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

• 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
• 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

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.

分子靶向癌症疗法，例如 Abl 靶向酪氨酸激酶抑制剂 (TKI)，已 将许多晚期癌症，包括慢性粒细胞白血病（CML）转变为慢性疾病。 尽管采取了有针对性的方法，但特别是第一代 CML 已经出现了血管毒性。 TKI 伊马替尼是安全的，但新一代 TKI 经常用于治疗耐药性 CML（尼罗替尼、达沙替尼、 ponatinib）使动脉血栓形成导致心肌梗死、中风或肢体缺血的风险增加 2-5 倍。 由于在药物批准之前没有经过验证的模型来测试血管毒性，因此确定了这种副作用 只有当不良事件发生并被识别后，没有数据可以指导闪电如何 为了预防这种情况或治疗这些癌症幸存者，该提案通过以下方式解决了这些知识空白。 我们和其他人表明，利用 CML TKI（一种既安全又有毒的药物）。 有毒的 CML TKI 在某些体外模型中会损害 EC，并会增强小鼠的动脉粥样硬化。 具有潜在 CV 危险因素的患者容易出现毒性反应，我们认为中毒性 CML 损害特定的内皮药物细胞 (EC) 功能，导致斑块形成、炎症、 由于这些药物是激酶抑制剂，因此我们进一步推测毒性。 是由信号蛋白磷酸化状态以有害方式调节引起的 EC 功能，并已使用蛋白质组学方法证明了这一点，因此，我们现在建议测试该功能。 假设有毒的 CML TKI 作用于 EC，损害屏障完整性，增强白细胞运输，减缓 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，药物诱导的 EC 蛋白质组谱可以预测血管 我们使用多种创新方法测试了两个目标： SA1 使用人类工程微血管 (hEMV) 询问每种 CML TKI 的影响 使用活体注射检查对血管通透性和血小板聚集的影响以及对小鼠的影响 显微镜量化白细胞-EC相互作用，颈动脉线损伤测量血管再 内皮化和 Apo-E-KO 小鼠使用 FACS 来量化动脉粥样硬化中的血管炎症。 SA2 使用基于磷酸化蛋白质组分析的靶向质谱分析来分析新兴物质的影响 CML TKI 和多种被批准用于治疗人类 EC 中的 CV 疾病的药物，以确定这是否可以 预测新 TKI 的毒性并确定减轻毒性的治疗方法和“解毒剂”。 反对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，从而改变心脏病学 CML TKI 的安全性并确定可快速转化为血管毒性的潜在治疗方法 心脏病学护理。