A Phase II, Open Label Assessment of Neoadjuvant Intervention With Metformin Against Tumour Expression of Signaling
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Difference in Ki67 staining
Anthony Joshua, M.D.
University Health Network, Toronto
Canada: Health Canada