Patients with advanced pancreatic cancer have a bleak prognosis, with a median survival time of <6 months. Pancreatic cancer is highly resistant to a broad spectrum of chemotherapeutic agents; chemotherapy produces an overall response rate of <10% with little survival advantage. Hence, there is an urgent need for more effective treatments. We recently discovered a new epigenetic mechanism of anticancer drug resistance, that is caused by two fibroblast growth factors expressed in solid tumors, i.e., acidic and basic fibroblast growth factors (aFGF and bFGF). These two proteins, at clinically relevant concentrations, induce an up to 10-fold resistance to drugs with diverse structures and action mechanisms. Inhibitors of these FGFs, including monoclonal antibodies and suramin (at low concentrations with no cytotoxicity), reverse the FGF-induced resistance and enhance the activity of chemotherapy in a number of solid tumor cells in vitro and in vivo. Our results indicate the following: (a) Pancreatic cancer cell lines and pancreatic patient tumors contain high levels of aFGF and bFGF. (b) FGFs induced resistance to drugs that have been used to treat pancreatic cancer. (c) Suramin, a nonspecific FGF antagonist, enhanced the activity of paclitaxel and gemcitabine in human pancreatic cancer cells and xenografts. These findings led to our first hypothesis that aFGF/bFGF is an important resistance mechanism of pancreatic cancer. We also found that FGFs caused different degrees of resistance for different drugs in the same cell line, and that bFGF activated different survival pathways in different cell lines. This led to our second hypothesis that the mechanisms ? of FGF-induced resistance are context-dependent and vary depending on the cell type and the stress inducer. We further found that suramin enhanced the chemosensitivity of three pancreatic tumors that expressed low, moderate and high FGF levels, leading to our third hypothesis that FGF inhibitors can enhance the chemosensitivity of pancreatic cancer. The goal of this application is to test these hypotheses. Finally, our preclinical results and early clinical results in nonsmall cell lung cancer patients indicate low-dose suramin as an effective chemosensitizer, but that the suramin effect is highly concentration-dependent with chemosensitization at low concentrations and antagonism at high concentrations. We propose to establish the plasma and tissue/tumor pharmacokinetics and pharmacodynamics of suramin in rodents and use these data to establish physiologically based pharmacokinetics models, to identify the optimal treatment schedule and for inter-species scale-up to humans. The proposed research has the potential of identifying a new treatment paradigm for pancreatic cancer. ? ? ?
|Li, Jing; Wientjes, M Guillaume; Au, Jessie L-S (2010) Pancreatic cancer: pathobiology, treatment options, and drug delivery. AAPS J 12:223-32|
|Zhao, Liang; Au, Jessie L-S; Wientjes, M Guillaume (2010) Comparison of methods for evaluating drug-drug interaction. Front Biosci (Elite Ed) 2:241-9|
|Zhao, Liang; Wientjes, M Guillaume; Au, Jessie L-S (2004) Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res 10:7994-8004|