Apart from cases of significant initial responses, treatment resistance remains the hallmark of metastatic disease.
Our multi-disciplinary team uses next-generation sequencing on tumours and plasma DNA and single-cell transcriptional profiling to look for clues to the causes of treatment resistance and follow these to develop clinically applicable biomarkers and improved therapeutic strategies. Repeated blood sampling is feasible in the majority of patients and analyses of plasma DNA allows tracking of genomic evolution to identify emergence of resistant clones as patients progress on a treatment and regression (in some cases) after treatment discontinuation.
Some of the team’s recent work, together with collaborators in Italy (Francesca Demichelis, University of Trento and Ugo de Giorgi, IRST, Meldola), used plasma DNA to track androgen receptor (AR) gene aberrations in advanced prostate cancer patients. These studies identified a strong association between plasma AR aberrations and resistance to second-line hormonal treatments, with selection of functionally-advantageous AR mutant clones in patients progressing on the steroid synthesis inhibitor abiraterone (see Plasma AR and abiraterone-resistant prostate cancer and Tumor clone dynamics in lethal prostate cancer, Science Translational Medicine).
Based on these data, we have been awarded funding from Prostate Cancer UK to develop plasma AR into a clinically applicable and qualified biomarker (the PARADIGM trial, Plasma AR DIrected management of Metastatic castration-resistant prostate cancer). We have also integrated plasma DNA analysis into multiple clinical trials, including the national platform STAMPEDE trial for men starting androgen deprivation therapy.
We are also expanding this strategy for the discovery of novel drivers of resistance in other cancer types. With our collaborators in the PCF-SELECT consortium we are developing a clinically useful plasma DNA targeted NGS assay.
Using optimised micro-fluidic approaches, we are using molecular bar coding of individual cells to obtain whole-transcriptome data at a cost of £2/cell and interrogate large population of single cells for treatment-resistant clones. The detection and characterisation of these populations is allowing us to generate hypotheses for improved treatment combinations and sequences to reduce the risk of relapse. Our team also leads genomic analyses in the STRATOSPHere consortium aiming to characterise hormone-naïve prostate cancer from men with metastatic prostate cancer starting long-term androgen deprivation therapy.
External peer-reviewed funding: Cancer Research UK, Prostate Cancer UK, Prostate Cancer Foundation, European Union, Irish Health Research Board, European Society of Medical Oncology, Medical Research Council.
We also receive funding, through collaborative agreements, from Janssen, Astellas, Innocrin and Arno.