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.
项目总结
项目成果
期刊论文数量(0)
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Anindita Das其他文献
Anindita Das的其他文献
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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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