Tyrosine Kinases and Thrombosis

酪氨酸激酶和血栓形成

基本信息

批准号：
10367450
负责人：
ALVIN H SCHMAIER
金额：
$ 54.01万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367450
关键词：
ABL1 gene Adverse event Agonist Aorta Apoptosis BCR gene Blood Coagulation Factor Blood Platelets Blood Vessels Blood coagulation Cardiovascular Diseases Cardiovascular system Cells Chronic Myeloid Leukemia Coagulation Process Collagen Combined Modality Therapy Defect Dose Endothelial Cells Enzymes Event Experimental Models F8 gene Factor V Factor VIII Gene Expression Generations Genes Genomics Goals Hyperactivity Imatinib Immune In Vitro Incidence Inflammation Inflammatory Investigation Ischemic Stroke LTK gene Laboratories Lead Lymphocyte Lymphocytic Infiltrate Malignant Neoplasms Morbidity - disease rate Mus Myocardial Infarction Nature Oncology Organ PPAR alpha Patients Peroxisome Proliferator-Activated Receptors Pharmacologic Substance Phenotype Pioglitazone Pre-Clinical Model Protein Tyrosine Kinase Reactive Oxygen Species Resistance Risk Rodent Signal Pathway Signal Transduction Stroke Therapeutic Therapeutic Agents Thromboplastin Thrombosis Time Translating Tyrosine Kinase Inhibitor Vascular Diseases Venous Venous Thrombosis aged artery occlusion cardiovascular risk factor factor IXa-factor VIIIa in vivo limb ischemia mRNA Expression man mouse model mutant non-genomic novel phase II trial phosphoproteomics platelet function response thrombotic transcriptome sequencing vascular inflammation

项目摘要

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.

项目概要酪氨酸激酶抑制剂（TKI）是治疗各种癌症的重要治疗剂。药剂在功效与目标或脱靶有害作用之间进行权衡，这一概念在《中》中变得很明显。当使用有效且广泛抑制的酪氨酸激酶时，可治疗慢性粒细胞白血病 (CML) 抑制剂 ponatinib（Iclusig，Ariad Pharmaceuticals，现为 Takeda）被认为有 31% 的发生率在一项 II 期试验中，心血管 (CV) 事件总体上占 21% 为重大不良事件 (SAE)。 (PACE) 4 年时动脉闭塞事件的发生率为 26%（心肌梗塞 14%，中风 11%，肢体缺血 11% - 一些患者发生超过 1 个器官事件） Ponatinib (poni) 是 5 种 TKI 之一。获批用于治疗 CML 我们创建了一个小鼠模型来检查 TKI 对凝血、血管和血小板的影响在稳态条件下接受各种 TKI 治疗的老年小鼠中，帕纳替尼与伊马替尼不同， Poni 治疗导致动脉血流减少闭塞时间、更大的静脉血栓和产生过度活跃的血小板——这些特征有助于我们的实验室已经确定了血栓形成的关键机制。首先，经poni处理的小鼠血管壁活性氧（ROS）增加，细胞凋亡和表达凝血因子 V 和 VIII 的炎性血管淋巴细胞浸润。其次，经过poni处理的小鼠的血小板对胶原蛋白的反应过度活跃。确定吡格列酮 (pio)（一种 PPAR 激动剂）与 poni 一起使用时可使血管壁正常化炎症和血小板过度活跃可纠正小鼠血栓形成风险本申请的总体假设是，小脑相关血栓形成是由免疫细胞血管表达促血栓基因的炎症和改变的血小板信号传导导致血小板高反应性。 Poni 治疗已确定了一种血栓前血管功能障碍的新机制，通过该机制，血管浸润淋巴细胞表达凝血酶 FV 和 FVIII，可能导致血栓形成。在人类的治疗剂量下，poni 抑制 p-LynY507（激活 GPVI 的负调节因子）。和活化的血小板对 p-LynY396 和 p-SykY352 几乎没有影响，表明这些血小板可能是事实上，接受 Poni 治疗的小鼠的血小板对较低浓度的 CRP 会产生反应。 pio 的基因组和非基因组 PPAR- 激动作用可以从基因和功能上纠正缺陷。该提案的具体目标如下：该提案的具体目标如下： 1) 确定 ponatinib 和其他 TKI 的作用机制诱导血管炎症 2) 确定 poni 诱导血小板过度活化的机制。这些研究将确定 poni 和其他 TKI 对血管壁和血小板影响的机制，他们提出了一种用于小脑相关血栓形成和纠正的临床前模型。最后，它们将作为 TKI 的 CVD 评估范例。