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) 已经改变了慢性粒细胞白血病 (CML) 从预后不良的致命疾病转变为预期寿命接近的可控制的慢性疾病正常人群的患病率增加，导致 CML 患病率增加，预计将继续至少到 2050 年才会上升。这一成功是由效力提高的新一代 BCR-ABL TKI 推动的。然而，一些 BCR-ABL TKI，尤其是达沙替尼、普纳替尼和尼洛替尼，已与心血管毒性，包括增加动脉血栓事件的风险，例如冠状动脉血栓形成，我们的实验室之前帮助开发了蛋白质组学。鉴定人脐静脉内皮细胞 (HUVEC) 磷酸化蛋白质组学特征的方法用 BCR-ABL TKI 治疗，可预测临床血管毒性并与内皮细胞 (EC) 相关 ECs 排列在血管腔内并保护脉管系统免受病理性血小板粘附和损伤。离线状态下，EC 功能障碍会损害 EC 的愈合能力，同时也会暴露出促血栓因素。在基底膜上，连同 EC 对促凝血蛋白的上调，尚未被探索 BCR-ABL TKI 毒性可能导致动脉血栓形成风险增加的机制。一种新型变构 BCR-ABL 抑制剂，扩大了 CML 的治疗范围，并于 2021 年获得批准 FDA 批准之前两次 BCR-ABL TKI 治疗失败的患者阿西米尼的心血管安全性。其对 EC 的体外影响尚不清楚，也没有针对 BCR-ABL TKI 血管的缓解策略我们实验室的新初步数据支持阿西米尼的毒性低于帕纳替尼、达沙替尼和阿西米尼。尼洛替尼在 HUVEC 划痕体外愈合试验中表明，帕纳替尼会损伤小鼠颈动脉内皮体内细胞伤口愈合，磷酸蛋白质组学筛选可以识别“逆转”有毒 BCR- 的药物 ABL TKI 磷酸化蛋白质组学特征并提高 BCR-ABL TKI 暴露后 EC 的存活率。使用体外测定比较阿西米尼与伊马替尼（无毒 BCR-ABL TKI）、普纳替尼、尼罗替尼和达沙替尼（均已知对 EC 有毒），并探索这些化合物在体内的 EC 毒性我们还建议使用蛋白质组学来确定小鼠颈动脉线损伤模型。使用阿西米尼治疗的 HUVEC 的蛋白质组学特征，筛选批准的心脏代谢药物的能力 “逆转”有毒 BCR-ABL TKI 的磷酸蛋白质组 EC 特征，并测试目标药物是否我们的筛选确定可以逆转 EC 的体外和体内毒性。本提案中的研究结果将。提供有关阿西米尼（一种慢性粒细胞白血病新疗法）潜在血管毒性的有价值的信息，提供更全面地了解当前 BCR-ABL TKI 的血管毒性，并快速识别用于治疗或预防 CML 幸存者血管毒性的可转化药物。