Researchers from the School of Biological Sciences developed the DNAzymes technology to help men with advanced (stage 4 or 3) prostate cancer that require effective treatment in circumstances where current therapies would be expected to fail succeed by providing novel method to inhibit therapy resistant disease
DNAzymes are short single stranded pieces of DNA with catalytic activity. DNAzymes do not require cellular machinery to cleave their target RNA. Ribonucleic acid or RNA is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes.
DNAzymes have binding arms allowing selectivity for their chosen target and a catalytic core that cleaves the RNA. DNAzymes are optimised using a number of parameters to ensure cleavage efficiency.
Prostate cancer is the most common cancer diagnosis in men and is the third leading cause of cancer-related death in the UK. Current therapeutic procedures involve surgery often coupled with radiation therapy and in advanced cancerous stages, hormone therapy and chemotherapy.
Prostate cancer is associated with alterations in Androgen Receptor functions. The Androgen Receptor signalling pathway is a fundamental process in the growth of many cancers and in particular prostate cancer. Current methods of treating this type of cancer take advantage of this androgen dependence by disrupting the signalling pathway to prevent tumour growth.
Although initially successful in the majority of patients, these therapies invariably fail and the tumours progress to an aggressive therapy resistant stage, termed castrate resistant prostate cancer. Importantly, Androgen Receptor signalling continues to drive tumour growth, due to e.g. receptor mutations or alternative splicing events, and therefore remains a therapeutic target for the disease.
There were around 46,700 new cases of prostate cancer in the UK in 2014, that’s 130 cases diagnosed every day making prostate cancer the second most common cancer in the UK. There were 11,300 deaths caused by prostate cancer in the UK in 2014, 92,300 deaths in Europe and 307,000 worldwide in 2012. The global prostate cancer therapeutics market was valued between $5 billion to $9 billion in 2016 according to different reports.
DNAzymes have been designed to target the Androgen Receptor and to be active in circumstances where current therapies would be predicted to fail (e.g. Androgen Receptor splice variants or mutations). DNAzymes have been identified that successfully cleave their target mRNA with high efficiency.
(a) Schematic summarising how DNAzymes work.
(b) Cleavage reactions were performed and % cleavage of the target RNA quantified.
Our lead DNAzymes show more than 98% activity in cleaving target RNA. Cleavage of target RNA leads to down-regulation of androgen receptor protein levels, which in turn reduces prostate cancer proliferation.