New 3D tumor models to rapidly test drugs for brain cancer therapy

新的 3D 肿瘤模型可快速测试脑癌治疗药物

基本信息

批准号：
8577052
负责人：
Miqin Zhang
金额：
$ 26.68万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2013-09-23 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577052
关键词：
Alginates Animal Model Biochemical Brain Neoplasms Cancerous Cell Count Cell Culture Techniques Cell Line Cells Chitosan Clinic Clinical Clinical Research Complex Cues Drug Costs Drug Kinetics Drug resistance Environment Environmental Risk Factor Extracellular Matrix Failure Genes Genetically Engineered Mouse Glioblastoma Glycosaminoglycans Human Human Cell Line Hypoxia Implant In Vitro Malignant Neoplasms Malignant neoplasm of brain Measures Mechanics Medical Methods Modeling Molecular Mus Nude Mice Patients Pharmaceutical Preparations Pharmacodynamics Phenotype Polymers Population Property Proxy Recurrence Relapse Research Research Personnel Resected Resistance Role Signal Transduction Specimen Structure System Testing Therapeutic Time Tissues Tumor Debulking Ursidae Family Xenograft procedure cancer cell cancer stem cell cancer therapy chemotherapy clinically relevant cost drug candidate drug development drug efficacy drug testing experience improved in vitro Model in vivo insight killings model design monolayer mouse model neoplastic cell outcome forecast public health relevance response scaffold self renewing cell self-renewal stem stem cell biology stem cell division stem cell therapy success therapy design therapy resistant tumor tumor initiation tumor microenvironment tumorigenic

项目摘要

DESCRIPTION (provided by applicant): There are currently no reliable in vitro models for brain tumors that predict drug response in humans. Clinical and research evidence indicates that a small population of cancer stem cells (CSCs) in tumors are primarily responsible for tumor initiation, progression, recurrence, and resistance to therapeutics. These cells have self- renewal capacity and unlimited proliferative potential. Although the targeting of CSCs represents a potential treatment approach, it is very challenging to isolate CSCs from human cell lines or primary cancer specimens since they represent such a small proportion of the entire tumor cell population. Existing methods for isolation and expansion of CSCs are ineffective, cumbersome, expensive, and unreliable. Here we aim to develop clinically relevant and predicative in vitro human tumor models for rapid and low-cost drug assessment for anti- CSC therapy. The proposed research uses an advanced 3D system made of complex scaffold of chitosan and alginate (CA), two naturally occurring polymers that bear proxy structure of glycosaminoglycans, a major component of native extracellular matrix (ECM). These CA scaffolds will serve as a niche to selectively renew and rapidly enrich CSCs. Once the preliminary system is established with optimal structural and mechanical properties that demonstrate CSC renewal, we plan to further improve and fine-tune our tumor model by introducing environmental factors such as biochemical coatings, hypoxia, and human stromal signaling factors into CA scaffolds for human glioblastoma culture. The established optimal CA scaffold model is expected to support the formation of CSC-enriched tumor spheroids from cell lines, primary GBM cells, and freshly resected GBM tissue. A small number of cells from the spheroids implanted in nude mice are expected to form orthotopic tumors and recapitulate GBM phenotypes. GBM is selected as the target tumor for the proposed study due to its fatality and dismal prognosis and our extensive clinical and research experience of GBM treatments. Specific aims of the proposed research are to: 1) determine the role of microstructure and mechanical properties of CA scaffolds on enrichment of CSCs and establish CSC-enriched tumor spheroid models; 2) investigate the role of microenvironmental cues of CA scaffolds in CSC enrichment, and tumorigenic capacities of CSC-enriched tumor spheroids; and 3) use the tumor models in drug tests for personalized cancer treatment and design of therapeutic strategies that specifically target CSCs for GBM therapy. This research will provide a new platform for effectively evaluating potential therapeutic drugs by providing a more accurate and stable tumor microenvironment, thus considerably shortening the time and reducing the cost of drug development. The developed tumor models will also allow researchers and medical practitioners to study molecular mechanisms that regulate self-renewal and differentiation of CSCs, and provide insight into the origin of tumor formation and resistance to treatments.

描述（由申请人提供）：目前尚无可靠的体外模型来预测人类药物反应。临床和研究证据表明，肿瘤中的癌症干细胞（CSC）少数主要是造成肿瘤的启动，进展，复发和对治疗剂的耐药性。这些细胞具有自我更新能力和无限的增殖潜力。尽管CSC的靶向代表了一种潜在的治疗方法，但将CSC与人类细胞系或原发性癌症标本中分离出来非常具有挑战性，因为它们代表了整个肿瘤细胞群中的一小部分。 CSC隔离和扩展的现有方法无效，繁琐，昂贵且不可靠。在这里，我们旨在开发与临床相关和谓词的体外人类肿瘤模型，以快速和低成本的药物评估进行抗CSC治疗。拟议的研究使用了由壳聚糖和藻酸盐（CA）的复杂支架制成的先进的3D系统，这是两个天然存在的聚合物，这些聚合物带有糖胺聚糖的代理结构，这是天然细胞外基质（ECM）的主要组成部分。这些CA支架将成为有选择性更新和快速富集CSC的利基市场。一旦建立了具有最佳结构和机械性能的初步系统，以证明CSC更新，我们计划通过将环境因素（例如生化涂层，缺氧和人类基质信号传导因素引入人类globloblastoma培养物的CA支架），以进一步改善和微调肿瘤模型。预计已建立的最佳CA支架模型将支持从细胞系，原代GBM细胞和新鲜切除的GBM组织中形成富含CSC的肿瘤球体。植入裸小鼠的球体中的少数细胞有望形成原位肿瘤并概括GBM表型。 GBM因其死亡和预后以及我们对GBM治疗的广泛临床和研究经验而被选为拟议研究的靶肿瘤。拟议的研究的具体目的是：1）确定CA支架在CSC富集中的微观结构和机械性能的作用，并建立富含CSC的肿瘤球体模型； 2）研究Ca支架的微环境线索在CSC富集中的作用，以及富含CSC的肿瘤球体的肿瘤能力； 3）在药物测试中使用肿瘤模型进行个性化的癌症治疗和设计，这些治疗策略专门针对GBM治疗的CSC。这项研究将为有效评估潜在治疗的新平台提供一个新的平台通过提供更准确，更稳定的肿瘤微环境，从而大大缩短时间并降低药物发育成本。开发的肿瘤模型还将允许研究人员和医生研究调节CSC自我更新和分化的分子机制，并洞悉肿瘤形成的起源和对治疗的耐药性。