Multiscale Pharmacodynamic Studies of Combination Gemcitabine and Trabectedin for the Treatment of Pancreatic Cancer
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Pancreatic adenocarcinoma is a highly aggressive malignancy. Due to the lack of specific symptoms and limitations in diagnostic methods, diagnosis often occurs at a late stage and the disease is usually resistant to all extant treatment. Gemcitabine, as the first-line therapy for the treatment of pancreatic cancer, has modest therapeutic effects. Better treatment strategies are needed. Drug combinations are widely used for the treatment of cancer, and combining gemcitabine with other drugs may improve efficacy and reduce toxicity. Multi-scale pharmacokinetic (PK) and pharmacodynamic (PD) modeling serves as a way to assess “big data” from different sources and at varying levels. This dissertation investigates the interactions between gemcitabine and trabectedin using multi-scale PD approaches. Trabectedin is a potent marine-derived DNA-interacting compound. Based on the mechanisms of action, we hypothesized that trabectedin may work synergistically with gemcitabine for the treatment of pancreatic cancer. These mechanisms involve using both drugs to target DNA and cause cell cycle arrest. Additionally, trabectedin down-regulates transcription factors in the growth pathway and induces cell apoptosis. We proposed a multi-scale PKPD study to examine these drug interactions. The study employs cellular, subcellular, and proteomic scales. We developed PD models for each scale in connection to each of the others. In this way, the information from each previous scale was incorporated and integrated into the model for the next level. The Scale 1 study (cellular scale) investigates single and combined drug effects of gemcitabine and trabectedin on cell counts of two pancreatic cancer cell lines (MiaPaCa-2 and BxPC-3). The Scale 1 PD model describes drug combination effects in the dimensions of time and concentration. A semi-mechanism based PD model characterized the combined drug effects on total cell counts. The combination of gemcitabine and trabectedin exerted modest synergistic effects on cell dynamics. The Scale 2 study (subcellular scale) examined the combined drug effects on cell numbers in different cell cycle and apoptosis phases. Four mechanism-based cell cycle models characterized the combined drug effects for vehicle control, gemcitabine, trabectedin, and combinations of the two drugs. Overall, synergism occurs due to the combined drug effects on cell cycle (additivity) and apoptosis (synergism). The Scale 3 study examined the single and combined drug effects of gemcitabine and trabectedin on the time course of numerous protein expression. The LC-MS techniques along with western blot methods permitted proteomic profiling of MiaPaCa-2 cells from in vitro studies. A systems pharmacological model characterized the single and combined drug effects on the dynamics of signal transduction in pancreatic cancer cells. The proteomic PD model was constructed by integrating various pathways, it incorporates the interactions and cross-talk of different pathways, and provides a systems-level view of diverse mechanisms. The drug combination has synergistic effects upon pathways such as migration, apoptosis, and cell cycle arrest. The proposed systems proteomic model may be used as a virtual and computational platform for the selection of possible drug combination candidates. In summary, diverse experimental data from cell culture studies were used to develop a multi-scale PD model that integrates information from proteomic, cell cycle, and cellular scales. This multi-scale PD model was employed to characterize combined drug effects. These experimental and mathematical methods and results explain the complexities of the drug effects by integrating data from different sources and provides insights on optimizing drug therapy for pancreatic cancer.