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
基本信息
- 批准号:10632086
- 负责人:
- 金额:$ 54.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdultAntineoplastic AgentsBasic ScienceBreast Cancer PatientBreast Cancer TreatmentBreast Cancer survivorCancer ControlCancer PatientCancer SurvivorshipCardiacCardiac MyocytesCardiomyopathiesCardiotoxicityCardiovascular systemCessation of lifeChemotherapy-Oncologic ProcedureClinicalClinical ResearchClinical TrialsCoculture TechniquesCombined Modality TherapyCoupledCyclic GMPCyclic GMP-Dependent Protein KinasesDataDevelopmentDoseDoxorubicinERBB2 geneEarly DiagnosisEarly treatmentEpidermal Growth Factor ReceptorErectile dysfunctionFDA approvedFRAP1 geneHeartHeart DiseasesHeart InjuriesHeart failureHumanHypertrophyIL18 geneIn VitroIncidenceInflammationInflammatoryInjuryInterleukin-1 betaLaboratoriesMalignant NeoplasmsMammary NeoplasmsMeasuresMediatorMedicineModelingModernizationMonoclonal AntibodiesMorbidity - disease rateMusMyocardial Reperfusion InjuryMyocardial dysfunctionMyocardiumOutcomeOutcome StudyPatientsPharmaceutical PreparationsPhase I Clinical TrialsPlayPopulationProtein KinasePulmonary HypertensionRegimenResearchResistance developmentRiskRoleSequential TreatmentSignal PathwaySignal TransductionSirolimusSurvivorsTLR4 geneTestingTherapeuticTherapeutic EffectTransgenic MiceTrastuzumabTreatment EfficacyViagraWithholding TreatmentWomanWorkattenuationcancer cellcancer survivalcancer therapycardioprotectioncell killingchemotherapyclinically relevantcytokinedesigndiabeticeffective therapyexperienceheart functionimprovedin vivoinhibiting antibodyinhibitorinhibitor therapyinnovationinterestkinase inhibitormTOR InhibitormTOR inhibitionmalignant breast neoplasmmortalitymouse modelnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsoverexpressionphosphodiesterase Vpreventprotective effectresponseside effectsildenafiltreatment strategytriple-negative invasive breast carcinomatumortumor growthtumor progression
项目摘要
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。到
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Anindita Das', 18)}}的其他基金
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:
10522272 - 财政年份:2022
- 资助金额:
$ 54.72万 - 项目类别:
Novel small molecules for protection against doxorubicin cardiotoxicity in TNBC
用于保护 TNBC 免受阿霉素心脏毒性的新型小分子
- 批准号:
10617848 - 财政年份:2022
- 资助金额:
$ 54.72万 - 项目类别:
Novel Therapy for Protection against Diabetes and its Complications in Ischemic Heart Disease
预防糖尿病及其缺血性心脏病并发症的新疗法
- 批准号:
10330933 - 财政年份:2021
- 资助金额:
$ 54.72万 - 项目类别:
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