The role of the platelet-leucocyte axis in antiandrogen therapy induced cardiovascular disease

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Androgen-deprivation therapy (ADT) is a key element of prostate cancer treatment in locally advanced and metastatic disease. ADT is associated with cardiovascular disease (CVD) including atherosclerotic plaque progression and plaque instability. Thrombosis and inflammation are key mechanisms in the pathogenesis of atherosclerosis and CVD and increased platelet activity and platelet-monocyte interaction are associated with an increased risk of CVD. Androgen pathway signaling has a myriad of effects on platelet activity and other atherosclerosis-associated cell types which are incompletely understood. The aim of the proposed study is to elucidate the mechanistic link between ADT for prostate cancer and CVD with a focus on thromboinflammation and the role of platelets and their interaction with other immune cells. A longitudinal cohort study is proposed to comprehensively characterize platelet activity, platelet-leucocyte interaction, monocyte activation, T-cell subsets, and the platelet transcriptome in peripheral blood of prostate cancer patients before and during ADT compared to healthy controls. Flow-cytometric analysis will be used to characterize phenotype and interaction of platelets and leucocytes. Platelet reactivity will be measured using light transmission aggregometry. RNA sequencing will provide further mechanistic insights into platelet function during ADT. Complementary in vitro studies will investigate the effects of androgen-blockade on the megakaryocyte activity and phenotype as well as on platelet-macrophage interaction. Additionally, effects of different antiplatelet therapies in this context will be studied in vitro. The identification of potential therapeutic targets or diagnostic biomarkers could help to optimally guide preventive measures and thereby reduce the excess cardiovascular risk of prostate cancer patients undergoing ADT.