Application of circulation tumour cell (CTC) analysis in docetaxel treatment response prediction/monitoring and investigation of resistance mechanisms

循环肿瘤细胞（CTC）分析在多西紫杉醇治疗反应预测/监测和耐药机制研究中的应用

• 批准号: 2009464
• 金额: --
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2009464
• 关键词: Application; circulation; tumour; cell; CTC

The genetic alterations in cancer cells change progressively as the cancer advances in response to therapy. They need to be frequently monitored to select the best treatment at different disease progression time-points. This is practically difficult using tissue biopsies, which are currently the routine cancer diagnosis method, due to their invasive nature and cost. Circulating tumour cells (CTCs) are those which have shed from the primary tumour into the circulation, and are carried to distant sites to form metastases. CTC analysis requires only a blood sample, which is easily repeated, allowing frequent molecular/genetic analysis during disease progression and treatment to select the best treatment in a cost-effective, minimally invasive and timely manner. Androgen depravation therapy (ADT) has been used in the management of locally advanced and metastatic hormone-sensitive prostate cancer (mHSPC) since the 1940s. ADT causes remission in more than 90% of cases, however after 2-3 years the disease will inevitably evolve into castration-resistant prostate cancer (CRPC) and become refractory to further hormonal ablation. In 2004, the chemotherapeutic agent Docetaxel, in combination with prednisone, was approved by the Food and Drug Administration (FDA) as the first-line treatment for CRPC. Further to this, recent results from three phase III clinical trials, show significant OS benefits to advanced mHSPC patients when ADT in combination with docetaxel is given as a first-line treatment. However only half of patients respond to docetaxel due to inherent or acquired resistance, which is a significant clinical problem as no therapy for docetaxel-resistant CRPC currently exists. In this project we will evaluate the benefit of using CTC analysis using our novel techniques for their potential to stratify/monitor prostate cancer patient treatment. We will perform number count and genetic/molecular analyses of CTCs isolated from patient treated with docetaxel at Barts Hospital (with patient consent). The two patient cohorts are: 1. newly diagnosed patients with advanced cancer treated with ATD and docetaxel. 2. CRPC patients treated with docetaxel alone. Blood samples will be collected before treatment, before 2nd cycle, before 5th cycle and after the completed 6 cycles of treatment. CTCs will be isolated using the Parsortix (ANGLE, collaborating industrial partner) and number count and downstream molecular analysis will be performed. Changes in CTC count and gene expression will be analysed and correlated with changed in clinical data. We expect to identify certain genetic alterations associated with chemotherapeutic response, which can be determined in the future in blood samples before and/or during treatment to inform the best treatment required for each patient. With the success of this study we expect that people with prostate cancer can be monitored frequently CTC blood tests to guide treatment modification for the best outcome. These genetic analyses of CTC may also help us to understand the molecular mechanisms of docetaxel resistance. Skills Priority Alignment: Advanced Therapeutics, Quantitative Biology

癌细胞中的遗传改变随着癌症对治疗的响应而进展而逐渐改变。他们需要经常监测，以在不同的疾病进展时间点选择最佳治疗。由于其侵入性和成本，使用组织活检实际上是困难的，组织活检是目前常规的癌症诊断方法。循环肿瘤细胞（CTC）是从原发性肿瘤脱落到循环中并被携带到远处部位以形成转移的那些细胞。CTC分析仅需血液样本，且易于重复，可在疾病进展和治疗过程中进行频繁的分子/遗传分析，以经济有效、微创和及时的方式选择最佳治疗方案。自20世纪40年代以来，雄激素恶化治疗（ADT）已用于治疗局部晚期和转移性前列腺癌（mHSPC）。ADT在超过90%的病例中引起缓解，然而，2-3年后，该疾病将不可避免地演变为去势抵抗性前列腺癌（CRPC），并且变得难以进一步激素消融。2004年，化疗药物多西他赛与泼尼松联合被美国食品药品监督管理局（FDA）批准为CRPC的一线治疗药物。此外，三项III期临床试验的近期结果显示，ADT联合多西他赛作为一线治疗时，晚期mHSPC患者的OS获益显著。然而，只有一半的患者由于先天性或获得性耐药而对多西他赛有反应，这是一个重要的临床问题，因为目前还不存在对多西他赛耐药的CRPC的治疗。在这个项目中，我们将评估使用CTC分析的好处，使用我们的新技术，其潜在的分层/监测前列腺癌患者的治疗。我们将对从Barts医院接受多西他赛治疗的患者中分离的CTC进行数量计数和遗传/分子分析（征得患者同意）。这两个患者队列是：1.接受ATD和多西他赛治疗的新诊断晚期癌症患者。2.接受多西他赛单药治疗的CRPC患者。将在治疗前、第2个周期前、第5个周期前和完成6个周期治疗后采集血样。将使用Parsortix（ANGLE，合作工业伙伴）分离CTC，并进行数量计数和下游分子分析。将分析CTC计数和基因表达的变化，并将其与临床数据的变化相关联。我们希望确定与化疗反应相关的某些遗传改变，这些遗传改变可以在未来在治疗前和/或治疗期间在血液样本中确定，以告知每个患者所需的最佳治疗。随着这项研究的成功，我们希望前列腺癌患者可以经常进行CTC血液检测，以指导治疗调整，以获得最佳结果。这些CTC的遗传分析也有助于我们了解多西他赛耐药的分子机制。技能优先调整：高级治疗学，定量生物学