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，抗血管生成剂会创建“归一化窗口”，在此期间，同时施用的细胞毒性剂的递送和功效增强了。然而，最近的研究表明，血管归一化导致血液脑屏障的恢复，并导致血管依赖于细胞毒性药物向脑肿瘤的递送。这些结果提出了有关输送方式以及用于1）肿瘤脉管系统归一化的抗血管生成和细胞毒性药物组合的基本问题； 2）增强脑肿瘤分布后细胞毒性疗法的结果？这促使设计了新型疗法的设计，允许使用1）靶向原发性肿瘤和次要微侵入性沉积物的替代药物递送模式； 2）专门针对肿瘤细胞和相关脉管系统的工程治疗蛋白； 3）允许在体内跟踪药物输送车，治疗蛋白和命运的诊断蛋白。在该提议中，我们将使用可分泌的抗血管生成（AA），血小板蛋白（TSP）-1和促凋亡性可分泌的可分泌性肿瘤坏死因子凋亡诱导配体（S-Trail）来设计人类神经干细胞（NSC），已知通过死亡受体（DR）诱导型号（dr）均一的范围（dr），促进了n/sc的范围。已知的抗血管生成剂在已建立的恶性和原发性浸润性脑肿瘤（神经胶质瘤）中。基于我们的共同入选者Lawler博士的最新研究，TSP-1使脉管系统正常化，还诱导了死亡受体（DR）4/5在肿瘤相关的内皮细胞（EC）上表达4/5的表达，从而使其启发至跟踪诱导的杀戮，S-Trail后血后正常化和AATSP-1的EC启动的治疗效果以及AATSP-1的EC启动均可在Malignant中均可在Malignant中进行测试。我们假设AATSP-1将通过标准化脉管系统和EC中DR4/5表达的上调来增强S-Trail对肿瘤细胞的细胞毒性作用。这最终将导致肿瘤细胞的根除增强，并在原发性肿瘤质量和逃避原发性肿瘤肿块的微侵入性肿瘤细胞中杀死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中，EC和NSC将使我们能够尽早，快速地评估治疗功效，从而调整和调整所提出的治疗方法。为了模拟临床方案，治疗性NSC将封装在生物相容性的合成细胞外基质（SECMS）中，并在我们最近开发的Glioma切除模型中进行了测试。一旦得到验证，我们就设想了一种治疗方式，在该方法中，在脑肿瘤手术时，将去除主要的肿瘤肿块，并将在SECMS中引入基因工程的治疗细胞，并允许靶向剩余的肿瘤细胞和大脑中的微侵入性肿瘤沉积物。这将对挽救许多脑癌患者的生命产生重大影响。