Elucidating how Dysbiosis, Senescence and Inflammatory Storms Impact Prostate Carcinogenesis and Treatment Resistance to Transform Care.

Prostate cancer is the commonest cancer in men, and one of the commonest killers from cancer in men. It is increasing in incidence globally with increasing numbers of deaths in continents previously thought to be less impacted by this disease including Asia and Africa. In the UK, 1 in 8 men will have prostate cancer in their lifetime (50,000/year) and a man will die from prostate cancer every 45-minutes. Interestingly, although prostate cancer remains a major cause of cancer mortality across Europe, its incidence and mortality are significantly higher in Northern Europe; this, and the increasing incidence in Asia and Africa, is likely due to dietary and other lifestyle changes. The Caribbean islands of Martinique and Guadalupe have the highest incidence of prostate cancer in the world, with this being associated with exposure to the carcinogenic chemical chlordecone used as an insecticide in banana plantations; chloredecone increases prostatic exposure to male androgen hormones supporting other accumulating evidence that these hormones are involved in carcinogenesis. Further understanding of how dietary changes impact prostate cancer risk, through changes in diet, gastrointestinal tract function and bacteria in our gastrointestinal tract need further study. It is envisioned that a better understanding of what causes prostate cancer will decrease suffering from this most common of male cancers.

Our work has helped transform understanding of aggressive prostate cancers, describing the DNA damage that causes these diseases in genomic sequencing studies, as well as identifying the different types of prostate cancers including cancers associated with inherited mutations of genes involved in DNA repair such as BRCA2 and ATM or more common gene variations (called single nucleotide polymorphisms or SNPs) that increase the signalling of the male hormone receptor. We have also used this information to develop multiple new treatments for prostate cancer including abiraterone, cabazitaxel, enzalutamide, olaparib as well as change guidelines on genetic testing of both normal DNA for inherited mutations as well as prostate cancer DNA for tumour mutations/alterations. Despite this, and men living longer than ever with these diseases, men are still dying every day from lethal prostate cancer and a better understanding of what causes these diseases is necessary to improve care and decrease suffering from these.

We have postulated that changes in androgen levels associated with diet induce inflammation in the prostate, that can rapidly become self-perpetuating and lead to damaged DNA in prostatic cells that will eventually lead to malignancies. We will study these processes in various models of prostate cancer, utilising the acquired information to improve the anti tumour activity of standard treatments such as radiotherapy and hormonal therapy while also dissecting the complex cellular interactions that fuel the development and growth of these cancers.

We envision that this research will transform our understanding of the way prostate cancer develops and grows, and lead to transformative strategies impacting prostate cancer prevention and treatment.

BACKGROUND: Prostate cancer (PCa) is the commonest male cancer in the UK, with 1 in 8 men developing PCa (50,000/year) and a man dying from PCa every 45-minutes in the UK. PCa is also increasing in incidence globally probably due to diet/lifestyle changes, including in Africa and Asia. We have transformed understanding of PCa biology, genetic risk, genomics, and care, developing molecular stratification and blood-based biomarkers. Despite this, PCa still causes major morbidity and mortality. Novel prevention and therapeutic strategies are urgently needed.

PRELIMINARY DATA: We have data supporting a model of prostate carcinogenesis that implicates self-perpetuating inflammatory storms resulting from cell senescence and induced by oncogenic insults generating oxidative stress, DNA damage at exposed chromatin including DNA repair genes and androgen receptor response elements. This process is accelerated by germline DNA repair defects and SNPs increasing AR signalling.

HYPOTHESES: We hypothesise that diet, GI dysmotility and dysbiosis drive prostate carcinogenesis and can impact outcomes to established treatments, at least in part by impacting paracrine intercellular relationships.

AIMS: 1) We will elucidate in PCa models how diet content (lipid; fibre), gut dysmotility and dysbiosis impact prostate epithelial cell oncogenic insults to drive senescence, SASP related inflammation, and fuel inflammatory storms that cause DNA damage, activate DNA repair and oncogenic events. 2) We will also determine how these impact outcomes from established treatments including radiotherapy, endocrine therapy, taxanes and PARP inhibition. 3) Finally, we will dissect putatively paracrine inter-cellular relationships between prostatic and inflammatory cells that fuel PCa development, growth and survival utilising immunocytochemistry, single nucleus RNAseq and co-culture studies.

IMPLICATIONS: We will develop novel, transformative, PCa prevention and treatment strategies.