RshApo2L/TRAIL and Conatumumab bind to transmembrane death receptors and trigger the extrinsic cellular apoptotic pathway through a caspase-signaling cascade resulting in cell death. Tumor size time series data from rodent tumor xenograft (COLO205) studies following administration of either of these two pro-apoptotic receptor agonists (PARAs) were combined to develop an intracellular-signaling tumor-regression model that includes two levels of signaling: upstream signals unique to each compound (representing initiator caspases), and a common downstream apoptosis signal (representing executioner caspases) shared by the two agents. Pharmacokinetic (PK) models for each drug were developed based on plasma concentration data following intravenous (IV) and/or intraperitoneal (IP) administration of the compounds and were used in the subsequent intracellular-signaling tumor-regression modeling. A model relating the PK of the two PARAs to their respective and common downstream signals, and to the resulting tumor burden was developed using mouse xenograft tumor size measurements from 448 experiments that included a wide range of dose sizes and dosing schedules.
Deficiencies in the original model's ability to describe data from some of the experimental groups led to exploration of several hypotheses for a reduction of drug effect. Both empirical and semi-mechanistic reduction-of-drug-effect models were investigated. All three modified models showed marked improvement of fit, especially for data from the long-term dosing experiments; the greatest improvement (by model-comparison metrics) came from incorporation of a pro-survival signal – consistent with the hypothesis that PARAs may also cause the upregulation of pro-survival factors that can lead to a reduction in their effectiveness with treatment.
Combination therapy data, for which a PARA was co-dosed with a cytotoxic agent, was analyzed using an interaction model. The model was generally able to describe the data; however, the type of data available could only minimally inform the interaction model because of the substantial effects of the chosen monotherapy regimens.
|Advisor:||D'Argenio, David Z.|
|Commitee:||Khoo, Michael C. K., MacKay, J. Andrew|
|School:||University of Southern California|
|School Location:||United States -- California|
|Source:||DAI-B 74/03(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Biomedical engineering|
|Keywords:||Anti-tumor, Apoptosis, Caspase, Drug-induced activation, Extrinsic pathway, Para, Pkpd, Systems modeling|
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