15 research outputs found
A Dynamical Systems Model for Combinatorial Cancer Therapy Enhances Oncolytic Adenovirus Efficacy by MEK-Inhibition
Oncolytic adenoviruses, such as ONYX-015, have been tested in clinical trials for currently untreatable tumors, but have yet to demonstrate adequate therapeutic efficacy. The extent to which viruses infect targeted cells determines the efficacy of this approach but many tumors down-regulate the Coxsackievirus and Adenovirus Receptor (CAR), rendering them less susceptible to infection. Disrupting MAPK pathway signaling by pharmacological inhibition of MEK up-regulates CAR expression, offering possible enhanced adenovirus infection. MEK inhibition, however, interferes with adenovirus replication due to resulting G1-phase cell cycle arrest. Therefore, enhanced efficacy will depend on treatment protocols that productively balance these competing effects. Predictive understanding of how to attain and enhance therapeutic efficacy of combinatorial treatment is difficult since the effects of MEK inhibitors, in conjunction with adenovirus/cell interactions, are complex nonlinear dynamic processes. We investigated combinatorial treatment strategies using a mathematical model that predicts the impact of MEK inhibition on tumor cell proliferation, ONYX-015 infection, and oncolysis. Specifically, we fit a nonlinear differential equation system to dedicated experimental data and analyzed the resulting simulations for favorable treatment strategies. Simulations predicted enhanced combinatorial therapy when both treatments were applied simultaneously; we successfully validated these predictions in an ensuing explicit test study. Further analysis revealed that a CAR-independent mechanism may be responsible for amplified virus production and cell death. We conclude that integrated computational and experimental analysis of combinatorial therapy provides a useful means to identify treatment/infection protocols that yield clinically significant oncolysis. Enhanced oncolytic therapy has the potential to dramatically improve non-surgical cancer treatment, especially in locally advanced or metastatic cases where treatment options remain limited.National Institutes of Health (U.S.) (Grant R01 CA118545)National Institutes of Health (U.S.) (Grant R01 CA095701)National Institutes of Health (U.S.) (Grant U54 CA11297)National Institutes of Health (U.S.) (Grant U54-CA112967
Biogeochemical Influences Associated with Sedimentation in Riparian Forests of the Southeastern Coastal Plain
Regional Differences in Stream Water Nitrogen, Phosphorus, and Sediment Responses to Forest Harvesting in the Conterminous USA
Soil carbon and nitrogen dynamics in the first year following herbicide and scalping in a revegetation trial in south-east Queensland, Australia
Soil nitrogen mineralization and fate of (15NH4)2SO4 in field-incubated soil in a hardwood plantation of subtropical Australia: the effect of mulching
Soil organic matter dynamics and nitrogen availability in response to site preparation and management during revegetation in tropical Central Queensland, Australia
There is considerable interest in finding a cost-effective method of site preparation that effectively controls weeds during planting and further reduces the need for recurring herbicide applications. In this study, two weed control methods, herbicide and scalping, were examined. Both methods may have implications for soil organic matter (SOM) dynamics and nitrogen (N) which could consequently affect plant survival and vegetation establishment. This study aimed to investigate the dynamics of SOM, carbon (C) and N pools under site manipulation practices and the associated early plant survival and growth in tropical Australia