BMP4 Engineered Mesenchymal Stem Cell Therapy for Glioblastoma

BMP4 工程间充质干细胞治疗胶质母细胞瘤

基本信息

批准号：
9065529
负责人：
ALFREDO QUINONES-HINOJOSA
金额：
$ 33.35万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-08 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9065529
关键词：
Accounting Adherence Adipose tissue Adjuvant Radiotherapy Adult Affect Age Allogenic Animals Antineoplastic Agents Apoptosis Autologous Blood - brain barrier anatomy Bone Marrow Brain Brain Neoplasms Cells Characteristics Clinical Clinical Trials Devices Effectiveness Endothelium Engineering Excision Future Glioblastoma Glioma Goals Grant Health Human Immune Immunotherapeutic agent In Vitro Invaded Investigation Lead Local Therapy Longevity Malignant Neoplasms Malignant neoplasm of brain Mesenchymal Stem Cells Microfluidics Modeling Morbidity - disease rate Mus Nature Oncogenic Operative Surgical Procedures Patients Plague Primary Brain Neoplasms Proteins Radiation Radiation therapy Radio Reaction Recurrence Research Research Design Resistance Safety Source Stem cells Surface Survival Rate Targeted Radiotherapy Techniques Testing Therapeutic Therapeutic Effect Translating Tropism Tumor Burden Tumor Escape Viral Xenograft Model bone morphogenic protein brain parenchyma cancer cell cancer type cell motility cellular engineering chemoradiation clinical application effective therapy genetically modified cells implantation in vivo in vivo Model ineffective therapies migration mortality mouse model nanobiotechnology neoplastic cell novel novel therapeutics research study response stem cell therapy targeted delivery treatment strategy tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common primary brain tumor in adults, and accounts for 20% of all primary brain tumors. GBM has a median survival rate of only 14.6 months despite current best treatment practices which include surgery and chemoradiation. A significant reason for this morbidity and mortality is the ability of GBM to invade normal brain parenchyma, making localized treatment ineffective. In order for treatment to be effective, these invading cells need to be targeted. One promising approach involves the use of mesenchymal stem cells (MSCs), which have been found by our group and by others to migrate preferentially to cancer cells. Moreover, MSCs can be engineered to synthesize and release anti-tumor proteins, such as bone morphogenic protein 4 (BMP4), which has been found to affect brain tumor initiating cells (BTICs). MSCs can be obtained from bone marrow (BM-MSC) and adipose tissue (AMSC). The use of BM-MSCs has been limited because these cells are difficult to obtain, have limited ex vivo proliferation capacity, and decrease in effectiveness with increasing donor age. AMSCs may therefore be a better option. In this grant, we propose to use a novel source for human MSCs, adipose tissue from our patients, and genetically modify these cells to secrete BMP4 for the treatment of GBM. In contrast to BM-MSCs, human AMSCs (hAMSCs) provide a therapeutically comparable source of cells which are more readily accessible and have better ex vivo expansibility. Our overall hypothesis is that virally-modified hAMSCs expressing BMP4 in combination with adjuvant radiotherapy constitute an effective treatment against intracranial GBM. To achieve these goals, we will pursue the following specific aims: (Aim 1) To determine the tumor tropism, endothelial adherence, blood brain barrier crossing capability, and anti-glioma response of virally-modified BMP4-secreting primary hAMSCs in vitro-we have shown this with commercial hAMSCs and we propose to do it now with Freshly extracted Adipose Tissue (F.A.T.); (Aim 2) To determine the safety and efficacy of virally-modified BMP4-secreting hAMSCs in combination with targeted radiation therapy on human GBM in an in vivo murine model. The techniques to be used in vitro and in vivo in this proposal have been developed and further characterized by our team and by our collaborators. In vitro studies will be conducted using new advancements in the fields of microfluidics and nanobiotechnology. In vivo studies will employ a mammalian xenograft model that engrafts human BTIC- derived GBM, which bests recapitulates human GBM. Additionally, we will use the small animal radiation research platform (SARRP), a novel device developed and used by our team and collaborators, which allows the delivery of targeted beams of radiation therapy to tumor-bearing mice analogous to confocal beam therapy in humans. The SARRP is capable of focusing a beam of radiation with an accuracy of 0.2 mm, recreating radiotherapy for humans on the scale of a mouse. In addition to our experiments on commercial hAMSCs, we will obtain primary hAMSCs intraoperatively from human patients and test their anti-tumor efficacy to maximize the clinical translatability of this study. The results of this stuy will demonstrate whether hAMSCs can provide a treatment that is safe and effective for not only patients with GBM, but many types of primary and metastatic brain cancers. The results of this study may likely lead to clinical trials, with a revolutionary new way of treating patients with brin cancer.

