Application of dynamic pathway modeling for personalized medicine

The generation of high-quality quantitative data and the development of dynamic pathway models allow us to unravel disease promoting mechanisms and opens novel possibilities for early detection of cancer and personalized optimization of treatment. Our pioneering work on mathematical modeling of the interaction of the hormone Epo with its cell surface receptor EpoR on erythroid progenitor cells (Becker et al. Science 2010) serves as a paradigm. Anemia is characterized by low hemoglobin levels in the blood due to reduced numbers of red blood cells (erythrocytes) and occurs frequently in the context of chronic diseases such as in the latest stages of lung cancer or chronic kidney disease. The main cofounders are inflammation and chemotherapy in lung cancer and the lack of Epo production in the kidney, inflammation and uremic toxins in the case of chronic kidney disease. Just in Germany this affects per year more than 100,000 chronic kidney patients and up to 40,000 lung cancer patients. Anemia impairs quality of life of these patients, compromises palliative treatments and can lead to events with lethal outcome such as lung embolism, thrombosis or cardiac adverse events. Although patients are very different the current treatment guidelines are generic for each disease. The lack of markers for the response of the patients to the different therapeutically employed Epo derivatives (Erythropoiesis Stimulating Agents; ESAs) frequently leads to sub-optimal dosing and sporadically overdosing. The resulting hemodynamic stress has been correlated with thrombovascular and cardiac adverse events. We developed a mechanism-based multiscale dynamic pathway model that was calibrated based on pharmacokinetic and pharmacodynamics data of individual patients to assist clinical decisions in the personalization of anemia treatment in lung cancer and chronic kidney disease (patents EP2957293 (2015), EP3355061 (2018)).
This mathematical model is capable to propose optimized personalized intervention strategies for anemia management employing a minimal effective dose of ESAs and/or blood transfusions. This approach leads to safer hemodynamic profiles, and eventually a reduction in the risk of adverse events and mortality.