The Effects of Metformin on the mTORC Pathway in Prostate Cancer
Michelle R Downes, Joan Sweet, Vanessa Zannella, Barbara Bowes, Marianne Koritzinsky, Andrew J Evans, John Trachtenberg, Michael Jewett, Antonio Finelli, Neil Fleshner, Michael Pollak, Anthony M Joshua. University Health Network, Toronto, ON, Canada; Princess Margaret Hospital, Toronto, ON, Canada; Ontario Cancer Institute, Toronto, ON, Canada; Jewish General Hospital, Montreal, QC, Canada
Background: Biguanides, including metformin, have been used in the management of type 2 diabetes for decades. Epidemiological studies report reduced cancer incidence and mortality rates in diabetic patients receiving metformin. Animal studies suggest hyperinsulinaemia increases the growth of prostate cancer xenografts via the insulin receptor and additionally, insulin is known to stimulate the androgen signalling pathway. Metformin activates AMPK upstream of the mammalian target of rapamycin complex (mTORC), thus inhibiting downstream signalling and protein synthesis. It may also directly target mTORC independently of AMPK. The aim of the study was to investigate whether neoadjuvant metformin administration in a cohort of non-diabetic patients would result in identifiable changes in protein expression of known components of the mTORC signalling pathway.
Design: Non diabetic patients (n=24) with Gleason score 7/10 prostate cancer on core biopsy (minimal inclusion criteria: 30% involvement of one core), received metformin for 4-12 weeks prior to radical prostatectomy. Sections from the prostatectomy specimen were chosen to correlate with the anatomical location of their biopsy proven tumour. A single case (n=1) was excluded due to insufficient tumour for immunohistochemical (IHC) studies and two patients (n=2) withdrew. IHC for Ki-67, P-ACC, P-AMPK, P-4EBP1, p53 and ERG was performed on the biopsy and corresponding tumour focus from the radical prostatectomy. An H-score was manually assigned for P-ACC, P-AMPK and P-4EBP1. A computational Ki-67 analysis was performed with the Aperio nuclear positivity algorithm. p53 and ERG IHC was manually assessed as either positive or negative.
Results: Analysis of P-4EBP1 has shown a significant decrease in staining (p<0.001). No significant decrease in P-AMPK or P-ACC has been identified. 18/22 cases of Ki-67 have been analysed and demonstrate a 28.7% relative decrease (p=0.015). Statistical analysis of p53 and ERG is in progress.
Conclusions: This data suggests that neoadjuvant metformin prior to radical prostatectomy results in altered protein expression of components of the mTORC signalling pathway. This finding may lead to an alternative treatment protocol for prostate cancer.
Category: Genitourinary (including renal tumors)
Wednesday, March 6, 2013 1:00 PM
Poster Session VI # 139, Wednesday Afternoon