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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.