In vivo imaging of encapsulated stem cells in mouse models of tumor resection

肿瘤切除小鼠模型中封装干细胞的体内成像

基本信息

批准号：
9405283
负责人：
Khalid A Shah
金额：
$ 33.47万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9405283
关键词：
Adjuvant Adjuvant Chemotherapy Adult Aminolevulinic Acid Boston Brain Brain Neoplasms Cancer Patient Carmustine Cell Survival Cells Clinical Clinical Research Collaborations Deposition Development Disease Drug Kinetics Encapsulated Engineering Ensure Epidermal Growth Factor Receptor Excision Extracellular Matrix Fluorescence Fluorescent Dyes Future Genetic Engineering Glioblastoma Glioma Goals Home environment Homing Human Human Engineering Image In Vitro Injection of therapeutic agent Invaded Laboratories Ligands Magnetic Resonance Imaging Malignant - descriptor Malignant neoplasm of brain Mesenchymal Stem Cells Microinvasive Microscopy Modeling Mus Nature Operative Surgical Procedures Optics Pathology Patients Phenotype Play Positron-Emission Tomography Primary Brain Neoplasms Primary Neoplasm Progression-Free Survivals Publishing Radiation therapy Recurrence Research Personnel Resected Residual state Resistance Role Safety Savings Simplexvirus Site Solid Stem cells Surgically-Created Resection Cavity TNF gene TNFSF10 gene Testing Therapeutic Thymidine Kinase Time Transplantation Treatment Efficacy Tumor Debulking Tumor Volume Universities Utah Virus antitumor agent apoptosis inducing factor base cell killing cell motility cell suicide cellular engineering chemotherapeutic agent clinically translatable design image guided imaging biomarker in vivo in vivo imaging intravital microscopy killings mortality mouse model nanobodies neoplastic cell novel outcome forecast preclinical study prevent public health relevance standard care suicide gene targeted treatment therapeutic protein tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The standard treatment for malignant glioblastoma multiforme (GBM) includes maximal surgical tumor resection followed by radiation therapy and adjuvant chemotherapy. However, recurrence rates of GBM and the associated patient mortality are nearly 100%. Despite the key role of tumor resection in clinical GBM therapy, most of the pre-clinical studies focus on treating solid intact intracranial GBM tumors without mimicking the clinical scenario of surgical resection. Therefore, implementation of tumor resection in mouse models that recapitulate the clinical disease features are critical in developing clinically translatable therapies for GBM. In the proposed studies, we will first create and characterize different GBM resection models using patient derived CD133+ GBMs based on 3 different phenotypes (invasive, semi-invasive and nodular). While resection of primary tumor has shown clinical benefit, systemically delivered chemotherapeutic agents or direct injection of viruses and placement of carmustine (BCNU) wafers in tumor resection cavities has provided very limited additional benefit. Based on our recent findings that encapsulation of mesenchymal stem cells (MSC) is necessary to prevent rapid "wash- out" of stem cells