Novel strategies to understand, predict, and prevent vascular toxicity of targeted CML therapies

理解、预测和预防 CML 靶向治疗的血管毒性的新策略

基本信息

批准号：
10541815
负责人：
Iris Z Jaffe
金额：
$ 66.17万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541815
关键词：
3-Dimensional Acute Address Adhesions Adverse event Antidotes Antineoplastic Agents Apolipoprotein E Atherosclerosis Biological Assay Biomedical Engineering Blood Cells Blood Platelets Blood Vessels Blood flow Cancer Survivor Cardiotoxicity Cardiovascular system Caring Cell Communication Cell physiology Chronic Disease Chronic Myeloid Leukemia Dasatinib Data Development Disease Drug Approval Drug toxicity Endothelial Cells Endothelium Exposure to Functional disorder Generations Human Human Engineering Imatinib Impairment In Vitro Inflammation Inflammatory Injury Ischemia Knockout Mice Knowledge Leukocyte Trafficking Leukocytes Libraries Life Expectancy Malignant Neoplasms Mass Spectrum Analysis Measures Metabolic Diseases Methods Modeling Molecular Target Mus Myocardial Infarction Patients Peripheral Persons Pharmaceutical Preparations Phenotype Phosphorylation Physiological Platelet aggregation Pre-Clinical Model Predisposing Factor Proteomics Proto-Oncogene Proteins c-abl Publishing Resistance Risk Risk Factors Rupture Safety Signaling Protein Stroke Survivors Testing Thrombosis Toxic effect Toxicity Tests Translating Tyrosine Kinase Inhibitor Umbilical vein Validation Vascular Diseases Vascular Permeabilities artery occlusion cancer care cancer survival cancer therapy cell injury healing heart disease risk hemodynamics human model improved in vitro Model in vivo in vivo Model innovation innovative technologies intravital microscopy kinase inhibitor leukemia leukemia treatment limb ischemia member molecular targeted therapies mortality new therapeutic target novel novel anticancer drug novel strategies novel therapeutics phosphoproteomics prevent proteomic signature response side effect targeted cancer therapy vascular inflammation vascular risk factor wound healing

项目摘要

Molecularly targeted cancer therapies, such as Abl-targeted tyrosine kinase inhibitors (TKIs), have converting many terminal cancers, including chronic myeloid leukemia (CML), into chronic diseases. Despite the targeted approach, vascular toxicities have emerged. Specifically, the first-generation CML TKI imatinib is safe, yet newer generation TKIs frequently used for resistant CML (nilotinib, dasatinib, ponatinib) confer a 2-5 fold increased risk of arterial thrombosis causing MI, stroke, or limb ischemia. With no validated models to test for vascular toxicity prior to drug approval, this side effect was identified only when adverse events accrued and once recognized, there are no data to guide clinicians as to how to prevent this or to treat these cancer survivors. This proposal addresses these gaps in knowledge by leveraging the CML TKIs, a drug class with both safe and toxic members. We and others showed that toxic CML TKIs damage ECs in some in vitro models and enhance atherosclerosis in mice. As CML patients with underlying CV risk factors are predisposed to toxicity, we hypothesize that the toxic CML drugs impair specific endothelial cell (EC) functions that lead to plaque development, inflammation, rupture, thrombosis and ischemia. As these drugs are kinase inhibitors, we further posit that the toxicity is caused by modulation of the phosphorylation state of signaling proteins in a manner that is deleterious to EC function and have shown this using proteomic approaches. Thus, we now propose to test the hypothesis that toxic CML TKIs act on ECs to impair barrier integrity, enhance leukocyte trafficking, slow wound healing, and increase interaction with platelets, thereby promoting an atherosclerosis phenotype prone to rupture and thrombosis, and that the drug-induced EC proteomic profile can predict vascular toxicity and identify mitigating treatments. We test this with 2 aims using multiple innovative approaches: SA1 interrogates the impact of each CML TKI using human engineered microvessels (hEMVs) to examine the impact on vascular permeability and platelet aggregation and in mice using intravital microscopy to quantify leukocyte-EC interaction, carotid wire injury to measure vascular re- endothelialization, and Apo-E-KO mice with FACS to quantify vascular inflammation in atherosclerosis. SA2 uses a targeted mass spectrometry based phosphoproteomic assay to profile the effects of emerging CML TKIs and a broad range of drugs approved for CV disease in human ECs to determine if this can predict toxicity of new TKIs and identify mitigating therapies. Predicted toxicities and “antidotes” that oppose the toxic proteomic signature will be tested using the in vitro and in vivo models described in SA1. Completion of the aims will transform cardiooncology by validating preclinical models to predict vascular safety of CML TKIs and identify potential treatments for vascular toxicity that can be rapidly translated to cardiooncology care.

分子靶向的癌症疗法，例如靶向ABL的酪氨酸激酶抑制剂（TKI）将包括慢性髓样白血病（CML）在内的许多末端癌症转化为慢性疾病。尽管有针对性的方法，但仍出现了血管毒性。具体而言，第一代CML tki imatinib是安全的，但较新的TKI经常用于抗性CML（Nilotinib，dasatinib， PONATINIB）会议2-5倍增加了动脉血栓形成的风险，导致MI，中风或肢体缺血。在没有经过验证的模型来测试药物批准之前的血管毒性，因此确定了这种副作用只有当不良事件累积并一旦被认可时，就没有数据指导临床医生有关如何为了防止这种情况或治疗这些癌症生存。该提议通过利用CML TKI，这是一个具有安全和有毒成员的药物类别。我们和其他人表明有毒的CML TKI损害某些体外模型中的EC，并增强小鼠动脉粥样硬化。作为CML 具有基本CV风险因素的患者易于毒性，我们假设有毒CML 药物会损害特定的内皮细胞（EC）功能，导致牙菌斑发育，炎症，破裂，血栓形成和缺血。由于这些药物是激酶抑制剂，我们进一步确认毒性是由信号传导蛋白的磷酸化状态以被删除的方式引起的 EC功能并使用蛋白质组学方法显示了这一点。那，我们现在建议测试假设有毒CML TKI对EC的作用以损害屏障完整性，增强白细胞运输，缓慢伤口愈合并增加与血小板的相互作用，从而促进动脉粥样硬化表型容易破裂和血栓形成，并且药物诱导的EC蛋白质组学特征可以预测血管毒性并识别缓解治疗方法。我们使用多种创新方法用2个目标对此进行测试： SA1使用人类工程微分（HEMV）询问每个CML TKI的影响使用插入性检查对血管通透性和血小板聚集的影响以及小鼠的影响显微镜以量化白细胞-EC相互作用，颈动脉线损伤以测量血管重新内皮化和带有FACS的Apo-e-KO小鼠，以量化动脉粥样硬化中的血管感染。 SA2使用靶向质谱基的磷酸蛋白质组学测定法来介绍新出现的影响 CML TKI和人类EC中CV疾病批准的广泛药物，以确定是否可以预测新TKI的毒性并确定缓解疗法。预测的毒性和“解毒剂” 相反的有毒蛋白质组学特征将使用SA1中描述的体外和体内模型进行测试。目标的完成将通过验证临床前模型来预测血管来改变心脏病学 CML TKI的安全性并确定可快速翻译成血管毒性的潜在治疗方法心脏协会护理。