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

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