Despite significant initial responses to therapy, treatment resistance remains the hallmark of metastatic disease. Our group is a multi-disciplinary team focusing on studying treatment resistance in advanced urological cancers. Since starting up five years ago, we have been integrating solid tumour and circulating cell-free DNA genomics, transcriptomics and epigenomics with functional studies to track tumour clone dynamics in patients progressing through multiple lines of treatment. Using this approach, we aim to identify cancer vulnerabilities to be exploited therapeutically and design clinical trials of biomarker-directed strategies for rational treatment selection and sequencing.
Some of our recent work used plasma DNA to track androgen receptor (AR) gene aberrations in advanced prostate cancer patients and identified a strong association between plasma AR aberrations and resistance to second-line hormonal treatments. Our group have also identified a plasma DNA methylation signature associated with the presence of circulating prostate cancer DNA. These findings and others have led to the initiation of the PARADIGM study (NCT04067713, Plasma Analysis for Response Assessment and to Direct the manaGement of Metastatic prostate cancer) evaluating if the detection of circulating prostate cancer DNA is associated with treatment response.
We have integrated our plasma DNA analysis into multiple clinical trials, including the national platform STAMPEDE trial for men starting androgen deprivation therapy. This complements our work leading the genomic analysis of solid tumour material from this trial as part of the STRATOSPHERE consortium, aiming to characterise hormone-naïve prostate cancer from men with metastatic prostate cancer.
We are also part of multiple ongoing international efforts working to implement plasma analysis into clinical practice. In the PCF-SELECT international consortium we are developing a clinically useful plasma DNA targeted NGS assay and in the CRUK Accelerator Award funded PRIME project we are working to integrate all that we have learnt during these past years into a plasma based multimodal test for prostate cancer.
Our group receives support from Cancer Research UK (CRUK), Prostate Cancer UK (PCUK), The European Union (EU), The Medical Research Council (MRC), the Prostate Cancer Foundation (PCF) and the Prostate Cancer Research Charity (PCRC), and our work wouldn’t be possible without the support of our patients and their families.