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TUMOR RESISTANCE MECHANISMS TO ANTI-VEGF THERAPY IN PROSTATE CANCER (Sukyung Woo)

前列腺癌抗 VEGF 治疗的肿瘤抵抗机制 (Sukyung Woo)

基本信息

批准号：
8723256
负责人：
Sukyung Woo
金额：
$ 21.3万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8723256
关键词：
Angiogenesis Inhibition Angiogenesis Inhibitors Angiogenic Factor Bypass Cancer Etiology Castration Cessation of life Clinical Research Clinical assessments Coculture Techniques Data Development Disease Drug resistance Event Evolution Fibroblast Growth Factor Future Goals Hepatocyte Growth Factor Human Hypoxia In Vitro Malignant Neoplasms Malignant neoplasm of prostate Mediating Mentors Modality Modeling Molecular Morbidity - disease rate Oklahoma Pathway interactions Patients Platelet-Derived Growth Factor Play Pre-Clinical Model Prostate Cancer therapy Public Health Refractory Resistance Role Sampling Signal Pathway Signal Transduction Staging Stromal Cells Symptoms Therapeutic Time Translational Research Tumor Angiogenesis Tumor Angiogenic Factor United States Up-Regulation Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Xenograft Model Xenograft procedure advanced disease aging population angiogenesis anti-cancer therapeutic anticancer research base bevacizumab chemotherapy clinical practice combinatorial cytokine design docetaxel hormone therapy in vivo innovation insight men palliation pro-hepatocyte growth factor research and development research study resistance mechanism response tumor tumor microenvironment tumor progression tumorigenic

项目摘要

Drug resistance is a major obstacle of most of anticancer therapeutics. Several clinical studies have described reduced response to antiangiogenic therapy targeting VEGF pathway over time followed by regrowth of treated tumors. As tumor angiogenesis is governed by multiple pathways, one difficulty in antiangiogenic therapy is the selective up-regulation of other pro-angiogenic factors, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), which bypasses VEGF and renders tumors refractory to anti-VEGF therapy. Although targeting VEGF pathway carries an enormous therapeutic potential, it is very likely that resistance to inhibition of these pathways will emerge as a potential obstacle to be overcome in clinical practice. The main goal of this study is to elucidate potential cellular and molecular mechanisms mediating tumor resistance to anti-VEGF therapy. The main hypothesis is that induction of other proangiogenic signaling, independent of VEGF, is the leading mechanism of development of tumor resistance and is associated with hypoxia in tumor microenvironment. Application of the innovative approaches to study this significant relationship could greatly expand our limited understanding of bypass mechanisms of tumors to anti-VEGF agents and provide rationale to select multi-targeting agents that counteract such mechanisms of resistance mediated by alternative proangiogenic signaling. This goal will be accomplished through the following Specific Aims: 1) Identify the pathways involved in crosstalk between VEGF and VEGF-independent proangiogenic signaling transduction in stroma-tumor co-cultures; 2) Evaluate the roles of stromal cells rescuing tumors from the anti-VEGF therapy-induced hypoxia; and 3) Identify in vivo resistance signatures to anti-VEGF treatments using xenograft model. From these experiments, we will identify potential pathways of resistance to be targeted, and to validate in vitro and in vivo pre-clinical models for identifying resistance to targeted agents, thereby proving insight into the design of future therapeutic strategies for tumors refractory to anti-VEGF therapy.

耐药性是大多数抗癌药物治疗的主要障碍。几项临床研究已经描述了随着时间的推移，对靶向VEGF途径的抗血管生成治疗的反应降低，随后治疗的肿瘤再生长。由于肿瘤血管生成受多种途径控制，抗血管生成治疗的一个困难是选择性上调其他促血管生成因子，包括血小板衍生生长因子（PDGF）、成纤维细胞生长因子（FGF）和肝细胞生长因子（HGF），其绕过VEGF并使肿瘤对抗VEGF治疗难治。尽管靶向VEGF通路具有巨大的治疗潜力，但对这些通路的抑制的抗性很可能成为临床实践中需要克服的潜在障碍。本研究的主要目的是阐明介导肿瘤对抗VEGF治疗耐药的潜在细胞和分子机制。主要假设是，诱导其他促血管生成信号传导，独立于VEGF，是肿瘤耐药性发展的主要机制，并与肿瘤微环境中的缺氧有关。应用创新的方法来研究这种重要的关系可以大大扩展我们对肿瘤旁路机制对抗VEGF药物的有限理解，并为选择多靶向药物提供理论基础，这些药物可以抵消由替代性促血管生成信号传导介导的耐药机制。这一目标将通过以下具体目标来实现：1）鉴定在基质-肿瘤共培养物中VEGF和VEGF非依赖性促血管生成信号转导之间的串扰所涉及的途径; 2）评价基质细胞从抗VEGF治疗诱导的缺氧中拯救肿瘤的作用;和3）使用异种移植模型鉴定抗VEGF治疗的体内抗性特征。从这些实验中，我们将确定潜在的耐药途径作为目标，并验证体外和体内临床前模型，以确定耐药靶向药物，从而证明洞察未来的治疗策略的设计肿瘤难治性抗VEGF治疗。