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.

项目概要/摘要 基因工程神经干细胞（NSC）是治疗高度攻击性大脑的一种有前途的疗法 癌症胶质母细胞瘤（GBM）。工程化 NSC 具有独特的肿瘤归巢能力，使它们能够传递 抗癌基因产物直接进入局部和侵袭性GBM病灶。我们组和其他人的临床前研究 研究表明，杀肿瘤 NSC 通常可以使原位 GBM 异种移植物减少 70-90%，并且显着减少 延长荷瘤小鼠的生存期。然而，GBM 体积的这些最初急剧减少并没有 维持和治疗持久性仍然是基于 NSC 的治疗的主要挑战。 GBM 逃逸发生 使用携带不同治疗有效负载的 NSC 进行治疗后，以及在实体和实体的临床前模型中 手术后 GBM。我们最近发现了具有强大抗肿瘤作用的新型肿瘤归巢药物递送载体 可以使用细胞重编程从“诱导神经干细胞”（iNSC）开发癌症活性 技术，称为转分化（TD）。杀肿瘤 iNSC 疗法减少 GBM 异种移植物 230- 4 周内折叠，存活率增加一倍以上。与野生型 NSC 疗法类似，肿瘤不 被根除，GBM 重新发育。介导 GBM 再生以响应单因素的事件 NSC/iNSC 治疗剂尚不清楚。我们的结果表明移植的 iNSC 药物载体被清除 来自大脑，但反复脑室内（ICV）输注可恢复载体水平。我们还有 有证据表明 GBM 细胞对 iNSC 递送的药物产生耐药性。这让我们可以假设 GBM 可以通过重复给药来克服对 iNSC 治疗的耐药性，以解决载体丢失和多药治疗的问题 iNSC 递送以解决肿瘤耐药性问题。通过这笔赠款，我们建议检验这一假设，定义 在 NSC 治疗期间有助于 GBM 动态适应的事件并制定转化策略 最初的肿瘤杀死转变为持续的 GBM 抑制。我们将研究载体清除、归巢和肿瘤 整个 GBM 适应和复发过程中的耐药性。然后我们将通过重复调节 iNSC 治疗 通过 ICV 输注和携带多种药物有效负载的 iNSC 进行给药，以改善治疗 通过克服 iNSC 损失和对单一药物具有抵抗力的 GBM 病灶的出现来实现耐久性 治疗。所有测试都将使用我们新型的鼠源性 GBM 细胞手术切除模型来完成 具有免疫能力的动物和患者来源的 CD133+ 人 GBM 细胞，以最大限度地提高临床相关性 我们的发现并了解免疫系统对 iNSC 治疗持久性的影响。结果 这些研究对于创造持久的基于 NSC 的肿瘤疗法至关重要，该疗法能够产生持久的效果 患者试验中的 GBM 抑制。