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.

候选人：我有能力成为一名独立的学术物理学家，科学家和专家， 血液恶性肿瘤的代谢依赖性。我致力于提高治愈率， 我的儿科急性髓细胞白血病（AML）患者的治疗毒性驱使我。 优化细胞毒性化疗至耐受极限。所以，为了有意义地改善儿童AML的预后- 这是一种死亡率约为50%的毁灭性疾病，我们必须确定并靶向AML-原始细胞依赖性。我们实验室 研究人员发现，经证实的耐受性良好的药物阿托伐醌（AQ）具有抗白血病作用。这促使我设计和 开展有限机构试验，以（1）评估如何将AQ纳入前期儿科AML治疗 方案和（2）收集生物标本用于我的AQ实验。审判也使刚刚开放的 儿童肿瘤组III期试验，收集新诊断的AML患者使用AQ的数据。我的目标 是查明AQ靶向白血病细胞的机制，并了解和靶向代谢 维持它们的路径。我致力于揭示这些途径，以更好地治疗儿童AML。 职业发展计划：我的数据表明AQ显著抑制AML原始细胞的氧化 磷酸化（OXPHOS）塑造了我的职业目标。我的导师团队和德州医疗中心 丰富的资源，包括贝勒医学院（Baylor College of Medicine）的研究生课程，将帮助我学会 精确地针对AML原始细胞失调的代谢。我将经常与我的主要导师，博士。 Sreekumar，审查我的Aim 1a实验数据，并与我的专家奖学金监督讨论结果 以马克思我的第二位导师Redell博士将继续帮助我在儿童肿瘤学小组的 复杂性我的K 08将提供75%的研究时间和启动资金 颁奖的第四个年头。然后，我将争取一个R 01专注于针对儿童AML原始细胞的代谢失调。 研究计划：我的工作表明，AQ通过抑制电子传递链的 复合物III，从而抑制OXPHOS。我假设OXPHOS抑制触发了综合应激 ISR途径导致细胞死亡。我们现在知道耐化疗的AML细胞 依赖于OXPHOS，服用AQ治疗肺炎的成人AML患者复发较少。测试 我的假设，我将使用集中的技术来评估AML细胞的代谢依赖性和AQ的影响 在他们身上。我将使用CRISPR-Cas9基因编辑和我们的患者来源的异种移植物来确定 已知促进化疗抵抗的因子增加了AQ-induced凋亡， 哪些患者可能最受益于针对OXPHOS依赖性的治疗。我将测量AQ-induced 细胞凋亡，并通过比较RNAseq- 产生了敏感和耐药样本转录组。了解AML原始细胞的代谢失调 这将为我的职业生涯奠定坚实的基础，并帮助为AML儿童找到更好的治疗方法。