ABSTRACT
The standard of care treatment for neovascular age-related macular degeneration, delivered as ocular injection, is based on anti-vascular endothelial growth factor (anti-VEGF). The course of treatment may need to be modified quickly for certain patients based on their response. Models that track both the concentration and the response to an anti-VEGF treatment are presented. The specific focus is to assess the existence of analytical solutions for the different types of models. Both an ODE-based model and a map-based model illustrate the dependence of the solution on various biological parameters and allow the measurement of patient-specific parameters from experimental data. A PDE-based model incorporates diffusive effects. The results are consistent with observed values, and could provide a framework for practitioners to understand the effect of the therapy on the progression of the disease in both responsive and non-responsive patients.
Subject(s)
Angiogenesis Inhibitors , Models, Theoretical , Vascular Endothelial Growth Factor A , Visual Acuity , Angiogenesis Inhibitors/pharmacology , Disease Progression , Humans , Intravitreal Injections , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Visual Acuity/drug effectsABSTRACT
Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.
Subject(s)
Apoptosis/drug effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplasms/metabolism , Pyridinium Compounds/pharmacology , bcl-X Protein/metabolism , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacology , Apoptosis/genetics , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cyclic N-Oxides , Disease Models, Animal , Diterpenes/pharmacology , Drug Resistance, Neoplasm/genetics , Drug Synergism , Epoxy Compounds/pharmacology , Female , Gene Dosage , Humans , Indolizines , Male , Mice , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Neoplasms/genetics , Phenanthrenes/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sulfonamides/pharmacology , Xenograft Model Antitumor Assays , bcl-X Protein/geneticsABSTRACT
Reproducibly differential responses to different classes of antihypertensive agents are observed among hypertensive patients and may be due to interindividual differences in hypertension pathology. Computational models provide a tool for investigating the impact of underlying disease mechanisms on the response to antihypertensive therapies with different mechanisms of action. We present the development, calibration, validation, and application of an extension of the Guyton/Karaaslan model of blood pressure regulation. The model incorporates a detailed submodel of the renin-angiotensin-aldosterone system (RAAS), allowing therapies that target different parts of this pathway to be distinguished. Literature data on RAAS biomarker and blood pressure responses to different classes of therapies were used to refine the physiological actions of ANG II and aldosterone on renin secretion, renal vascular resistance, and sodium reabsorption. The calibrated model was able to accurately reproduce the RAAS biomarker and blood pressure responses to combinations of dual-RAAS agents, as well as RAAS therapies in combination with diuretics or calcium channel blockers. The final model was used to explore the impact of underlying mechanisms of hypertension on the blood pressure response to different classes of antihypertensive agents. Simulations indicate that the underlying etiology of hypertension can impact the magnitude of response to a given class of therapy, making a patient more sensitive to one class and less sensitive others. Given that hypertension is usually the result of multiple mechanisms, rather than a single factor, these findings yield insight into why combination therapy is often required to adequately control blood pressure.
