Novel Strategy of PDE5-mTOR Inhibition in Attenuation of Cancer Drug Cardiotoxicity

项目概要 阿霉素 (DOX) 化疗方案在许多癌症治疗中发挥着重要作用。与长 足月癌症幸存者中，大量癌症患者仍然面临早期心血管疾病的风险 DOX 化疗引起的发病率和死亡率。此外，临床研究表明，顺序 DOX与ErbB2抑制剂、曲妥珠单抗治疗在改善癌症控制方面具有协同作用 乳腺癌患者的进展和生存，并且优于单独使用任何一种药物。然而，组合 ErbB2 抑制剂与 DOX 联合治疗会导致严重且侵袭性的心力衰竭。至 为了克服这个临床问题，我们提出了一种新的 PDE5 抑制剂西地那非（伟哥）联合疗法 和mTOR抑制剂雷帕霉素预防DOX和序贯DOX引起的严重心脏毒性 在患有乳腺癌的小鼠中使用曲妥珠单抗。我们将评估西地那非的治疗效果 雷帕霉素对 DOX 诱导的体外心肌细胞死亡和体内心脏功能的影响。此外，我们将 通过测量 TLR4 的表达来确定炎症在心脏毒性发展中的作用， NLRP3 和促炎细胞因子，包括 IL-1β 和 IL-18。 cGMP依赖性蛋白激酶的作用 G (PKG) 激活和 mTOR 抑制以及相关的下游信号通路可预防 将研究 DOX 引起的心脏功能障碍。我们还将研究西地那非和雷帕霉素的效果 增强 DOX 和 DOX 联合曲妥珠单抗的抗肿瘤功效并改善心脏功能的治疗 在自发性和正交异性乳腺癌临床相关小鼠模型中的功能。此外，我们 将确定西地那非和雷帕霉素在减弱心脏特异性 ErbB2 肥大中的作用 转基因小鼠。由于西地那非和雷帕霉素是临床批准的药物，因此拟议的研究可能会有所帮助 开发新型联合疗法来治疗数千名经历致命癌症的患者 DOX 和曲妥珠单抗在全球范围内造成的衰弱心脏毒性作用。

Project Summary Doxorubicin (DOX) chemotherapy regimens play a prominent role in many cancer treatments. With long term cancer survivorship, a substantial population of cancer patients remain at risk of early cardiovascular morbidity and mortality due to DOX chemotherapy. Moreover, clinical studies have revealed that sequential treatment of DOX with the ErbB2 inhibitor, Trastuzumab has synergistic effects in improving the control of cancer progression and survival in breast cancer patients, and is better than either drug alone. However, the combination therapies with the ErbB2 inhibitor coupled with DOX cause severe and aggressive form of heart failure. To overcome this clinical problem, we propose a novel combination therapy with PDE5 inhibitor, sildenafil (Viagra) and mTOR inhibitor, rapamycin in preventing the severe cardiotoxicity caused by DOX and DOX with sequential use of Trastuzumab in breast cancer-bearing mice. We will evaluate the therapeutic effect of sildenafil and rapamycin on DOX-induced cardiomyocyte death in vitro and cardiac function in vivo. In addition, we will determine the role of inflammation in the development of cardiotoxicity by measuring the expression of TLR4, NLRP3 and pro-inflammatory cytokines including IL-1β and IL-18. The role of cGMP-dependent protein kinase G (PKG) activation and mTOR inhibition with associated downstream signaling pathways in protecting against DOX-induced cardiac dysfunction will be studied. We will also investigate the effect sildenafil and rapamycin treatment in potentiating the anti-tumor efficacy of DOX and DOX with Trastuzumab and improvement of cardiac function in the clinically relevant mouse models of spontaneous and orthotropic breast cancer. Furthermore, we will determine the effect of sildenafil and rapamycin in attenuation of hypertrophy in cardiac specific ErbB2 transgenic mice. Because sildenafil and rapamycin are clinically approved drugs, the proposed studies may help in developing novel combination therapy for treatment of thousands of cancer patients experiencing the lethal and debilitating cardiotoxic effects of DOX and Trastuzumab worldwide.