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

项目摘要 多柔比星（DOX）化疗方案在许多癌症治疗中起着重要作用。长 长期癌症存活率，大量癌症患者仍处于早期心血管疾病的风险中， DOX化疗导致的发病率和死亡率。此外，临床研究表明， 用ErbB 2抑制剂治疗DOX，曲妥珠单抗在改善癌症控制方面具有协同作用 在乳腺癌患者中的进展和生存率，并且优于单独使用任何一种药物。然而， 用ErbB 2抑制剂与DOX联合的疗法引起严重和侵袭性形式的心力衰竭。到 为了克服这一临床问题，我们提出了一种新的联合治疗与PDE 5抑制剂，西地那非（伟哥） 和mTOR抑制剂雷帕霉素在预防DOX和DOX序贯给药引起的严重心脏毒性中的作用 曲妥珠单抗在乳腺癌小鼠中的应用。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TLR 4的表达来确定炎症在心脏毒性发展中的作用， NLRP 3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抑制与相关的下游信号通路在保护免受 将研究DOX诱导的心功能不全。我们还将研究西地那非和雷帕霉素对 在增强DOX和DOX与曲妥珠单抗的抗肿瘤功效和改善心脏功能方面的治疗 在自发性和正交各向异性乳腺癌的临床相关小鼠模型中发挥作用。而且我们 将确定西地那非和雷帕霉素在心脏特异性ErbB 2肥大衰减中的作用。 转基因小鼠因为西地那非和雷帕霉素是临床批准的药物， 在开发新的联合疗法，治疗成千上万的癌症患者经历致命的 和使人衰弱的心脏毒性作用。

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.