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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

基本信息

批准号：
9447282
负责人：
Shawn Hingtgen
金额：
$ 33.22万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-26 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9447282
关键词：
Address Adult Affect Aftercare Alpha Cell Animals Apoptotic Autologous Behavior Blood - brain barrier anatomy Brain Cell Therapy 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 environment Homing Human Immune Immune system In Vitro Infusion procedures Injection of therapeutic agent Luciferases Malignant Neoplasms Malignant neoplasm of brain Mediating Modeling Molecular Mus Oncogenes 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 base bioluminescence imaging cancer cell cancer invasiveness cell killing cell type clinically relevant cytotoxic defined contribution gene product improved killings migration mouse model neoplastic cell nerve stem cell novel preclinical study prevent response stem cell therapy transcription factor transdifferentiation tumor

项目摘要

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.

项目总结/文摘