Stem cell mediated targeting of tumor cells and associated vasculature in gliomas

干细胞介导的神经胶质瘤中肿瘤细胞和相关脉管系统的靶向

基本信息

批准号：
8657491
负责人：
Khalid A Shah
金额：
$ 37.47万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657491
关键词：
Angiogenesis Inhibitors Apoptosis Apoptotic Biocompatible Blood - brain barrier anatomy Blood Vessels Boston Brain Brain Neoplasms Cancer Patient Cells Cerebrospinal Fluid Clinical Clinical Research Collaborations Cytotoxic Chemotherapy Cytotoxic agent Deposition Development Diagnostic Drug Combinations Drug Delivery Systems Drug Kinetics Encapsulated Endothelial Cells Engineering Excision Extracellular Matrix Future Genetic Engineering Glioblastoma Glioma Home environment Human Human Engineering Image In Vitro Intracranial Neoplasms Laboratories Lead Ligands Magnetic Resonance Imaging Malignant - descriptor Malignant neoplasm of brain Mediating Modality Modeling Mus Operative Surgical Procedures Outcome Pathology Patients Primary Neoplasm Proteins Research Research Personnel Resected Simulate Site Stem cells TNFRSF10A gene TNFSF10 gene Testing Therapeutic Therapeutic Effect Therapeutic Intervention Thrombospondin 1 Time Treatment Efficacy Tumor Necrosis Factor-alpha Tyrosine Kinase Inhibitor Up-Regulation Vascular Endothelial Growth Factor Receptor adult stem cell angiogenesis base cell type cytotoxic death receptor-4 design efficacy testing human TNFRSF10A protein in vivo killings mouse model neoplastic cell nerve stem cell neuropathology novel optical imaging pre-clinical preclinical study restoration scaffold therapeutic protein tumor

项目摘要

DESCRIPTION (provided by applicant): A number of previous pre-clinical studies suggest that anti-angiogenic agents create "normalization window" during which delivery and efficacy of concurrently administered cytotoxic agents is enhanced. However, recent studies have shown that vessel normalization results in the restoration of blood brain barrier and consequential inefficient vessel dependent delivery of cytotoxic drugs to brain tumors. These results have raised fundamental questions about modes of delivery and the types of anti-angiogenic and cytotoxic drug combinations used to 1) normalize tumor vasculature; and 2) enhance the outcome of cytotoxic therapy post-normalization for brain tumors? This has prompted the design of novel therapies that allow use of 1) alternative modes of drug delivery that targets both the primary tumors and secondary micro-invasive deposits in the brain; 2) engineered therapeutic proteins that specifically target both tumor cells and associated vasculature; and 3) diagnostic proteins that allow tracking of drug delivery vehicles, therapeutic proteins and fate of tumors in vivo. In this proposal, we will engineer human neural stem cells (NSC) with secretable antiangiogenic (aa), thrombospondin (TSP)-1 and pro-apoptotic secretable tumor necrosis factor apoptosis inducing ligand (S-TRAIL) which is known to induce apoptosis via death receptor (DR)4/5 and initially compare the "normalization" potential of NSC-aaTSP-1 with systemic delivery of known anti-angiogenic agents in established malignant and primary invasive brain tumors (gliomas). Based on the recent studies by our Co-Investigator, Dr. Lawler, that TSP-1 normalizes vasculature and also induces death receptor (DR)4/5 expression on tumor associated endothelial cells (EC) priming them to TRAIL-induced killing, the therapeutic effect of S-TRAIL post vessel normalization and EC priming by aaTSP-1 will be tested in both malignant and invasive glioma models. We hypothesize that aaTSP-1 will enhance the cytotoxic effects of S-TRAIL on tumor cells by normalizing the vasculature and also upregulation of DR4/5 expression in EC. This will ultimately lead to enhanced eradication of tumor cells and also killing of EC in both the primary tumor mass and the micro-invasive tumor cells escaping the primary tumor mass. A close integration of fluorescent and bioluminescent imaging markers into glioma cells, EC and NSC will allow us to assess therapeutic efficacy early and quickly and thus to adjust and fine-tune the proposed therapeutic approaches. In an effort to simulate a clinical scenario, the therapeutic NSC will be encapsulated into biocompatible synthetic extracellular matrix (sECMs) and tested in our recently developed resection model of glioma. Once validated, we envision a therapeutic modality in which at the time of brain tumor surgery, the main tumor mass will be removed and genetically engineered therapeutic cells will be introduced in sECMs and allowed to target the remaining tumor cells and micro-invasive tumor deposits in the brain. This will have a major impact in saving the lives of many brain cancer patients.

描述（由申请人提供）：许多先前的临床前研究表明，抗血管生成剂创建“正常化窗口”，在此期间同时施用的细胞毒剂的递送和功效得到增强。然而，最近的研究表明，血管正常化会导致血脑屏障的恢复，从而导致细胞毒性药物向脑肿瘤的血管依赖性递送效率低下。这些结果提出了关于递送方式以及用于以下目的的抗血管生成和细胞毒性药物组合的类型的基本问题：1）使肿瘤脉管系统正常化； 2）增强脑肿瘤正常化后细胞毒治疗的效果？这促使人们设计出新的疗法，允许使用：1）针对原发性肿瘤和大脑中继发性微创沉积物的替代药物输送模式； 2）专门针对肿瘤细胞和相关脉管系统的工程治疗蛋白； 3) 诊断蛋白，可追踪药物输送载体、治疗蛋白和体内肿瘤的命运。在本提案中，我们将用分泌型抗血管生成 (aa)、血小板反应蛋白 (TSP)-1 和促凋亡的分泌型肿瘤坏死因子凋亡诱导配体 (S-TRAIL) 改造人类神经干细胞 (NSC)，已知该配体可通过以下方式诱导细胞凋亡：死亡受体 (DR)4/5 并初步比较 NSC-aaTSP-1 与已知抗血管生成药物在已确定的恶性和原发性侵袭性脑肿瘤中的全身递送的“正常化”潜力（神经胶质瘤）。根据我们的共同研究员 Lawler 博士最近的研究，TSP-1 使脉管系统正常化，并诱导肿瘤相关内皮细胞 (EC) 上的死亡受体 (DR)4/5 表达，从而启动它们进行 TRAIL 诱导的杀伤， S-TRAIL 在血管正常化和 aaTSP-1 启动 EC 后的治疗效果将在恶性和侵袭性神经胶质瘤模型中进行测试。我们假设 aaTSP-1 将通过使血管系统正常化以及上调 EC 中 DR4/5 的表达来增强 S-TRAIL 对肿瘤细胞的细胞毒性作用。这最终将导致增强对肿瘤细胞的根除，并杀死原发性肿瘤块和逃离原发性肿瘤块的微侵袭性肿瘤细胞中的EC。将荧光和生物发光成像标记物紧密整合到神经胶质瘤细胞、EC和NSC中将使我们能够及早、快速地评估治疗效果，从而调整和微调所提出的治疗方法。为了模拟临床场景，治疗性 NSC 将被封装到生物相容性合成细胞外基质 (sECM) 中，并在我们最近开发的神经胶质瘤切除模型中进行测试。一旦经过验证，我们设想了一种治疗方式，在脑肿瘤手术时，主要肿瘤块将被切除，基因工程治疗细胞将被引入 sECM 中，并允许靶向剩余的肿瘤细胞和微侵袭性肿瘤沉积物。大脑。这将对挽救许多脑癌患者的生命产生重大影响。