This study will investigate the effect of neoadjuvant metformin therapy in the inhibition of growth and proliferation of prostate cancer cells prior to radical prostatectomy.
Prostate cancer is the most commonly diagnosed malignancy in men in North America, with close to a quarter of a million cases diagnosed in 2007 alone (Joshua et al, 2007). The activation of the PTEN/ AKT pathway is thought to be of importance in prostatic carcinogenesis as it correlates with a poor prognosis (Yoshimoto et al, 2007) (Schmitz et al, 2007). Components of this cellular pathway have pleiotropic targets including the mTOR complex. In model systems, tumours exhibiting activation of PI3K/AKT kinase are sensitive to mTOR inhibitors. Metformin (1,1-dimethylbiguanide hydrochloride) belongs to the biguanide class of oral hypoglycaemic agents and is a commonly prescribed medication for a number of conditions. It is the first-line drug of choice for the treatment of type 2 diabetes. Its mechanism of action is thought to be the primary inhibition of hepatic glucose output through inhibition of gluconeogenesis. Subsequently, metformin causes a decline in the circulating insulin level (Hundal et al, 2000). Metformin causes inhibition of the mTOR complex. The mTOR complex is primarily inhibited through activation of AMPK (a component of the PTEN/AKT pathway). Metformin causes reduced hepatic glucose output leading to decreased levels of circulating insulin which causes the secondary inhibition of the mTOR complex. Metformin has also been shown to inhibit cyclin D1 expression and retinoblastoma protein (Rb) phosphorylation. Inhibition of Cyclin D1 and Rb phosphorylation cause inhibition of G1/S phase transition of the cell cycle. This results in the inhibition of cell proliferation (Matsushime et al, 1994). This study will investigate the effect of neoadjuvant metformin therapy in the inhibition of growth and proliferation of prostate cancer cells prior to radical prostatectomy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
500mg tablets t.i.d. for 4-12 weeks prior to Radical Prostatectomy
University Health Network
Toronto, Ontario, Canada
Difference in Ki67 staining
Time frame: Pre-Surgery
Other immunohistochemical assays: IR, IGF-1R, p70S6K, AMPK, MVD, Cleaved caspase 3, PTEN, c-Myc
Time frame: Pre-Surgery
Differences in measures of insulin resistance: waist/hip ratio, fasting blood glucose, post-prandial blood glucose, weight
Time frame: Pre-Surgery, Post-Surgery
Differences in PSA levels
Time frame: Pre-Surgery, Post-Surgery
Incidence of adverse events, serious adverse events, and grade 3-4 toxicities
Time frame: Pre-Surgery, Post-Surgery
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