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:
    10318914
  • 负责人:
  • 金额:
    $ 65.56万
  • 依托单位:
  • 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

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,如靶向酪氨酸激酶抑制剂(TKI), 将包括慢性髓性白血病(CML)在内的许多晚期癌症转化为慢性疾病。 尽管有针对性的方法,血管毒性已经出现。第一代CML TKI伊马替尼是安全的,但新一代TKI经常用于耐药CML(尼洛替尼,达沙替尼, 泊那替尼)赋予引起MI、中风或肢体缺血的动脉血栓形成的2-5倍增加的风险。 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, 只有当不良事件发生时,并且一旦被识别,没有数据指导临床医生如何 来预防或治疗这些癌症幸存者。本建议通过以下方式弥补这些知识差距: 利用CML TKI,这是一种既安全又有毒的药物类别。我们和其他人表明, 毒性CML TKI在一些体外模型中损害EC并增强小鼠的动脉粥样硬化。作为慢粒 有潜在CV风险因素的患者易发生毒性,我们假设毒性CML 药物损害特定的内皮细胞(EC)功能,导致斑块发展,炎症, 破裂、血栓形成和局部缺血。由于这些药物是激酶抑制剂,我们进一步证实, 是由信号蛋白磷酸化状态的调节引起的, EC功能,并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 假设毒性CML TKI作用于EC以损害屏障完整性、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蛋白质组学谱可以预测血管 毒性并确定缓解治疗方法。我们使用多种创新方法测试这两个目标: SA 1使用人类工程微血管(hEMV)询问每种CML TKI的影响, 检查对血管通透性和血小板聚集的影响, 显微镜定量白细胞-EC相互作用,颈动脉丝损伤测量血管再狭窄, 内皮化和Apo-E-KO小鼠用FACS定量动脉粥样硬化中的血管炎症。 SA 2使用基于靶向质谱的磷酸化蛋白质组学测定来分析新出现的 CML TKI和一系列获批用于人EC中CV疾病的药物,以确定这是否可以 预测新TKI的毒性并确定缓解疗法。预测的毒性和“解毒剂”, 将使用SA 1中描述的体外和体内模型测试对抗毒性蛋白质组特征。 目标的完成将通过验证临床前模型来预测血管 CML TKI的安全性,并确定血管毒性的潜在治疗方法, 心脏肿瘤护理。

项目成果

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Iris Z Jaffe其他文献

Lipid droplets in the endothelium: The missing link between metabolic syndrome and cardiovascular disease?
内皮中的脂滴:代谢综合征和心血管疾病之间缺失的联系?

Iris Z Jaffe的其他文献

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{{ truncateString('Iris Z Jaffe', 18)}}的其他基金

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:
    10095549
  • 财政年份:
    2021
  • 资助金额:
    $ 65.56万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 65.56万
  • 项目类别:
Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity
认证跨物种平台来研究癌症治疗相关的心血管毒性
  • 批准号:
    10687058
  • 财政年份:
    2019
  • 资助金额:
    $ 65.56万
  • 项目类别:
Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity
认证跨物种平台来研究癌症治疗相关的心血管毒性
  • 批准号:
    10001482
  • 财政年份:
    2019
  • 资助金额:
    $ 65.56万
  • 项目类别:
Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity
认证跨物种平台来研究癌症治疗相关的心血管毒性
  • 批准号:
    10242677
  • 财政年份:
    2019
  • 资助金额:
    $ 65.56万
  • 项目类别:
Mechanisms for Sex Differences in CVD Pathology and Development of a Targeted Therapeutic
CVD 病理学性别差异的机制和靶向治疗的开发
  • 批准号:
    10053450
  • 财政年份:
    2018
  • 资助金额:
    $ 65.56万
  • 项目类别:
Smooth Muscle Mineralocorticoid Receptors in Vascular Aging and Hypertension
血管老化和高血压中的平滑肌盐皮质激素受体
  • 批准号:
    8759190
  • 财政年份:
    2014
  • 资助金额:
    $ 65.56万
  • 项目类别:
Smooth Muscle Mineralocorticoid Receptors in Vascular Aging and Hypertension
血管老化和高血压中的平滑肌盐皮质激素受体
  • 批准号:
    9111994
  • 财政年份:
    2014
  • 资助金额:
    $ 65.56万
  • 项目类别:
Smooth Muscle Mineralocorticoid Receptors in Vascular Aging and Hypertension
血管老化和高血压中的平滑肌盐皮质激素受体
  • 批准号:
    8904701
  • 财政年份:
    2014
  • 资助金额:
    $ 65.56万
  • 项目类别:
Smooth Muscle Mineralocorticoid Receptors in Vascular Aging and Hypertension
血管老化和高血压中的平滑肌盐皮质激素受体
  • 批准号:
    9083718
  • 财政年份:
    2014
  • 资助金额:
    $ 65.56万
  • 项目类别:

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