Cell based miRNA Expression as a Marker of Response to Bevacizumab (Avastin) Therapy of Patients with Colorectal Cancer

基于细胞的 miRNA 表达作为结直肠癌患者对贝伐单抗（阿瓦斯汀）治疗反应的标志

• 批准号: 244723291
• 负责人: Dr. Christin Gasch
• 金额: --
• 依托单位: Host Response to Cancer Lab (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/244723291?language=en
• 关键词: Cell; based; miRNA; Expression; Marker

The use of anti-angiogenic therapies, such as Bevacizumab (Avastin), which disrupt vascular endothelial growth factor (VEGF) signalling, has significantly extended the treatment options for patients with metastatic colorectal cancer (CRC). Nevertheless, a significant number of patients does not respond to this high-cost therapy; while others suffer from severe side effects such as impaired wound healing and an increased risk of stroke. These problems are compounded by the fact that there is as yet no clear marker for selecting patients that may benefit from anti-VEGF-therapy.Circulating tumor cells (CTCs), shed from the tumor, and circulating endothelial progenitor cells (CEPs), mobilized from the bone marrow (BM), are detected in the blood from cancer patients. Both populations of cells have been shown to be associated with tumor progression and resistance to a range of treatments, including anti-angiogenesis therapy. However, first studies investigating the predictive value of these cells in patients receiving Bevacizumab treatment have revealed controversial results. CTCs/CEPs as they are currently defined describe a complex cell population of cells with genetic and phenotypic heterogeneity. Currently, it is still unknown which properties enable individual CTCs to grow out to solid metastasis. Additionally, a subpopulation of CEPs that plays a crucial role in the development of therapy resistance has not yet been identified.Thus, the objective of my project is (i) to investigate the heterogeneity of CTCs/CEPs using miRNA expression profiling and (ii) to develop a panel of miRNAs that will be used in combination with single cell analysis of CTCs/CEPs to determine patients´ response to Bevacizumab treatment. The expression of miRNAs that are pathologically relevant in malignancy/tumor angiogenesis will be analyzed on single CEPs/CTCs using a combination of In Situ hybridization (ISH) and immunocytochemistry (ICC). Furthermore, CRC patients receiving Bevacizumab will be analyzed for CTCs/CEPs and cell based miRNA-expression at six different time points of treatment. The correlation to clinical data will lead to the identification of miRNAs expressed in CTCs/EPCs that are predictive of disease progression. These miRNAs and their function will be further studied using cell transfection experiments the results of which I believe will contribute to the development of novel strategies to overcome therapy resistance.

抗血管生成疗法的使用，如贝伐单抗（阿瓦斯汀），可破坏血管内皮生长因子（VEGF）信号，已显着扩大了转移性结直肠癌（CRC）患者的治疗选择。然而，大量患者对这种高成本疗法没有反应；而其他人则遭受严重的副作用，如伤口愈合受损和中风风险增加。这些问题由于目前还没有明确的标记来选择可能从抗vegf治疗中获益的患者而变得更加复杂。从肿瘤脱落的循环肿瘤细胞（ctc）和从骨髓中动员的循环内皮祖细胞（cep）在癌症患者的血液中被检测到。这两种细胞群已被证明与肿瘤进展和对一系列治疗的耐药性有关，包括抗血管生成治疗。然而，研究这些细胞在接受贝伐单抗治疗的患者中的预测价值的初步研究揭示了有争议的结果。目前所定义的ctc / cep描述了具有遗传和表型异质性的复杂细胞群。目前，仍不清楚是哪些特性使单个ctc生长出实体转移。此外，在治疗耐药发展中起关键作用的cep亚群尚未被确定。因此，我的项目目标是(i)使用miRNA表达谱研究ctc / cep的异质性，（ii）开发一组miRNA，将与ctc / cep的单细胞分析结合使用，以确定患者对贝伐单抗治疗的反应。利用原位杂交（ISH）和免疫细胞化学（ICC）的结合，在单个cceps / ctc上分析与恶性肿瘤/肿瘤血管生成病理相关的mirna的表达。此外，接受贝伐单抗治疗的结直肠癌患者将在六个不同的治疗时间点分析ctc / cep和基于细胞的mirna表达。与临床数据的相关性将导致ctc /EPCs中表达的mirna的鉴定，这些mirna可预测疾病进展。这些mirna及其功能将通过细胞转染实验进一步研究，我相信这些结果将有助于开发克服治疗耐药性的新策略。