Thursday, May 16, 2024
5/16/2024
Project Summary Tyrosine kinase inhibitors (TKIs) are important therapeutic agents to treat various cancers. However, any agent has a tradeoff between efficacy and on or off target deleterious effects. This notion became evident in the treatment of chronic myelogenous leukemia (CML) when a potent and broadly inhibitory tyrosine kinase inhibitor, ponatinib (Iclusig, Ariad Pharmaceuticals, now Takeda) was recognized to have a 31% incidence of cardiovascular (CV) events of which 21% overall were significant adverse events (SAEs). In a Phase II trial (PACE) at 4 yrs. the incidence of arterial occlusive events was 26% (myocardial infarction 14%, stroke 11%, and limb ischemia 11% - some patients have more than 1 organ event). Ponatinib (poni) is one of 5 TKIs approved for the treatment of CML We have created a murine model to examine the effects of TKIs on blood coagulation, vascular, and platelet function. In aged mice treated with the various TKIs under steady-state conditions, ponatinib, unlike imatinib, demonstrated an increased risk of arterial and venous thrombosis. Poni treatment leads to decreased arterial occlusion times, larger venous clots and generates hyperactive platelets - features that contribute to heightened thrombosis. Our laboratory has identified key mechanisms underlying the prothrombotic phenotype of poni. First, poni-treated mice have increased vessel wall reactive oxygen species (ROS), apoptosis, and inflammatory vascular lymphocyte infiltrates that expresses coagulation factors V and VIII. Second, platelets from poni-treated mice are hyperactive to in response to collagen. Additionally, we have determined that pioglitazone (pio), a PPAR¿ agonist, when given with poni normalizes the vessel wall inflammation and platelet hyperactivity to correct murine thrombosis risk The overall hypothesis of this application is that poni-associated thrombosis results from immune cell vascular inflammation expressing prothrombotic genes and altered platelet signaling resulting in platelet hyperreactivity. Poni treatment has identified a novel mechanism of prothrombotic vascular dysfunction by which vascular infiltrating lymphocytes express coagulation enzymes FV and FVIII potentially to contribute to thrombosis. At therapeutic dosing in man, poni inhibits p-LynY507, a negative regulator of activated GPVI, in both unstimulated and activated platelets with little effect on p-LynY396 and p-SykY352, suggesting that these platelets may be more reactive. In fact, poni-treated mice have platelets that react to lower concentrations of CRP. These defects are genetically and functionally corrected by pio’s genomic and non-genomic PPAR¿ agonism. The specific aims of the proposal are as follows: The specific aims of the proposal are as follows: 1) Determine the mechanism of ponatinib- and other TKI- induced vascular inflammation 2) Identify the mechanisms of poni-induced platelet hyperactivation. These studies will determine the mechanisms of poni and other TKI effects on vessel wall and platelets that lead to cardiovascular events. They present a pre-clinical model for poni-associated thrombosis and correction with pio, a PPAR¿ agonist. Last, they will serve as a paradigm for CVD assessment for TKIs in general.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
