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Endothelium as a mediator of BCR-ABL tyrosine kinase inhibitor vascular toxicity

内皮作为 BCR-ABL 酪氨酸激酶抑制剂血管毒性的介质

基本信息

批准号：
10784589
负责人：
Richard Travers
金额：
$ 7.61万
依托单位：
TUFTS MEDICAL CENTER
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：
2022-08-22 至 2025-08-21
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10784589
关键词：
Adhesions Aorta Apoptosis Basement membrane Bcr-Abl tyrosine kinase Binding Sites Biological Assay Biology Blood Platelets Blood Vessels Cardiovascular Diseases Cardiovascular system Carotid Arteries Cell Line Cell Survival Cell model Cell physiology Chronic Disease Chronic Myeloid Leukemia Collaborations Coronary artery Dasatinib Data Disease Drug Targeting Endothelial Cells Endothelium Evans blue stain Event Exposure to Female Functional disorder Generations Goals Health Human Imatinib Impaired wound healing Impairment In Vitro Inflammatory Injury Leukocytes Libraries Life Expectancy Mediator Metabolic Diseases Modeling Morbidity - disease rate Mus Mutation Pathologic Patients Peripheral Pharmaceutical Preparations Population Prevalence Prognosis Proliferating Protective Agents Proteins Proteomics Research Resistance Risk Safety Stroke Survivors Testing Thrombosis Time Toxic effect Training Tyrosine Kinase Inhibitor Umbilical vein Up-Regulation artery occlusion bcr-abl Fusion Proteins cardiometabolism cardiovascular risk factor career development cell type clinical predictors endothelial dysfunction healing improved in vitro Assay in vivo inhibitor male migration mortality mouse model novel novel therapeutics phosphoproteomics platelet function prevent screening side effect success thrombotic wound healing

项目摘要

Tyrosine kinase inhibitors (TKIs) that target BCR-ABL have transformed Chronic Myelogenous Leukemia (CML) from a deadly condition with a poor prognosis to a manageable chronic disease with a life expectancy close to that of the normal population, resulting in an increase in the prevalence of CML that is expected to continue to rise until at least 2050. This success is driven by newer generations of BCR-ABL TKIs with improved potency. Some BCR-ABL TKIs however, most notably dasatinib, ponatinib and nilotinib, have been associated with cardiovascular toxicity including increased risk of arterial thrombotic events such as coronary artery thrombosis, peripheral arterial occlusion, and cerebrovascular accidents. Our lab previously helped develop a proteomic approach which identified a phospho-proteomic signature of human umbilical vein endothelial cells (HUVECs) treated with BCR-ABL TKIs that predicts clinical vascular toxicity and correlates with endothelial cell (EC) dysfunction in vitro. ECs line the vessel lumen and protect the vasculature from pathologic platelet adhesion and thrombosis. Conversely, EC dysfunction that impairs the ability of ECs to heal also exposes prothrombotic factors on the basement membrane that, along with EC upregulation of pro-coagulant proteins, are unexplored mechanisms by which BCR-ABL TKI toxicity could contribute to increased risk of arterial thrombosis. Asciminib, a novel allosteric BCR-ABL inhibitor, has expanded the landscape of treatment in CML and in 2021 received FDA approval for patients who have failed two prior BCR-ABL TKIs. The cardiovascular safety profile of asciminib and its effects on ECs in vitro is unknown, nor are mitigating strategies available for BCR-ABL TKI vascular toxicity. New preliminary data from our lab support that asciminib is less toxic than ponatinib, dasatinib, and nilotinib in a HUVEC scratch would healing assay in vitro, that ponatinib impairs mouse carotid artery endothelial cell wound healing in vivo, and that phospho-proteomic screening can identify drugs that “reverse” the toxic BCR- ABL TKI phospho-proteomic signature and improve EC survival after BCR-ABL TKI exposure. We propose to use in vitro assays to compare the EC toxicity of asciminib to imatinib (non-toxic BCR-ABL TKI), ponatinib, nilotinib, and dasatinib (all known to be toxic to ECs), and explore the EC toxicity of these compounds in vivo in a mouse carotid artery wire injury model. We also propose to use proteomics to determine the phospho- proteomic profile of HUVECs treated with asciminib, screen approved cardiometabolic drugs for their ability to “reverse” the phospho-proteomic EC signature of toxic BCR-ABL TKIs, and test whether the target drugs identified by our screen can reverse EC toxicity in vitro and in vivo. The results of the studies in this proposal will provide valuable information about the potential vascular toxicity of asciminib, a novel therapy for CML, provide a more comprehensive understanding of the vascular toxicity of current BCR-ABL TKIs, and identify rapidly translatable agents to treat or prevent vascular toxicity in CML survivors.

靶向BCR-ABL的酪氨酸激酶抑制剂（TKI）已转化为慢性粒细胞白血病（CML）从一种预后不良的致命疾病转变为一种可控制的慢性疾病，正常人群，导致CML的患病率增加，预计将继续至少要到2050年。这一成功是由新一代BCR-ABL TKI的效力提高所推动的。然而，一些BCR-ABL TKI，尤其是达沙替尼、泊那替尼和尼洛替尼，心血管毒性包括动脉血栓形成事件如冠状动脉血栓形成的风险增加，外周动脉闭塞和脑血管意外。我们的实验室以前帮助开发了一种蛋白质组学鉴定人脐静脉内皮细胞（HUVECs）磷酸化蛋白质组特征的方法接受BCR-ABL TKI治疗，可预测临床血管毒性并与内皮细胞（EC）相关体外功能障碍。内皮细胞排列在血管腔中，保护血管系统免受病理性血小板粘附，血栓形成相反，损害EC愈合能力的EC功能障碍也暴露了促血栓形成因素在基底膜上，沿着EC促凝蛋白的上调， BCR-ABL TKI毒性可能导致动脉血栓形成风险增加的机制。阿西替尼，一种新型的变构BCR-ABL抑制剂，扩大了CML的治疗范围，并于2021年获得 FDA批准用于既往两次BCR-ABL TKI失败的患者。Asciminib的心血管安全性特征其对体外EC的影响尚不清楚，BCR-ABL TKI血管治疗的缓解策略也不清楚毒性来自我们实验室的新的初步数据支持阿昔替尼的毒性低于泊那替尼、达沙替尼和尼洛替尼在体外HUVEC划痕愈合试验中显示，泊那替尼损害小鼠颈动脉内皮细胞细胞伤口愈合，磷酸化蛋白质组学筛选可以鉴定出“逆转”毒性BCR的药物。 ABL TKI磷酸化蛋白质组特征和BCR-ABL TKI暴露后EC存活率的改善。我们建议使用体外试验比较asciminib与伊马替尼（无毒BCR-ABL TKI）、泊那替尼、尼洛替尼和达沙替尼（均已知对EC有毒），并在体内研究这些化合物的EC毒性。一种小鼠颈动脉钢丝损伤模型。我们还建议使用蛋白质组学来确定磷酸- 用asciminib处理的HUVEC的蛋白质组学谱，筛选批准的心脏代谢药物， “逆转”毒性BCR-ABL TKI的磷酸化蛋白质组学EC特征，并测试靶向药物是否通过我们的筛选确定的可以逆转EC在体外和体内的毒性。本提案中的研究结果将提供了关于阿昔替尼（一种新型CML治疗方法）潜在血管毒性的有价值信息，更全面地了解当前BCR-ABL TKI的血管毒性，并快速识别治疗或预防CML幸存者的血管毒性。