Mitochondrial Dysfunction underlies treatment related hepatotoxicity in Hispanics with acute lymphoblastic leukemia
线粒体功能障碍是西班牙裔急性淋巴细胞白血病治疗相关肝毒性的基础
基本信息
- 批准号:10675403
- 负责人:
- 金额:$ 44.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-14 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Aconitate HydrataseAcute Lymphocytic LeukemiaAdolescent and Young AdultAdultAdult Acute Lymphocytic LeukemiaAftercareAlanine TransaminaseAmino Acid SubstitutionAmino AcidsApoptosisAsparagineAspartate TransaminaseBilirubinBioenergeticsBiologicalBiological MarkersBody mass indexCaucasiansCellsCessation of lifeCharacteristicsChildChildhoodClinicalCluster AnalysisClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComputer ModelsCytoprotectionDNADataEnzymesEthnic OriginEthnic PopulationEtiologyExhibitsFrequenciesFutureGeneticGenetic PolymorphismGenetic VariationGenotypeGlutamineHepatocyteHepatotoxicityHigh PrevalenceHispanicHispanic PopulationsHydrogen PeroxideImpairmentIncidenceInferiorLinkLipidsLiverLos AngelesMalignant Childhood NeoplasmMeasurementMeasuresMediatingMetabolicMetabolic DiseasesMitochondriaModelingMutationNot Hispanic or LatinoObesityOutcomeOxidation-ReductionOxidative StressOxygenPatient riskPatientsPediatric HospitalsPermeabilityPharmaceutical PreparationsPharmacogenomicsPhase III Clinical TrialsPopulationPrevalenceProteinsReactive Oxygen SpeciesRecommendationRegimenReportingResearchRiskSOD2 geneSamplingSeveritiesSuperoxide DismutaseSuperoxidesSurvival RateTherapeutic EffectToxic effectTrainingTreatment-related toxicityUnderrepresented Populationsage groupantioxidant enzymeasparaginasebiological adaptation to stresscancer typechemotherapyclassification treesclinical phenotypecohortcomputerized toolsdrug induced liver injuryexperiencegenetic varianthigh body mass indexhigh riskimprovedinsightmachine learning methodmitochondrial dysfunctionnovel therapeuticsoxidationpediatric patientspredictive modelingpredictive toolsregression treesrisk varianttherapeutically effectivetherapy developmenttreatment risktrendyoung adult
项目摘要
PROJECT TITLE: Mitochondrial dysfunction underlies treatment related hepatotoxicity in Hispanics with
acute lymphoblastic leukemia
ABSTRACT:
Acute Lymphoblastic leukemia is the most common type of cancer in children with higher prevalence in
Hispanics. While overall survival for children with acute lymphoblastic leukemia (ALL) has reached approximately
90%, the outcome for adult patients with ALL remains poor (<45%). Hispanic children and adolescent and young
adult (AYA) both also suffer inferior outcomes. The intensive use of asparaginase in pediatric regimens has
enhanced the cure rate of children, but the higher rate of asparaginase-related toxicity in adults has limited its
widespread use in this age group. Hepatotoxicity is a particularly important drug-induced contraindication, as
current recommendations of withholding asparaginase treatment when grade 3 or 4 hepatotoxicity develops,
which occurs in approximately 30% of ALL patients, may compromise its therapeutic effect. Hispanic patients
developed hepatotoxicity at an increased rate compared with other ethnicities. Obese and/or older children are
particularly at risk for hepatotoxicity. Unfortunately, pharmacogenomic studies of asparaginase in ALL are limited
and mostly focus on Caucasian pediatric patients. In a predominantly non-Hispanic population, we previously
reported that genetic variant rs4880 in SOD2, which encodes a key mitochondrial enzyme protective against
reactive oxygen species (ROS), is associated with asparaginase-induced hepatotoxicity in adult ALL patients.
The high-risk CC genotype is more common in Hispanic individuals, who also exhibit a greater prevalence of
ALL and asparaginase-induced hepatotoxicity than other ethnicities. In a largely Hispanics cohort of 143 pediatric
patients with ALL who have received asparaginase based regimen, we found higher elevation of liver enzymes
post treatment with asparaginase in Hispanics than non-Hispanics. The rs4880 CC genotype was significantly
also more frequent in Hispanics and was associated with elevated liver enzymes post asparaginase treatment
and higher body mass index which was also higher is Hispanic patients. Altogether, these data suggest an
oxidative stress etiology involved in a wide range of metabolic disorders leading to liver toxicities associated with
asparaginase in patients with ALL. Here we propose to explore the link between the mitochondrial enzymes and
mitochondrial dysfunction and asparaginase induced hepatotoxicity in Hispanics. We hypothesize that
mitochondrial dysfunction and oxidative stress contribute to asparaginase-induced hepatotoxicity in
Hispanics. Our aims are: Aim 1) Identify genetic and metabolic alterations in the mitochondria that contribute
to asparaginase-induced hepatotoxicity in Hispanics. Aim 2) Develop a computational model to predict
asparaginase-induced hepatotoxicity in Hispanic patients with ALL.
Our study will provide functional evidence of the association between the mitochondrial dysfunction and
asparaginase related hepatotoxicity in Hispanics and provide clinically useful tool for predicting asparaginase-
induced hepatotoxicity in Hispanic patients with ALL. More broadly, our findings will reveal mechanistic insights
needed to develop therapies with reduced toxicity and improved efficacy in patients with ALL.
项目标题:线粒体功能障碍是西班牙裔糖尿病患者治疗相关肝毒性的基础
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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Houda Alachkar其他文献
Houda Alachkar的其他文献
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{{ truncateString('Houda Alachkar', 18)}}的其他基金
Leveraging the TCR Repertoire to identify target neoantigens in FLT3-ITD positive Acute Myeloid Leukemia
利用 TCR 库识别 FLT3-ITD 阳性急性髓系白血病的目标新抗原
- 批准号:
10618925 - 财政年份:2021
- 资助金额:
$ 44.24万 - 项目类别:
Leveraging the TCR Repertoire to identify target neoantigens in FLT3-ITD positive Acute Myeloid Leukemia
利用 TCR 库识别 FLT3-ITD 阳性急性髓系白血病的目标新抗原
- 批准号:
10410355 - 财政年份:2021
- 资助金额:
$ 44.24万 - 项目类别:
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