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

抑制 PDE5-mTOR 减弱癌症药物心脏毒性的新策略

• 批准号: 10632086
• 负责人: Anindita Das
• 金额: $ 54.72万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632086
• 关键词: Adult; Antineoplastic Agents; Basic Science; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer survivor; Cancer Control; Cancer Patient; Cancer Survivorship; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cardiovascular system; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Coupled; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Development; Dose; Doxorubicin; ERBB2 gene; Early Diagnosis; Early treatment; Epidermal Growth Factor Receptor; Erectile dysfunction; FDA approved; FRAP1 gene; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Hypertrophy; IL18 gene; In Vitro; Incidence; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Laboratories; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediator; Medicine; Modeling; Modernization; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myocardial Reperfusion Injury; Myocardial dysfunction; Myocardium; Outcome; Outcome Study; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Population; Protein Kinase; Pulmonary Hypertension; Regimen; Research; Resistance development; Risk; Role; Sequential Treatment; Signal Pathway; Signal Transduction; Sirolimus; Survivors; TLR4 gene; Testing; Therapeutic; Therapeutic Effect; Transgenic Mice; Trastuzumab; Treatment Efficacy; Viagra; Withholding Treatment; Woman; Work; attenuation; cancer cell; cancer survival; cancer therapy; cardioprotection; cell killing; chemotherapy; clinically relevant; cytokine; design; diabetic; effective therapy; experience; heart function; improved; in vivo; inhibiting antibody; inhibitor; inhibitor therapy; innovation; interest; kinase inhibitor; mTOR Inhibitor; mTOR inhibition; malignant breast neoplasm; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; phosphodiesterase V; prevent; protective effect; response; side effect; sildenafil; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

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.

项目总结