Defining the Contribution of Cellular Hypoxia to the Cardiotoxicity of Anticancer Anthracyclines and Trastuzumab

用来治疗儿童和成人癌症的蒽环类药物(如阿霉素)的临床应用受到阻碍。 在一些患者中发展为心脏毒性。在乳腺癌的情况下， 根据剂量的不同，蒽环类药物引起的心力衰竭可能高达~26%。抗ERBB2抗体的使用 受体抗体曲妥珠单抗(Herceptin)联合蒽环类药物可增加临床心脏病的发生率 与单独使用曲妥珠单抗相比，失败率约为5倍。伴随而来的冠心病(CHD)是一种常见的 成人癌症患者的共病增加了心脏毒性的风险。暴露于心脏毒性化疗是 300万乳房幸存者心血管死亡风险高的一个主要因素 我们。癌症合并冠心病患者药物心脏毒性风险增加的分子基础 仍有待阐明。这种根本的知识差距阻碍了设计和实施 量身定制的临床策略，以减轻癌症和冠心病患者心脏毒性的发展。这个 冠心病的特征是存在心肌细胞缺氧。我们已获得初步数据显示， 慢性阻塞性肺疾病患者心肌组织中关键的蒽环类代谢酶的表达增加 先心病。此外，我们最近发现ERBB2基因座上的DNA甲基化是一种新的表观遗传学 曲妥珠单抗靶标ERBB2心肌表达的决定因素。我们现在的目标是确定 这些遗传、表观遗传和新陈代谢变化对药物引起的死亡率增加的贡献 癌症合并冠心病患者的心脏毒性。基于令人兴奋的初步数据，我们的中心假设是 心脏毒性蒽环类代谢物合成增加和心肌表达改变 与冠心病相关的ERBB2的增加是药物引起的心脏毒性增加的原因。目标1中的研究将 测定心肌细胞缺氧对其细胞内代谢和毒理动力学的影响 蒽环类药物。目的2将确定CBR3 V244M变异对功能的影响，这是一种遗传风险因素 我们确定的心脏毒性，在心肌细胞缺氧的情况下，对蒽环类药物的毒性动力学的影响。 由于蒽环类药物和ERBB2抑制剂之间的心脏毒性相互作用已有文献记载 曲妥珠单抗在乳腺癌治疗中，目标3中的研究将确定区别治疗的效果 ERBB2甲基化对曲妥珠单抗心脏毒性的影响。我们将定量评估两者之间的关联 接受曲妥珠单抗治疗的患者的ERBB2甲基化状态和心脏射血分数 转移性乳腺癌。这些综合研究将提供新的数据，以帮助设计更有效的 以及毒性较低的治疗方案，用于影响数百万美国人的癌症。

The clinical use of anthracyclines (e.g., doxorubicin) for the therapy of pediatric and adult cancers is hampered by the development of cardiotoxicity in some patients. In the breast cancer setting, the incidence of anthracycline-induced heart failure can be as high as ~26% depending on dose. The use of the anti-ERBB2 receptor antibody trastuzumab (Herceptin) plus anthracyclines can increase the incidence of clinical heart failure by ~5 fold in comparison to trastuzumab alone. Concomitant coronary heart disease (CHD), a prevalent comorbidity in adults with cancer, increases the risk for cardiotoxicity. Exposure to cardiotoxic chemotherapy is a major contributor to the high risk for cardiovascular mortality experienced by 3 million breast survivors in the US. The molecular basis of the increased risk for drug-induced cardiotoxicity in cancer patients with CHD remains to be elucidated. This fundamental gap in knowledge hampers the design and implementation of tailored clinical strategies to mitigate the development of cardiotoxicity in patients with cancer and CHD. The hallmark of CHD is the presence of cardiac cell hypoxia. We have obtained preliminary data indicating that the expression of key anthracycline metabolizing enzymes is increased in myocardial tissue from individuals with CHD. Also, we have recently shown that DNA methylation in the ERBB2 locus is a novel epigenetic determinant of the myocardial expression of the trastuzumab target ERBB2. Our objective now is to determine the contribution of these genetic, epigenetic, and metabolic changes to the increase in drug-induced cardiotoxicity in cancer patients with CHD. Based on exciting preliminary data, our central hypothesis is that the increased myocardial synthesis of cardiotoxic anthracycline metabolites and altered myocardial expression of ERBB2 associated with CHD are responsible for increased drug-induced cardiotoxicity. Studies in Aim 1 will determine the effect of cardiac cell hypoxia on the intracellular metabolism and toxicodynamics of anthracyclines. Aim 2 will determine the functional impact of the CBR3 V244M variant, a genetic risk factor for cardiotoxicity identified by us, on the toxicodynamics of anthracyclines in the context of cardiac cell hypoxia. Because of the well documented cardiotoxic interactions between anthracyclines and the ERBB2 inhibitor trastuzumab during treatment for breast cancer, studies in Aim 3 will determine the effects of differential ERBB2 methylation on the cardiotoxicity of trastuzumab. We will quantitatively assess associations between ERBB2 methylation status and cardiac ejection fraction in patients that had received trastuzumab for metastatic breast cancer. These integrative studies will provide new data to assist the design of more effective and less toxic therapeutic regimens for cancers affecting millions of Americans.