Study of mechanisms by which ponatinib induces vascular occlusive events in the treatment of Philadelphia chromosome-positive leukemia

  • Laura Cambier

Student thesis: Master typesMaster en sciences biologiques

Résumé

Philadelphia chromosome-positive leukemia is characterized by the production of the BCRABL tyrosine kinase in leukemia cells. This fusion protein induces the excessive proliferation of leukemia cells, preventing the normal production of blood cells. Tyrosine kinase inhibitors (TKls) were developed to inhibit the anarchie proliferation of leukemia cells in bone marrow by preventing the BCR-ABL target proteins phosphorylation. Ponatinib is the latest commercialized TKI and has the highest antileukemia activity among its drug family. Therefore, it represents the last treatment option for patients suffering from Philadelphia chromosome-positive leukemia in case of resistance and/or intolerance to other TKis.
However, this medication is often related to thrombotic events development in patients, leading to its temporary withdrawal from the market. This master thesis aims at better understanding the mechanisms by which ponatinib induces
vascular occlusive events in order to enhance the management and prophylaxis of this adverse drug reaction. Severa! mechanisms could explain the thrombosis development following ponatinib therapy. During this master thesis, two assumptions were investigated: a potential impact of ponatinib on plate let aggregation and on endothelial ce lis. Firstly, the impact of this TKI on primary hemostasis was assessed. This allowed to highlight that ponatinib should not induce
thrombosis by increasing platelet aggregation. Secondly, the impact of ponatinib on vascular endothelium was investigated by studying its effect on the hemostatic balance and on the metabolism of endothelial cells. Ponatinib seems to slightly activate endothelial cells and decrease their metabolism which could partly explain the increased risk of vascular occlusive events development in ponatinib-treated patients
la date de réponse2016
langue originaleAnglais
L'institution diplômante
  • Universite de Namur
SuperviseurJean-Michel Dogne (Promoteur)

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