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

Abstract

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.

Corpulence is the crucial factor: Association of testosterone and/or obesity with prostate cancer stage

“…leptin, IGF‐1), angiogenesis (e.g. IL‐6, IL‐8, vascular endothelial growth factor) and invasion (leptin, IL‐6) were shown to be altered in obese patients …”

“…First of all, a single assessment of adiposity and hormonal status does not reflect the prostate exposure to various bioactive factors throughout a lifespan or at least for the duration of malignant transformation. Another limitation was the failure to adjust for confounding factors, such as lifestyle, diet and dysregulated metabolic factors including hyperinsulinemia, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol and free fatty acids, which have been identified as risk factors of PC incidence and progression . Furthermore, the cohort of PC patients evaluated in the present trial consists of specially‐selected patients who might have been in a rather healthy condition with localized PC, because they all qualified to undergo radical prostatectomy.…”

“…IL-6, IL-8, vascular endothelial growth factor) and invasion (leptin, IL-6) were shown to be altered in obese patients. 24,25 Another important issue is the delayed PC detection in obese men as a result of an inverse relationship between BMI and serum PSA levels. Bañez et al reported that PSA serum values were 14% lower in obese (BMI 30-35 kg/m 2 ) and 18% lower in severely obese patients (BMI >35 kg/m 2 ), whereas the estimated total PSA mass was not affected, suggesting a hemodilution effect as a result of larger plasma volumes in obese men.…”

Synergistic Simvastatin and Metformin Combination Chemotherapy for Osseous Metastatic Castration-Resistant Prostate Cancer

“…Statins directly inhibit HMG-CoAR activity by binding its active site and are approved for treatment of hypercholesterolemia (13). Metformin (MET), an indirect activator of AMPKα, is FDA-approved for treatment of T2D (14). Use of lipophilic statins or MET has been associated with reduced risk of advanced prostate cancer and shown to reduce probability of biochemical failure, recurrence, and death from mCRPC, post surgery and radiotherapy (15–20).…”

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“…and oxidative stress [3–5]. These changes may contribute significantly to cancer progression via promoting tumor proliferation and survival, reduced tumor apoptosis, increased angiogenesis and invasion, de novo intratumoral steroidogenesis with transition to androgen independence.…”