CTCclinUT - clinical utility of CTCs in metastasized breast cancer patients enabled by diagnostic leukapheresis

CTCclinUT - 通过诊断性白细胞分离术实现 CTC 在转移性乳腺癌患者中的临床应用

• 批准号: 439913073
• 负责人: Professor Dr. Hans Neubauer, Ph.D.
• 金额: --
• 依托单位: Klinik für Frauenheilkunde und Geburtshilfe
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/439913073?language=en
• 关键词: CTCclinUT; clinical; utility; CTCs; metastasized

Over the last decades targeted therapy has become the preferred approach to treat breast cancer (BC). However, the predictive utility of the primary tumor to select a therapy is limited and obtaining serial biopsies of metastatic lesions is challenging. Thus, in order to manage BC the idea of deriving information on its molecular Achilles heel from liquid biopsies by analyzing e.g. circulating tumor cells (CTCs) is very intriguing. CTCs are shed into the blood by tumor tissue and are commonly considered as precursor cells for metastasis formation. The CTC count is a strong prognostic factor, which can be used to monitor treatment efficacy, but CTCs have not been implemented into clinical practice due to missing proof of their clinical utility to predict individualized, specific and successful treatment strategies. The main cause for this dilemma is the rarity of CTCs detected and isolated from blood, which is preventing both comparative basic analytic and pre-analytic CTC-research in order to uncover the different biology of CTCs. This, however, is absolutely needed in order to develop future individualized and CTC-based therapy decision. With the project presented here - CTCclinUt - we plan to overcome these challenges by performing longitudinal CTC-analyses of metastasized BC index patients who suffer from high CTC-numbers and who have undergone additional diagnostic leukapheresis (DLA) – a method pioneered in Duesseldorf to isolate tumor cells from a patient’s total blood volume. In combination with latest technologies for parallel high throughput molecular analyses this will enable us to investigate complex CTC populations for genomic mutations, gene copy number variations, and gene expression profiles on single cell level. In this way CTCclinUt will give us insights into the CTCs’ heterogeneous biology and their clonal evolution during disease and therapeutic intervention and will help us to understand resistance mechanisms activated during treatment history. The final aim will be to translate the CTCs’ molecular characteristics into optimized therapy regimen.

在过去的几十年里，靶向治疗已经成为治疗乳腺癌(BC)的首选方法。然而，原发肿瘤对选择治疗方法的预测作用是有限的，而获得转移灶的连续活检是具有挑战性的。因此，为了管理BC，通过分析循环肿瘤细胞(CTCs)等液体活检获得有关其分子阿喀琉斯跟的信息的想法非常耐人寻味。CTCs通过肿瘤组织进入血液，通常被认为是转移形成的前体细胞。CTC计数是一个很强的预后因子，可用于监测治疗效果，但由于缺乏临床实用价值的证据来预测个体化、特异性和成功的治疗策略，CTC尚未应用于临床实践。造成这一困境的主要原因是从血液中检测和分离的CTCs很少，这阻碍了为了揭示CTCs的不同生物学而进行的比较基础分析和分析前的CTC研究。然而，为了制定未来的个性化和基于CTC的治疗决策，这是绝对必要的。有了这里介绍的项目-CTCClinUt-我们计划通过对患有高CTC数并接受过额外诊断白细胞分离术(DLA)的转移性BC指数患者进行纵向CTC分析来克服这些挑战-DLA是Duesseldorf首创的一种从患者的总血量中分离肿瘤细胞的方法。与最新的并行高通量分子分析技术相结合，这将使我们能够在单细胞水平上研究复杂的CTC群体的基因组突变、基因拷贝数变异和基因表达谱。通过这种方式，CTClinUt将使我们深入了解CTCs的异质性生物学及其在疾病和治疗干预过程中的克隆进化，并将帮助我们了解治疗过程中激活的耐药机制。最终目标将是将CTCs的分子特征转化为优化的治疗方案。