IIP Studentship: Developing the next generation of predictive biomarkers in cancer

Abstract

A key driver in prostate cancer (PC) development and progression is aberrantly functional DNA repair mechanisms. DNA double strand breaks can be repaired by either homologous repair (HR) or error prone non-homologous end-joining (NHEJ), often resulting in genomic instability and resultant cellular transformation. Within 4-24% of PC patients, the SPOP protein is mutated, causing a loss of function and dysregulation in the multiple cellular processes it governs, including androgen receptor signalling and DNA repair. With SPOP found to be a key driver of HR, SPOP-mutant cells will have increased reliance on NHEJ, which, through inhibition of the key NHEJ protein DNA-PKcs, would potentially result in cell senescence or death due to inability to repair DNA damage. In vitro experiments conducted within this study indicate Cas9-mediated SPOP knock-out PC cells display elevated sensitivity to DNA-PKIs and are unable to repair ionising radiation- induced DNA damage providing evidence of a synthetic-lethality relationship. With current DNA-PKIs in early phase clinical trials and generally well tolerated, current data highlights a potential new sub-population in PC where patients with SPOP mutant tumours could show increased benefit of DNA-PKIs in combination with radiation therapy. Successful detection and stratification of PC into cohorts requiring sequentially more aggressive treatment represents a major clinical challenge; with current methods, such as PSA testing, lacking in sensitivity and selectivity. DNA-based nanotechnology is a rapidly advancing field utilising simple Watson-Crick base pairing fundamentals to develop new biosensors which holds the potential for rapid detection of multiple cancer biomarkers from non-invasive liquid biopsy samples with increased selectivity and sensitivity than current detection platforms. Through novel DNA probe designs targeting mRNA, microRNA and point mutations, such as those present in SPOP, experiments have been conducted which show great promise and attain the level of, if not surpass, the selectivity and sensitivity seen in by current PC detection methods.