post-transplantation in the tumor resection cavity, we will encapsulate human MSC engineered to express in vitro and in vivo imaging markers into synthetic extracellular matrices (sECMs) and evaluate them for their retention, survival and tumor homing in mouse resection models of GBM with different phenotypes. Based on our preliminary studies which indicate that a novel anti-tumor agent consisting of a secretable version of epidermal growth factor receptor targeted nanobody fused to tumor necrosis factor apoptosis inducing ligand (Enb-TRAIL), induces GBM cell killing in both TRAIL resistant and sensitive GBMs, encapsulated MSC-Enb- TRAIL will be tested in different GBM models of resection. To ensure the safety of our approach, we will ultimately engineer human MSC-Enb-TRAIL to express HSV-thymidine kinase (TK), an activatable cellular suicide gene that will allow us to selectively eradicate MSC post-GBM treatment. The incorporation of genetically engineered fluorescent and bioluminescent imaging (BLI) markers into MSC and GBMs will allow us to follow GBM cell invasion, fate of MSC and pharmacokinetics of therapeutic proteins and their efficacy by in vivo BLI, intravital microscopy (IVM), magnetic resonance imaging (MRI) and positron emission tomography (PET) and thus to fine tune the proposed approaches. Once validated, we will initiate a clinical study in which at the time of brain tumor surgery, the main tumor mass will be removed and sECMs encapsulated MSC will be introduced to target a broad spectrum of 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）：恶性多形性胶质母细胞瘤（GBM）的标准治疗包括最大程度的手术切除肿瘤，然后进行放射治疗和辅助化疗。然而，GBM 的复发率和相关的患者死亡率接近 100%。尽管肿瘤切除在临床 GBM 治疗中发挥着关键作用，但大多数临床前研究重点是治疗完整的颅内实体 GBM 肿瘤，而不是模仿手术切除的临床情况。因此，在重现临床疾病特征的小鼠模型中实施肿瘤切除对于开发 GBM 的临床可转化疗法至关重要。在拟议的研究中，我们将首先使用基于 3 种不同表型（侵入性、半侵入性和结节性）的患者来源的 CD133+ GBM 创建并表征不同的 GBM 切除模型。虽然原发肿瘤切除术已显示出临床益处，但全身递送化疗药物或直接注射病毒和将卡莫司汀 (BCNU) 晶片放置在肿瘤切除腔中所提供的额外益处非常有限。根据我们最近的发现，间充质干细胞 (MSC) 的封装对于防止肿瘤切除腔内移植后干细胞的快速“清洗”是必要的，我们将封装经过工程改造以表达体外和体内成像的人 MSC将标记物放入合成细胞外基质（sECM）中，并评估它们在具有不同表型的 GBM 小鼠切除模型中的保留、存活和肿瘤归巢。基于我们的初步研究表明，一种新型抗肿瘤药物由可分泌型表皮生长因子受体靶向纳米体与肿瘤坏死因子凋亡诱导配体（Enb-TRAIL）融合组成，可诱导 TRAIL 耐药和敏感的 GBM 细胞杀伤GBM、封装的 MSC-Enb-TRAIL 将在不同的 GBM 切除模型中进行测试。为了确保我们方法的安全性，我们最终将改造人类 MSC-Enb-TRAIL 以表达 HSV-胸苷激酶 (TK)，这是一种可激活的细胞自杀基因，使我们能够在 GBM 治疗后选择性地根除 MSC。将基因工程荧光和生物发光成像 (BLI) 标记物纳入 MSC 和 GBM 将使我们能够通过体内 BLI、活体显微镜 (IVM)、磁共振来跟踪 GBM 细胞侵袭、MSC 的命运和治疗蛋白的药代动力学及其功效成像（MRI）和正电子发射断层扫描（PET），从而微调所提出的方法。一旦得到验证，我们将启动一项临床研究，在脑肿瘤手术时，将切除主要肿瘤块，并引入封装 MSC 的 sECM，以靶向脑部中的广泛剩余肿瘤细胞和微侵袭性肿瘤沉积物。脑。这将对挽救许多脑癌患者的生命产生重大影响。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multifunctional receptor-targeting antibodies for cancer therapy.

DOI：
10.1016/s1470-2045(15)00039-x
发表时间：
2015-11-01
期刊：
The Lancet. Oncology
影响因子：
0
作者：
Yanni Zhu;Sung Hugh Choi;K. Shah
通讯作者：
K. Shah

microRNA-7 upregulates death receptor 5 and primes resistant brain tumors to caspase-mediated apoptosis.

microRNA-7 上调死亡受体 5 并引发抗性脑肿瘤发生 caspase 介导的细胞凋亡。

DOI：
发表时间：
2018-01-22
期刊：
影响因子：
15.9
作者：
Bhere, Deepak;Tamura, Kaoru;Wakimoto, Hiroaki;Choi, Sung Hugh;Purow, Benjamin;Debatisse, Jeremy;Shah, Khalid
通讯作者：
Shah, Khalid