Abstract 1799: Utilizing metformin to enhance the efficacy of androgen deprivation therapy in the treatment of prostate cancer

Abstract

Abstract The incidence of prostate cancer varies dramatically by geographic location, with developed countries exhibiting significantly higher levels of disease. Some attribute this to the ‘Westernized lifestyle’ of high energy diets coupled with lack of physical activity and consequent obesity. Rising obesity levels have been mirrored by increased diagnoses of non-insulin dependent diabetes (NIDDM). Whilst evidence for a causal association between obesity or NIDDM, and prostate cancer is mixed, clear evidence exists that obese prostate cancer sufferers have higher levels of prostate cancer-specific mortality. This may be due to obesity or diabetes-induced hyperinsulinemia, causing upregulated pro-proliferative insulin/insulin-like growth factor signaling. Our group has previously reported the association between diet-induced hyperinsulinemia and enhanced prostate cancer tumor growth in a murine xenograft model. Prostate cancer treatment varies depending on the stage/grade of the presenting disease. However, androgen ablation therapy remains the treatment of choice for advanced disease. Metformin (an oral biguanide used to treat NIDDM) has been shown to possess anti-neoplastic properties in vitro and in vivo. Studies have also shown that metformin treated diabetics experience less cancer diagnoses and/or prostate cancer-specific mortality. We assessed the potential additive benefit of androgen ablation therapy (bicalutamide) in combination with metformin. Using MTT and clonogenic assays we assessed the effect of bicalutamide and/or metformin on cell proliferation rates in LNCaP, PC3, DU145 and PC3AR2 prostate cancer cell lines. Exposing the cell lines to micromolar concentrations of bicalutamide or millimolar concentrations of metformin resulted in significant dose-dependent reductions in cellular proliferation (p<0.0001). Combined treatment with bicalutamide and metformin caused a further 10-fold reduction in cell proliferation. This effect was pronounced in cell lines expressing functional androgen receptors. Combining bicalutamide and metformin significantly reduces prostate cancer cell proliferation rates, further than monotherapy alone. These preliminary results are being further evaluated to determine whether this positive interaction is additive or synergistic. We are also assessing the combination regimen in vivo using a murine xenograft model and are performing mechanistic studies to determine how bicalutamide and metformin interact. This combination regimen may potentially improve prostate-cancer specific survival via the direct anti-neoplastic properties described above. In addition, although not investigated here, metformin, within the combination treatment regimen may improve overall survival rates by reducing the risk of anti-androgen induced metabolic syndrome, and its consequent cardiovascular related mortality. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1799.