Assessment of the translatability of the APOE*3Leiden.CETP mouse model and understanding the mechanistic background of drug-induced cardiovascular safety issues; a computational and systems toxicology-based approach. | RVO.nl | Rijksdienst

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Assessment of the translatability of the APOE*3Leiden.CETP mouse model and understanding the mechanistic background of drug-induced cardiovascular safety issues; a computational and systems toxicology-based approach.

Chronic myeloid leukemia (CML) is a cancer of the white blood cells. In Western countries it accounts for 15-20% of all adult leukemias. CML is now largely treated with targeted drugs called tyrosine kinase inhibitors (TKIs, tyrphostins) which have led to dramatically improved long term survival rates since the introduction of the first such agent, imatinib, in 2001. These drugs have revolutionized treatment of this disease and allow most patients to have a good quality of life when compared to the former chemotherapy drugs. After the successful introduction of imatinib several new, second generation, TKIs have been introduced, which are insensitive to resistance as observed in patients treated with imatinib. However, severe adverse (cardio)vascular (CV) side effects have been described for this second generation CML drugs, with as a potential common factor endothelial dysfunction leading to among others endothelial activation/inflammation, thrombosis (potentially resulting in myocardial infarction and stroke), and vasoconstriction (leading to increased blood pressure). These side effects have not been detected in conventional rodent safety models. In this project, we aim to develop the APOE*3Leiden.CETP mouse, an established small animal efficacy model for cardiovascular and metabolic diseases, as a translational safety model for testing the cardiovascular safety issues of these drugs, and more generic for investigation of the adverse effects of other classes of TKIs for different indications and for other drugs. Thus, the proposed research aims at the development of a humanized model, which is applicable much earlier during drug development. As a result, unnecessary preclinical rodent toxicity testing at late preclinical stage may be avoided. Secondly, to gain insight into the mechanistic background of the cardiovascular safety issues of anti-CML drugs using transcriptomics and bioinformatics analyses in a translational mouse model for cardiovascular diseases, and to further develop computational toxicology. Understanding of the mechanism is imperative since these medicines cause serious safety issues in CML patients treated with these drugs and will form a basis for the development of new and more safe drugs. Computational toxicology is indispensable herein, since it constitutes a promising in-silico tool for the evaluation of drug safety and the prediction of adverse off-target effects.

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