Abstract 3523: Targeting FOXM1 in pancreatic cancer

Pancreatic cancer (PC) is one of the deadliest malignancies of our time. The limited treatment options necessitate the identification of novel therapeutic targets and strategies. FOXM1 is overexpressed in many different human malignancies including PC and it contributes to multiple aspects of tumorigenesis. In addition, emerging data indicates that FOXM1 might contribute to drug resistance. Therefore, we hypothesized that targeting FOXM1 could interfere with PC development and sensitize pancreatic tumor cells to apoptosis induced by anticancer drugs. The goal of this study was to explore the potential of targeting FOXM1 in pancreatic cancer. First, we examined how FOXM1 knockdown by RNA interference (RNAi) may affect the tumorigenecity of MIA PaCa-2 highly aggressive human pancreatic cancer cell line. Depletion of FOXM1 inhibited the colony forming ability of the PC cells in anchorage-dependent and independent conditions. In addition, we found that FOXM1 knockdown strongly impaired the ability of PC cells to induce xenograft tumors in nude mice. Second, we explored the potential anticancer properties of Simoycin A and thiostrepton and other known FOXM1/proteasome inhibitors against PC in culture and in xenograft mouse models. We demonstrate that FOXM1/proteasome inhibitors efficiently inhibited the growth of multiple human PC cell lines in low micromolar concentrations, repressed the protein expression of FOXM1 and also induced potent cell death in PC cells. In addition, we show that FOXM1/proteasome inhibitors reduced tumor growth in vivo, in a xenograft model of PC. Third, recent emerging data suggest that targeting cancer by combination treatment offers a more efficient therapeutic approach. Combination treatment improves efficacy, lowers the dose needed for effect and also overcomes drug resistance. Consequently, we evaluated targeting FOXM1 in combination with DNA-damage and oxidative stress. We found that FOXM1 knockdown by RNAi or suppression by proteasome inhibitors inhibits long-term survival and sensitizes PC cells to cell death induced by DNA-damage and by oxidative stress. In addition, we found that ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors by direct interaction with them and it is the first compound that acts as inhibitor of proteasome inhibitors. Overall, our findings suggest that targeting FOXM1 alone or in combination with DNA-damage or oxidative stress could offer an effective therapeutic approach against PC. According to our data, administration of proteasome inhibitors in combination with ROS inducers/DNA damaging agents represents an innovative treatment strategy, which would utilize integral properties of cancer cells in order to specifically eliminate them. Further work is needed to verify that our preclinical results should warrant clinical trials. Citation Format: Marianna Halasi, Andrei L. Gartel. Targeting FOXM1 in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3523. doi:10.1158/1538-7445.AM2014-3523