Exploiting the Metabolic Dependencies of Pediatric AML
利用儿科 AML 的代谢依赖性
基本信息
- 批准号:10664637
- 负责人:
- 金额:$ 26.21万
- 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:2023-06-07 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAdult Acute Myeloblastic LeukemiaAffectAntimalarialsApoptosisAwardBiological AssayBone MarrowBone Marrow CellsCRISPR/Cas technologyCell DeathCell SurvivalCharacteristicsChemoresistanceChildChildhoodChildhood Acute Myeloid LeukemiaClinicalComplexCytotoxic ChemotherapyDataDependenceDevelopment PlansDiagnosticDiseaseDisease remissionDrug CombinationsDrug resistanceElectron TransportElectron Transport Complex IIIElementsEnvironmentEvaluationFDA approvedFLT3 geneFoundationsFundingFutureGene Expression ProfileGenesGoalsHematologic NeoplasmsHumanIn VitroInduction of ApoptosisInhibition of ApoptosisInstitutionKineticsKnowledgeLaboratoriesLaboratory FindingLearningLeukemic CellLiteratureMLL geneMalignant Childhood NeoplasmMass Spectrum AnalysisMeasuresMedical centerMedicineMentorsMentorshipMetabolicMetabolic PathwayMetabolismMitochondriaMyeloproliferative diseaseNewly DiagnosedOutcomeOxidative PhosphorylationPathway interactionsPatientsPediatric Oncology GroupPharmaceutical PreparationsPhosphorylation InhibitionPhysiciansPneumoniaPositioning AttributePublishingRecurrent diseaseRelapseResearchResearch PersonnelResistanceResourcesSamplingScholarshipScientistShapesStressTechniquesTestingTexasTherapeuticTimeTreatment ProtocolsTreatment-related toxicityWorkacute myeloid leukemia cellatovaquonebiological adaptation to stresscareercareer developmentchemotherapeutic agentchemotherapycohortcollegedesignexperimental studyimmunodeficient mouse modelimprovedleukemialeukemia treatmentmetabolomicsmortalitymouse modelpatient derived xenograft modelphase III trialpreclinical evaluationpreventprogramsrespiratorystandard carestem cell survivaltargeted agenttranscriptometranscriptome sequencing
项目摘要
The Candidate: I am well-positioned to become an independent academic physician-scientist and expert in
hematologic malignancies' metabolic dependencies. My commitment to improving cure-rates and decreasing
treatment toxicities for my pediatric acute myeloid leukemia (AML) patients drives me. We have already
optimized cytotoxic chemotherapy to its tolerability limit. So, to meaningfully improve pediatric AML outcomes—
a devastating disease with a ~50% mortality rate—we must identify and target AML-blast dependencies. Our lab
found that the proven, well-tolerated drug atovaquone (AQ) has anti-leukemia effects. This led me to design and
conduct a limited-institution trial to (1) assess how to incorporate AQ into upfront pediatric AML treatment
regimens and (2) collect biospecimens to use in my AQ experiments. The trial has also enabled the just-opened
Children's Oncology Group Phase III trial to collect data on AQ use in newly diagnosed AML patients. My goal
is to pinpoint the mechanism by which AQ targets leukemia cells and understand and target the metabolic
pathways that sustain them. I am committed to uncovering these pathways to better treat pediatric AML.
Career Development Plan: My data demonstrating that AQ significantly suppresses AML blasts' oxidative
phosphorylation (OXPHOS) has shaped my career goals. My mentorship team and the Texas Medical Center's
abundant resources, including Baylor College of Medicine's (BCM) graduate programs, will help me learn to
precisely target AML blasts' dysregulated metabolism. I will meet frequently with my primary mentor, Dr.
Sreekumar, to review data from my Aim 1a experiments and discuss results with my expert scholarship oversight
committee. My secondary mentor, Dr. Redell, will continue helping me navigate the Children's Oncology Group`s
complexities. BCM and my division will provide 75% protected research time and start-up funds in my K08
award's 4th year. I will then vie for an R01 focused on targeting pediatric AML blasts' dysregulated metabolism.
Research Plan: My work suggests that AQ induces apoptosis by inhibiting the electron transport chain's
complex III, thereby inhibiting OXPHOS. I hypothesize that OXPHOS suppression triggers the integrated stress
pathway (ISR) resulting in progression to cell death. We now know that chemotherapy-resistant AML cells
depend upon OXPHOS and that adult AML patients who take AQ for pneumonia have fewer relapses. To test
my hypothesis, I will use focused techniques to evaluate AML-cells' metabolic dependencies and AQ's impact
on them. I will use CRISPR-Cas9 gene-editing and our patient-derived xenografts to determine how soluble
factors known to promote chemotherapy-resistance augment AQ-induced apoptosis and to better understand
which patients might most benefit from treatments targeting OXPHOS dependency. I will measure AQ-induced
apoptosis in a large patient sample cohort and identify an AQ-sensitivity signature by comparing RNAseq-
generated sensitive- and resistant-sample transcriptomes. Understanding AML blasts' dysregulated metabolism
will form a strong foundation on which to build my career and help find better treatments for children with AML.
我很有能力成为一名独立的学术医师和科学家
项目成果
期刊论文数量(0)
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