描述（由应用提供）：胶质母细胞瘤（GBM）是成年人中最常见的原发性脑肿瘤，占所有原发性脑肿瘤的20％。 GBM的中位生存率仅为14.6个月的dospite当前最佳治疗实践，包括手术和化学放疗。这种发病率和死亡率的一个重要原因是GBM侵入正常脑实质的能力，使局部治疗无效。为了使治疗有效，需要针对这些入侵的细胞。一种有望的方法涉及使用间充质干细胞（MSC），这是我们组和其他人发现的，最好迁移到癌细胞。此外，可以设计MSC来合成和释放抗肿瘤蛋白，例如骨形态蛋白4（BMP4），已发现会影响脑肿瘤启动细胞（BTICS）。 MSC可以从骨髓（BM-MSC）和脂肪组织（AMSC）获得。 BM-MSC的使用受到限制，因为这些细胞难以获得，离体增殖能力有限，并且随着供体年龄的增加而有效性降低。因此，AMSC可能是一个更好的选择。在这笔赠款中，我们建议使用一种新的人类MSC来源，来自患者的脂肪组织，并基因修改这些细胞以分泌BMP4以治疗GBM。与BM-MSC相反，人类AMSC（HAMSC）提供了具有治疗可比的细胞来源，该来源更容易访问，并且具有更好的外体扩展性。我们的总体假设是，表达BMP4与可调放疗的病毒修饰的HAMSC构成了针对颅内GBM的有效治疗方法。为了实现这些目标，我们将追求以下具体目的：（目标1）确定肿瘤向状，内皮粘附，血脑屏障交叉能力以及病毒改性的BMP4分泌bmp4的抗脱脂瘤反应在体外hamscs intelly Hamscs和我们提出了与新鲜提取的组织（我们的提议）（我们提出的）（我们都在接受新鲜的hamscs（我们）。（AIM 2）确定在体内鼠模型中，与人类GBM上有针对性的放射治疗结合了病毒修饰的BMP4分泌HAMSC的安全性和有效性。该提案中要在体外和体内使用的技术是由我们的团队和我们的合作者进一步描述的。体外研究将使用微流体和纳米局技术领域的新进步进行。体内研究将采用哺乳动物的Xenographic模型，该模型植入人类BTIC衍生的GBM，该模型最能概括人类GBM。此外，我们将使用小型动物辐射研究平台（SARRP），这是一种由我们的团队和合作者开发和使用的新型装置，它允许将靶向辐射疗法的靶向光束传递到类似于人类共聚焦束治疗的肿瘤含量小鼠。 SARRP能够以0.2 mm的精度聚焦辐射束，从而在小鼠的尺度上为人类重现放射疗法。除了我们对商业HAMSC的实验外，我们还将从人类患者内术中获得原发性HAMSC，并测试其抗肿瘤有效性，以最大程度地提高这项研究的临床转换性。这种Stuy的结果将证明HAMSC是否可以提供不仅对GBM患者，而且对许多类型的原发性和转移性脑癌的治疗方法提供安全有效的治疗方法。这项研究的结果可能会导致临床试验，并采用革命性的治疗脑癌患者的新方法。