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Mechanism of Targeted Cancer Therapeutics-Induced Cardiotoxicity.
Mechanism of Targeted Cancer Therapeutics-Induced Cardiotoxicity.
상세정보
- 자료유형
- 학위논문(국외)
- 기본표목-개인명
- 표제와 책임표시사항
- Mechanism of Targeted Cancer Therapeutics-Induced Cardiotoxicity.
- 발행, 배포, 간사 사항
- 발행, 배포, 간사 사항
- 형태사항
- 158 p.
- 일반주기
- Source: Dissertations Abstracts International, Volume: 87-03, Section: B.
- 일반주기
- Advisor: Lal, Hind;Verma, Suresh K.
- 학위논문주기
- Thesis (Ph.D.)--The University of Alabama at Birmingham, 2025.
- 요약 등 주기
- 요약Targeted cancer therapies are known to cause cardiovascular (CV) complications in human patients. Agents such as osimertinib, a tyrosine kinase inhibitor (TKI), as well as immune checkpoint inhibitors (ICIs) have been demonstrated to induce severe cardiotoxicities, including heart failure and myocarditis. Nevertheless, the mechanisms of TKIs and ICIs-induced cardiotoxicity remain poorly understood. Herein, we developed the first in vivo preclinical model of osimertinib-induced cardiotoxicity using a transverse aortic constriction (TAC) mouse model. Osimertinib-treated mice displayed severe cardiac dysfunction, elevated markers of heart failure and fibrosis, and failed to undergo compensatory hypertrophic remodeling, resulting in cardiomyocyte death. Mechanistically, we identified suppression of ERK/AKT prosurvival signaling, mitochondrial dysfunction, and activation of Bax/Bcl-xl apoptosis pathway. FDA-approved HDAC inhibitor Vorinostat (SAHA), restored cardiac function and cell survival while improving osimertinib's efficacy in non-small cell lung cancer (NSCLC)-derived PC9 cells. In a separate set of studies, we examined ICIs-associated myocarditis employing a myeloid-specific programmed death-ligand (PD-L1) knockout (KO) mice. Deletion of PD-L1 led to early-onset cardiac dysfunction, systemic inflammation, increased infiltration of CCR2+ pro-inflammatory macrophages, and enhanced T cell activation, revealing a critical immunoregulatory role for myeloid PD-L1 in maintaining cardiac homeostasis. Our findings define the mechanisms of cardiotoxicity induced by targeted therapies and highlight histone deacetylase (HDAC) inhibitions and myeloid-specific immune modulation as potential targeted strategies to mitigate treatment-related cardiac events.
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 비통제 색인어
- 부출표목-단체명
- 기본자료저록
- Dissertations Abstracts International. 87-03B.
- 전자적 위치 및 접속
- 원문정보보기
MARC
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■1001 ▼aToro-Cora, Angelica.
■24510▼aMechanism of Targeted Cancer Therapeutics-Induced Cardiotoxicity.
■260 ▼a[S.l.]▼bThe University of Alabama at Birmingham. ▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a158 p.
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-03, Section: B.
■500 ▼aAdvisor: Lal, Hind;Verma, Suresh K.
■5021 ▼aThesis (Ph.D.)--The University of Alabama at Birmingham, 2025.
■520 ▼aTargeted cancer therapies are known to cause cardiovascular (CV) complications in human patients. Agents such as osimertinib, a tyrosine kinase inhibitor (TKI), as well as immune checkpoint inhibitors (ICIs) have been demonstrated to induce severe cardiotoxicities, including heart failure and myocarditis. Nevertheless, the mechanisms of TKIs and ICIs-induced cardiotoxicity remain poorly understood. Herein, we developed the first in vivo preclinical model of osimertinib-induced cardiotoxicity using a transverse aortic constriction (TAC) mouse model. Osimertinib-treated mice displayed severe cardiac dysfunction, elevated markers of heart failure and fibrosis, and failed to undergo compensatory hypertrophic remodeling, resulting in cardiomyocyte death. Mechanistically, we identified suppression of ERK/AKT prosurvival signaling, mitochondrial dysfunction, and activation of Bax/Bcl-xl apoptosis pathway. FDA-approved HDAC inhibitor Vorinostat (SAHA), restored cardiac function and cell survival while improving osimertinib's efficacy in non-small cell lung cancer (NSCLC)-derived PC9 cells. In a separate set of studies, we examined ICIs-associated myocarditis employing a myeloid-specific programmed death-ligand (PD-L1) knockout (KO) mice. Deletion of PD-L1 led to early-onset cardiac dysfunction, systemic inflammation, increased infiltration of CCR2+ pro-inflammatory macrophages, and enhanced T cell activation, revealing a critical immunoregulatory role for myeloid PD-L1 in maintaining cardiac homeostasis. Our findings define the mechanisms of cardiotoxicity induced by targeted therapies and highlight histone deacetylase (HDAC) inhibitions and myeloid-specific immune modulation as potential targeted strategies to mitigate treatment-related cardiac events.
■590 ▼aSchool code: 0005.
■650 4▼aImmunology.
■650 4▼aCellular biology.
■650 4▼aOncology.
■653 ▼aTargeted cancer therapies
■653 ▼aCardiovascular
■653 ▼aTyrosine kinase inhibitor
■653 ▼aImmune checkpoint inhibitor
■690 ▼a0982
■690 ▼a0379
■690 ▼a0992
■690 ▼a0769
■71020▼aThe University of Alabama at Birmingham▼bCellular and Molecular Physiology.
■7730 ▼tDissertations Abstracts International▼g87-03B.
■790 ▼a0005
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357907▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
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