Tyrosine Kinases and Thrombosis

酪氨酸激酶和血栓形成

• 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
• 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

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.

项目摘要 酪氨酸激酶抑制剂（TKI）是治疗各种癌症的重要治疗剂。但是，任何 代理在有效性与目标有害效果之间具有权衡。这个概念成为证据 当潜力和广泛抑制性酪氨酸激酶时​​，慢性粒细胞性白血病（CML）的治疗 抑制剂Ponatinib（iClusig，Ariad Pharmaceuticals，现为武田）被认为有31％的事件 心血管（CV）事件，其中21％是重大不良事件（SAE）。在II期试验中 （步伐）在4年。动脉闭塞事件的事件为26％（心肌梗塞14％，中风11％， 和肢体缺血11％ - 有些患者有1个以上的器官事件）。 Ponatinib（Poni）是5个TKIS之一 批准用于治疗CML 我们创建了一个鼠模型来检查TKI对血液凝血，血管和血小板的影响 功能。在稳态条件下用各种TKI处理的老年小鼠，庞替尼与伊马替尼不同， 证明动脉和静脉血栓形成的风险增加。 PONI治疗导致动脉降低 闭塞时间，较大的静脉布并产生多动血小板 - 有助于 血栓形成增加。我们的实验室已经确定了促血栓性的关键机制 PONI的表型。首先，Poni治疗的小鼠具有增加血管壁活性氧（ROS）， 表达凝血因子V和VIII的凋亡和炎性血管淋巴细胞浸润。 其次，来自PONI治疗的小鼠的血小板对胶原蛋白响应过度活跃。另外，我们还有 确定PPAR激动剂Pioglitazone（PIO）用PONI给予血管壁标准化时 炎症和血小板多动症以纠正鼠血栓形成风险 该应用的总体假设是由免疫细胞血管引起的PONI相关血栓形成 表达血栓性基因的炎症和血小板信号改变导致血小板过度反应性。 PONI治疗已经确定了一种新型的血栓性血管功能障碍的机制 浸润淋巴细胞表达凝血酶FV和FVIII可能有助于血栓形成。 PONI在人类中的治疗剂量抑制了活化GPVI的阴性调节剂P-Lyny507，这两个未刺激 激活的血小板对P-Lyny396和P-Syky352的影响很小，这表明这些血小板可能是 更具反应性。实际上，PONI治疗的小鼠的血小板对CRP的浓度较低。这些 缺陷在PIO的基因组和非基因组PPAR激动剂上在遗传和功能上纠正。这 该提案的具体目的如下： 该提案的具体目的如下：1）确定Ponatinib和其他TKI-的机制 诱导的血管感染2）确定PONI诱导的血小板过度活化的机制。 这些研究将确定PONI和其他TKI对容器壁和血小板的作用的机制 导致心血管事件。他们提出了用于PONI相关血栓形成和校正的临床前模型 与PPAR激动剂PIO。最后，它们将作为TKIS总体上CVD评估的范式。