Poster Presentation Lowy Cancer Symposium 2015

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death by cancer in Western countries, with very little improvement in survival rate over the last 40 years. Studies of PDAC tumour metabolism demonstrated that activation of specific glycolytic metabolic switches is of strong relevance [1]. We previously showed that the tumour metabolism inhibitor, PENAO, has strong in vitro and in vivo inhibitory activity against PDAC [2]. PENAO is a novel compound that targets mitochondrial function by inhibiting adenine nucleotide translocase. Given that mTOR signaling pathway, notably mTORC1, is critical for maintaining the glycolytic metabolism of pancreatic cancer cells [3], we combined PENAO with mTOR inhibitors in an attempt to further interfere with the proliferation of PDAC cells. PENAO was combined with three mTORC1 inhibitors (temsirolimus, everolimus and deforolimus) on four KRAS- mutated PDAC cell lines: MIA PaCa-2, AsPC-1, Panc-1 and Capan-1. Clear synergism of proliferation arrest measured by endpoint and real time proliferation assays (CI 0.59 - 0.82) was observed with all mTORC1 inhibitors. In a subcutaneous xenograft model of PDAC in mice, the combination of PENAO (0.25mg/kg/day) + everolimus (5mg/kg/day) was significantly more potent than single treatments at inhibiting tumour growth: growth delays were 4.2, 7.0 and 17.8 days for PENAO, everolimus and combination treatments, respectively. Tumour regression was observed when a stronger regimen was employed. This regression was consistent with a significant (2.1 fold, p<0.01) increase of necrotic regions in tumour sections from treated animals. There were no macroscopic signs of toxicity. Our findings demonstrate the potential of dual metabolism targeting in PDAC and warrants further investigations. Considering that both PENAO and mTOR inhibitors are currently being tested in clinical trials, a quick translation of this study to the clinic is realistic.