Novel patient biomarkers and mechanisms of TKI associated Cardiotoxicity

TKI 相关心脏毒性的新型患者生物标志物和机制

• 批准号: 10728954
• 负责人: Daniel Addison
• 金额: $ 63.79万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-05 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728954
• 关键词: Address; Adult; Affect; Agammaglobulinaemia tyrosine kinase; Age; American; Animal Model; Animals; Aorta; Arrhythmia; Atrial Fibrillation; Automobile Driving; Blood; Blood Pressure; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular system; Cells; Chronic Lymphocytic Leukemia; Clinical; Data; Development; EFRAC; Electrocardiogram; Event; Expectancy; Fibrosis; Gender; Genomics; Heart Atrium; Hematologic Neoplasms; Holter Electrocardiography; Human; Hypertension; IL17 gene; IL8 gene; Immune; Immune response; Immunogenomics; Immunologic Techniques; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune Response; Interleukin-1; Interleukin-6; Intervention; Lead; Left; Link; Malignant Neoplasms; Measures; Mediating; Mediator; Methods; Modeling; Monitor; Ohio; Oncology; Oral; Oral Administration; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Prediction of Response to Therapy; Predisposing Factor; Prospective Studies; Resources; Risk; Risk Factors; Role; Techniques; Testing; Therapeutically Targetable; Time; Toxic effect; Tyrosine Kinase Inhibitor; Up-Regulation; Ventricular; animal data; cardiac magnetic resonance imaging; cardiovascular effects; cohort; effective therapy; heart imaging; high risk; immune activation; improved; improved outcome; indexing; inhibitor; inhibitor therapy; insight; kinase inhibitor; monocyte; mortality; mouse model; multidisciplinary; novel; oncology program; patient biomarkers; pre-clinical; preclinical study; primary endpoint; prospective; prospective test; recruit; response; success

ABSTRACT: Nearly 250,000 adults are affected by chronic lymphocytic leukemia (CLL). Bruton’s Tyrosine kinase inhibitors (BTKIs) dramatically improve survival in CLL. However, up to 38% of patients develop atrial fibrillation (AF) and other cardiovascular toxicities. Ibrutinib is the first BTKI approved which has these toxicities but our data suggest new BTKIs (e.g., acalabrutinib, zanubrutinib) still associate with cardiotoxicity. The development of AF with BTKIs is challenging and is a major impediment in use of the effective therapies in patients. Thus, there is an urgent need to identify patients at risk for AF, and better understand targetable pathways that induce BTKI-associated AF. Our group has defined most of the early cardio-oncology issues with BTKIs. We have also developed animal models which suggest that BTKIs cause direct cardiotoxicity as well as an activation of the innate immune response that potentially contributes to cardiotoxicity and arrhythmia, and result in an early increase in left atrial (LA) fibrosis and volume (LA remodeling) preceding BTKI-associated AF. We will leverage the active cardio- oncology programs and resources here at OSU and at UCSF, to prospectively study these cardiovascular effects of BTKIs in humans. Our pre-clinical studies specifically implicate activation of the innate immune response, marked by elevation in circulating IL-6 (and IL-17) as key mediators of BTKI-associated AF development, and that this leads to LA remodeling and cardiotoxic AF. Yet, there are no prospective studies testing the effects of immune activation in mediating or predicting cardiotoxic events. To address these translational and clinical gaps, we will recruit 120 CLL patients initiating BTKIs and we will prospectively utilize serial cardiac magnetic resonance imaging (CMR) and leading-edge immunologic techniques to test our hypothesis, that BTKI- associated AF is driven by increased immune activation that induces cardiac remodeling and arrythmia. In Aim 1, we test the effect of BTKIs on LA fibrosis and volume pre-, 2, and 6 months after starting BTKI-therapy. We will determine the burden of BTKI-associated AF by applying serial mobile ECG monitoring over 1-year post- BTKI initiation. These results will be compared to 60 age-, gender-, and cardiac risk matched controls with early stage CLL, treated with standard observation alone. As we have observed that >50% of BTKI treated patients develop hypertension, we will also measure and relate ambulatory blood pressure to CMR measures. In Aim 2, we will examine the effects of BTKIs on innate immune response that define vulnerability to remodeling and clinical AF by studying circulating levels of IL-6, IL-17, and using unbiased single-cell genomics, systematically decipher the immune cells that contribute to remodeling and their key pro-inflammatory pathways. We will also define the relation of these parameters with other CMR measures. Finally, using our BTKI animal model, we will test the effect of targeted inhibition of pro-inflammatory pathways on cardiotoxic remodeling and AF risk. Upon completion, we will gain important insights into the mechanistic role of the kinase inhibitors in cardiotoxicity as well as how immune dysregulation contributes to arrhythmia in hematological malignancies.

抽象的： 近25万名成年人受慢性淋巴细胞性白血病（CLL）的影响。布鲁顿的酪氨酸激酶抑制剂 （BTKIS）显着提高了CLL的生存率。但是，多达38％的患者发生心房颤动（AF）和 其他心血管毒性。 Ibrutinib是第一个具有这些毒性的BTKI批准，但我们的数据表明 新的BTKIS（例如Acalabrutinib，Zanubrutinib）仍然与心脏毒性相关。与BTKI的AF的开发 是挑战，是患者有效疗法使用的主要障碍。那是紧急的 需要识别有AF风险的患者，并更好地理解影响BTKI相关的目标途径 AF。我们的小组定义了BTKIS的大多数早期心脏肿瘤问题。我们也发展了动物 表明BTKI引起直接心脏毒性以及先天免疫的激活的模型 有可能导致心脏毒性和心律不齐的反应，并提早增加左心房 （LA）纤维化和体积（LA重塑）先前是BTKI相关的AF。我们将利用活跃的心脏 - OSU和UCSF的肿瘤学计划和资源，前瞻性研究这些心血管效应 人类中的btkis。我们的临床前研究特别暗示了先天免疫反应的激活， 以循环IL-6（和IL-17）的升高为标志，是BTKI相关的AF发育的关键介体，并且 这导致LA重塑和心脏毒性AF。然而，没有前瞻性研究测试 介导或预测心脏毒性事件中的免疫激活。为了解决这些翻译和临床差距， 我们将招募120名CLL患者启动BTKI，我们可能会使用串行心脏磁 共振成像（CMR）和领先的免疫学技术来检验我们的假设，即BTKI- 相关的AF是由免疫反应增加的增加的驱动，从而诱导心脏重塑和行为。目标 1，我们测试BTKI对开始BTKI疗法后，2和6个月的LA纤维化和体积的影响。我们 将通过在1年内使用串行移动ECG监测来确定BTKI相关的AF的燃烧 BTKI倡议。这些结果将与60岁，性别和心脏风险的对照与早期的对照进行比较 阶段CLL，仅用标准观察治疗。正如我们观察到的，> 50％的BTKI治疗患者 发展高血压，我们还将测量并将门诊血压与CMR测量相关。在AIM 2中， 我们将研究BTKI对定义重塑和重塑脆弱性的先天免疫反应的影响 通过研究IL-6，IL-17的循环水平，并使用无偏的单细胞基因组学，有系统地研究临床AF 破译有助于重塑及其关键促炎途径的免疫细胞。我们也会 定义这些参数与其他CMR测量值的关系。最后，使用我们的BTKI动物模型，我们将 测试针对性抑制促炎途径对心脏毒性重塑和AF风险的影响。之上 完成，我们将获得对激酶抑制剂在心脏毒性中的机械作用的重要见解 免疫失调如何导致血液系统恶性肿瘤的心律不齐。