New Players for Advanced Prostate Cancer and the Rationalisation of Insulin-Sensitising Medication

Obesity and type 2 diabetes are recognised risk factors for the development of some cancers and, increasingly, predict more aggressive disease, treatment failure, and cancer-specific mortality. Many factors may contribute to this clinical observation. Hyperinsulinaemia, dyslipidaemia, hypoxia, ER stress, and inflammation associated with expanded adipose tissue are thought to be among the main culprits driving malignant growth and cancer advancement. This observation has led to the proposal of the potential utility of “old players” for the treatment of type 2 diabetes and metabolic syndrome as new cancer adjuvant therapeutics. Androgen-regulated pathways drive proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen deprivation therapy (ADT) exploits this dependence to systemically treat advanced prostate cancer resulting in anticancer response and improvement of cancer symptoms. However, the initial therapeutic response from ADT eventually progresses to castrate resistant prostate cancer (CRPC) which is currently incurable. ADT rapidly induces hyperinsulinaemia which is associated with more rapid treatment failure. We discuss current observations of cancer in the context of obesity, diabetes, and insulin-lowering medication. We provide an update on current treatments for advanced prostate cancer and discuss whether metabolic dysfunction, developed during ADT, provides a unique therapeutic window for rapid translation of insulin-sensitising medication as combination therapy with antiandrogen targeting agents for the management of advanced prostate cancer. 1. Obesity, Type 2 Diabetes and Prostate Cancer 1.1. Obesity and Cancer Risk Worldwide rates of obesity have doubled in a generation with a global estimate of ~500 million obese adults (with an additional 1.5 billion overweight) being followed by a generation of 40 million overweight children [1]. In both industrialised and developing countries these staggering numbers pose a soaring economic and health care burden as a result of chronic comorbidities including increased rates of cardiovascular disease, hypertension, stroke, and type 2 diabetes (T2DM) [2]. Obesity is also a risk factor for a growing number of cancers. Retrospective observational studies and meta-analyses, using body mass index (BMI; mass (kg)/height (m2)) as a measure of adiposity, have demonstrated an increased risk of breast, ovarian, colorectal, bladder, kidney, and endometrial cancers with increasing BMI [3–6]. Similarly, obesity attributes a 12% increased risk of prostate cancer diagnosis [3]