In vivo testing of Mycophenolic acid (MPA) in primary pancreatic cancer (PaCa) xenografts
Authors: Preeti Shah, Antonio Jimeno, Belen Rubio-Viqueira, Xianfeng Zhang, George Cusatis, Curtis Chong, Piotr Kulesza, Arvind P. Pathak, Ming Zhao, Jun Liu, Manuel Hidalgo
Journal: Cancer Research (2007)

2213    Background:  Pancreatic cancer (PaCa) is an almost universally fatal disease, and new therapeutic alternatives are needed. Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) is a known inosine mono phosphate dehydrogenase inhibitor (IMPDH) and is clinically used as an immune-suppressive agent following organ transplantation. Preliminary studies from our group testing a panel of 2,000 non-antitumor approved agents evidenced that MPA had activity  in vitro  against PaCa cell lines. In this study we performed a preclinical study to determine pharmacodynamic (PD) markers and to explore the activity of MPA in  in vivo  models of PaCa.  Methods : MPA was tested in vitro against a panel of pancreatic cancer cell lines in the range of 0-10uM by MTT assay. In a novel patient derived PaCa xenograft model, we studied MPA  in vivo  in 6 xenografts derived directly from patient tumors. Combination therapy with gemcitabine plus MPA was done on selected, gemcitabine-resistant cases to evaluate the modulation in activity of the drugs. Mice were treated daily with 125mg/Kg MPA ip. The efficacy of treatment was measured by determining the tumor growth inhibition at 28 days. PD markers of MPA were assessed using western blotting and immunohistochemistry of target proteins. GTP pools in  in vitro  samples and pharmacokinetics of the MPA levels in mouse was done using HPLC-tandem mass spectrometry. Fine needle aspirate (FNA)-based ex vivo testing was conducted exposing acquired cells to MPA mimicking  in vitro  conditions.  Results : MPA confirmed  in vitro  antitumor activity in a broader panel of PaCa cell lines. Two cell lines showing differential response were selected for PD studies. In order to investigate the mechanism and the involvement of IMPDH inhibition in the effect mediated by MPA on those cell lines  in vitro , guanosine replenishment was done and the response was read using MTT. Nucleotidal GTP pools in the cells were taken as a marker of IMPDH inhibition and showed a decrease with increasing MPA dosage  in vitro . The cell lines also showed a decrease in VEGF suggesting a potential anti-angiogenic effect by MPA. Single-agent MPA treatment  in vivo  in 6 patient-derived xenografts showed differential efficacy, with two cases being sensitive and four being resistant.  Ex vivo  and pharmacodynamic testing was conducted to characterize the basis of those differences. A decrement in VEGF protein was observed  in vivo  and encouraging combination data was documented.  Conclusions:  MPA showed activity in a subset of PaCa direct xenografts, making it a candidate drug for further development in PaCa .  Pharmacodynamic studies suggest that this efficacy may at least be mediated by an antiangiogenic effect. Updated pharmacodynamic, pharmacokinetic and tumor permeability data using magnetic resonance imaging will be presented in the meeting.