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

随着癌症进展对治疗的反应，癌细胞中的基因改变逐渐发生变化。需要经常监测它们，以便在不同的疾病进展时间点选择最佳治疗方案。这实际上很难使用组织活检，这是目前常规的癌症诊断方法，由于其侵入性和成本。循环肿瘤细胞(CTC)是指从原发肿瘤脱落到循环中，并被带到远处形成转移的细胞。CTC分析只需要一份易于重复的血液样本，允许在疾病进展和治疗期间进行频繁的分子/基因分析，以经济高效、微创和及时的方式选择最佳治疗方法。自20世纪40年代以来，雄激素恶化疗法(ADT)一直被用于治疗局部晚期和转移性激素敏感型前列腺癌(MHSPC)。ADT可使90%以上的病例缓解，然而，2-3年后，该病将不可避免地演变为去势抵抗型前列腺癌(CRPC)，并对进一步的激素消融无效。2004年，化疗药物多西他赛联合泼尼松被美国食品和药物管理局(FDA)批准为CRPC的一线治疗药物。此外，三个第三阶段临床试验的最新结果显示，当ADT与多西紫杉醇联合作为一线治疗时，晚期mHSPC患者的OS显著受益。然而，由于先天或获得性耐药，只有一半的患者对多西紫杉醇有反应，这是一个重大的临床问题，因为目前还没有治疗多西紫杉醇耐药的CRPC。在这个项目中，我们将使用我们的新技术评估CTC分析在前列腺癌患者治疗分层/监测中的潜力。我们将对在巴茨医院接受多西紫杉醇治疗的患者分离的CTCs进行数量计数和遗传/分子分析(在患者同意的情况下)。这两个患者队列是：1。新诊断的晚期癌症患者，用ATD和多西紫杉醇治疗。2.慢性前列腺癌患者单用多西他赛治疗。在治疗前、治疗2周期前、治疗5周期前和治疗6个周期结束后采集血样。将使用Parsortix(ANGE，合作工业伙伴)分离四氯化碳，并进行数量计数和下游分子分析。CTC计数和基因表达的变化将被分析，并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基因变化，这些变化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，我们预计可以对前列腺癌患者进行频繁的CTC血液检测，以指导治疗改进，以获得最佳结果。这些对CTC的遗传分析也可能有助于我们理解多西紫杉醇耐药的分子机制。技能优先调整：先进治疗学、数量生物学

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