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.

摘要： 近25万成年人患有慢性淋巴细胞白血病（CLL）。布鲁顿酪氨酸激酶抑制剂 （BTKIs）显著改善CLL的生存率。然而，高达38%的患者发生房颤（AF）， 其他心血管毒性。伊布替尼是第一个被批准的具有这些毒性的BTKI，但我们的数据表明， 新的BTKI（例如，acalabrutinib、zanurotinib）仍然与心脏毒性相关。房颤伴BTKI的发展 是具有挑战性的，并且是在患者中使用有效疗法的主要障碍。因此，迫切需要 需要识别有房颤风险的患者，并更好地了解诱导BTKI相关性房颤的靶向途径。 AF.我们小组已经确定了BTKI的大多数早期心脏肿瘤问题。我们还开发了动物 这些模型表明BTKIs引起直接的心脏毒性以及先天免疫的激活， 可能导致心脏毒性和心律失常并导致左心房收缩早期增加的反应 (LA)纤维化和体积（左心房重塑）之前BTKI相关的AF。我们将利用积极的心脏， 在俄勒冈州立大学和加州大学旧金山分校的肿瘤学项目和资源， BTKIs在人类我们的临床前研究特别涉及先天免疫反应的激活， 以循环IL-6（和IL-17）升高为标志，IL-6（和IL-17）是BTKI相关AF发展的关键介质， 这会导致左心房重构和心脏毒性房颤。然而，目前还没有前瞻性研究来测试 免疫激活介导或预测心脏毒性事件。为了解决这些翻译和临床差距， 我们将招募120名开始BTKI治疗的CLL患者， 共振成像（CMR）和前沿的免疫技术来测试我们的假设，BTKI- 相关的AF由诱导心脏重塑和心律失常的免疫激活增加驱动。在Aim中 首先，我们测试了BTKI治疗开始前、2个月和6个月后BTKI对LA纤维化和体积的影响。我们 将通过在术后1年内应用连续移动的ECG监测来确定BTKI相关AF的负担， BTKI启动。这些结果将与60名年龄、性别和心脏风险匹配的对照组进行比较， CLL期，仅接受标准观察治疗。正如我们所观察到的，>50%的BTKI治疗患者 如果发生高血压，我们还将测量动态血压并将其与CMR测量相关联。在目标2中， 我们将研究BTKIs对先天免疫反应的影响，先天免疫反应定义了重塑的脆弱性， 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，系统地 破译有助于重塑的免疫细胞及其关键的促炎途径。我们还将 定义这些参数与其他CMR措施的关系。最后，使用我们的BTKI动物模型，我们将 测试靶向抑制促炎通路对心脏毒性重塑和AF风险的影响。后 完成后，我们将获得重要的见解激酶抑制剂在心脏毒性的机制作用， 以及免疫失调如何导致恶性血液病的心律失常。