Repurposing statins for precision prevention of PTEN- prostate cancer

Background: Prostate cancer is commonly diagnosed and accounts for one in seven male cancer deaths in the UK. Strikingly little is known about its aetiology, a significant barrier to prevention efforts.

Epidemiological data indicate that risk factor profiles vary by molecular tumour subgroup, providing an explanation as to why studies fail to observe associations with lifestyle factors when prostate tumours are grouped together as a whole.

In a large prospective study, we reported that statin use was associated with substantially reduced risk of PTEN- prostate cancer, but not PTEN-intact disease.

Our exploratory data from this study and our preliminary laboratory data identify endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) as a potential contributing mechanism.

Aims: To understand molecular mechanisms contributing to the epidemiological association between statins and lower risk of fatal and PTEN- prostate cancer, we will 1) Examine the association of statins with risk of PTEN- prostate cancer in a novel molecular epidemiology study, 2) Determine the effect of statins on ER stress and the UPR in a pre-malignant and malignant cell lines with population-relevant genetic backgrounds, and 3) Explore the UPR pathway in normal and tumour prostate tissue by pre-diagnosis statin use and PTEN status.

Methods: We will expand our UK population-representative case cohort study of fatal prostate cancer to test the association between pre-diagnosis statin use and PTEN status.

Pre-malignant and malignant prostate cell lines will be modified to introduce genetic alterations relevant to the human population, and the effect of treatment with physiologically relevant statin concentrations on the UPR pathway will be assessed at gene, protein and functional levels.

In complementary analysis, we will generate whole transcriptome data from normal and tumour prostate tissue within our novel case-cohort study to explore UPR activation in association with pre-diagnosis statin use.

How the results of this research will be used: Statins are low cost, safe and commonly prescribed drugs to reduce cardiovascular disease risk.

Yet, high cholesterol remains prevalent in the population for a variety of reasons including poor adherence by patients and reluctance to prescribe high-intensity statin doses by physicians.

Elucidating biological mechanisms contributing to reduced rates of PTEN- tumours in statin users could help justify their secondary use for prostate cancer prevention.

Improved uptake of optimal statin therapy among eligible men could have dual benefit, reducing the risk of both cardiovascular disease and fatal prostate cancer, two major causes of mortality in men.