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

随着癌症对治疗的反应，癌细胞中的基因改变会随着癌症的进展而逐渐改变。他们需要经常监测，以便在不同的疾病进展时间点选择最佳治疗方法。由于组织活检的侵入性和成本，目前组织活检是常规的癌症诊断方法，但实际上很难做到这一点。循环肿瘤细胞（ctc）是从原发肿瘤转移到循环系统，并被携带到远处形成转移的细胞。CTC分析只需要一个血液样本，容易重复，允许在疾病进展和治疗期间频繁的分子/遗传分析，以经济、微创和及时的方式选择最佳治疗。自20世纪40年代以来，雄激素降解疗法（ADT）已被用于局部晚期和转移性激素敏感性前列腺癌（mHSPC）的治疗。ADT在90%以上的病例中引起缓解，但在2-3年后，该疾病不可避免地演变为去势抵抗性前列腺癌（CRPC），并且对进一步的激素消融变得难治。2004年，美国食品和药物管理局（FDA）批准化疗药物多西他赛联合强的松作为CRPC的一线治疗药物。此外，最近三项III期临床试验的结果显示，当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，由于固有或获得性耐药，只有一半的患者对多西他赛有反应，这是一个重大的临床问题，因为目前尚无针对多西他赛耐药CRPC的治疗方法。在这个项目中，我们将利用我们的新技术评估使用CTC分析的好处，因为它们有可能分层/监测前列腺癌患者的治疗。我们将对在Barts医院接受多西紫杉醇治疗的患者分离的ctc进行计数和遗传/分子分析（征得患者同意）。这两组患者分别是：1。ATD联合多西紫杉醇治疗新诊断的晚期癌症患者。2. 多西紫杉醇单独治疗CRPC患者。在治疗前、第2周期前、第5周期前和治疗完成6个周期后采集血样。ctc将使用Parsortix （ANGLE，合作的工业伙伴）进行分离，并进行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联系起来。我们希望确定与化疗反应相关的某些遗传改变，未来可以在治疗前和/或治疗期间的血液样本中确定，从而为每位患者提供所需的最佳治疗。随着这项研究的成功，我们期望前列腺癌患者可以经常监测CTC血液检查，以指导治疗调整，以获得最佳结果。这些遗传分析也有助于我们了解多西他赛耐药的分子机制。技能优先排序：高级治疗学，定量生物学

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