野生型NSC治疗相似，肿瘤不是 消除了，GBMS重新开发。这些事件调解了GBM的遗憾，以回应单一的事件 NSC/INSC疗法尚不清楚。我们的结果表明，移植的INSCS药物载体被清除 从大脑中，但重复的脑室内（ICV）输注恢复了载体水平。我们也有 GBM细胞对INSC传递药物具有抗性的证据。这使我们可以假设GBM 可以通过重复给药来克服对INSC治疗的抵抗，以解决载体损失和多机构 INSC递送以解决肿瘤抗性。通过这项赠款，我们建议检验这一假设，定义 在NSC处理过程中有助于GBM动态适应的事件以及制定转换的策略 最初的肿瘤杀死持续的GBM抑制作用。我们将研究载体清除，归巢和肿瘤 整个GBM适应性和复发性的阻力。然后，我们将通过重复调节INSC治疗 通过ICV输注和携带多药有效载荷的INSC的剂量，目的是改善治疗 通过克服INSC损失和对单位代理具有抗性的GBM焦点的出现，耐用性 治疗。所有测试将使用我们的新型手术切除模型在鼠衍生的GBM细胞中进行 免疫能力的动物和患者来源的CD133+人GBM细胞，以最大化临床相关性 我们的发现和理解免疫系统对INSC治疗耐用性的影响。结果 这些研究对于创建耐用NSC的肿瘤疗法至关重要 在患者试验中抑制GBM。