Exploiting the Metabolic Dependencies of Pediatric AML

利用儿科 AML 的代谢依赖性

• 批准号: 10664637
• 负责人: Alexandra Stevens
• 金额: $ 26.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10664637
• 关键词: Acute Myelocytic Leukemia; Adult Acute Myeloblastic Leukemia; Affect; Antimalarials; Apoptosis; Award; Biological Assay; Bone Marrow; Bone Marrow Cells; CRISPR/Cas technology; Cell Death; Cell Survival; Characteristics; Chemoresistance; Child; Childhood; Childhood Acute Myeloid Leukemia; Clinical; Complex; Cytotoxic Chemotherapy; Data; Dependence; Development Plans; Diagnostic; Disease; Disease remission; Drug Combinations; Drug resistance; Electron Transport; Electron Transport Complex III; Elements; Environment; Evaluation; FDA approved; FLT3 gene; Foundations; Funding; Future; Gene Expression Profile; Genes; Goals; Hematologic Neoplasms; Human; In Vitro; Induction of Apoptosis; Inhibition of Apoptosis; Institution; Kinetics; Knowledge; Laboratories; Laboratory Finding; Learning; Leukemic Cell; Literature; MLL gene; Malignant Childhood Neoplasm; Mass Spectrum Analysis; Measures; Medical center; Medicine; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Myeloproliferative disease; Newly Diagnosed; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Pediatric Oncology Group; Pharmaceutical Preparations; Phosphorylation Inhibition; Physicians; Pneumonia; Positioning Attribute; Publishing; Recurrent disease; Relapse; Research; Research Personnel; Resistance; Resources; Sampling; Scholarship; Scientist; Shapes; Stress; Techniques; Testing; Texas; Therapeutic; Time; Treatment Protocols; Treatment-related toxicity; Work; acute myeloid leukemia cell; atovaquone; biological adaptation to stress; career; career development; chemotherapeutic agent; chemotherapy; cohort; college; design; experimental study; immunodeficient mouse model; improved; leukemia; leukemia treatment; metabolomics; mortality; mouse model; patient derived xenograft model; phase III trial; preclinical evaluation; prevent; programs; respiratory; standard care; stem cell survival; targeted agent; transcriptome; transcriptome sequencing

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