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

耐药性是大多数抗癌治疗的主要障碍。一些临床研究已经描述了随着时间的推移，针对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。由于肿瘤血管生成是由多种途径控制的，抗血管生成治疗的一个难点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），这些因子绕过VEGF，使肿瘤对抗VEGF治疗难以耐受。虽然靶向VEGF通路具有巨大的治疗潜力，但对这些通路抑制的耐药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抗vegf治疗的潜在细胞和分子机制。主要假设是，诱导其他独立于VEGF的促血管生成信号是肿瘤耐药发生的主要机制，并与肿瘤微环境缺氧有关。应用创新的方法来研究这种重要的关系，可以极大地扩展我们对肿瘤对抗vegf药物的旁路机制的有限理解，并为选择多靶向药物来对抗由替代促血管生成信号介导的这种耐药机制提供理论依据。这一目标将通过以下具体目标来实现：1)确定基质-肿瘤共培养中VEGF和VEGF独立的促血管生成信号转导之间的串扰通路；2)评价基质细胞在抗vegf治疗诱导的缺氧中挽救肿瘤的作用；3)利用异种移植物模型确定抗vegf治疗的体内耐药特征。通过这些实验，我们将确定潜在的靶向耐药途径，并验证体外和体内临床前模型，以确定对靶向药物的耐药性，从而为抗vegf治疗难治性肿瘤的未来治疗策略设计提供见解。

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.