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：我很容易成为独立的学术医师科学家和专家 血液学恶性肿瘤的代谢依赖性。我致力于改善治愈率和减少的承诺 治疗我的小儿急性髓样白血病（AML）患者的毒性使我受益匪浅。我们已经 优化的细胞毒性化学疗法达到其耐受性极限。因此，为了有意义地改善小儿AML的结果 - 死亡率约50％的毁灭性疾病 - 我们必须识别并靶向aml-blast依赖性。我们的实验室 发现已验证的，耐受良好的药物Atovaquone（AQ）具有抗白血病作用。这使我设计了 对（1）评估如何将AQ纳入前期小儿AML治疗的限量机构试验 方案和（2）收集在我的AQ实验中使用的生物测量。试验也使刚刚开放 儿童肿瘤学组III期试验，以收集有关新诊断的AML患者AQ使用的数据。我的目标 是为了查明AQ靶向白血病细胞并理解和靶向代谢的机制 维持它们的途径。我致力于发现这些途径以更好地治疗小儿AML。 职业发展计划：我的数据表明AQ极大地抑制了AML爆炸的氧化 磷酸化（OXPHOS）塑造了我的职业目标。我的Mentalship Team和Texas Medical Center的 包括贝勒医学院（BCM）研究生课程在内的丰富资源将帮助我学习 精确靶向AML爆炸的代谢失调。我会经常与我的主要导师博士见面。 Sreekumar，与我的专家科学监督一起回顾我的目标1A实验和讨论结果的数据 委员会。我的次要导师雷德尔博士将继续帮助我浏览儿童肿瘤学小组 复杂性。 BCM和我的部门将在我的K08中提供75％的保护时间和启动资金 奖项的第四年。然后，我将争夺重点靶向儿科AML Blasts的代谢失调的R01。 研究计划：我的工作表明AQ通过抑制电子传输链诱导凋亡 复合物III，从而抑制Oxphos。我假设OXPHOS抑制会触发综合应力 途径（ISR）导致向细胞死亡的发展。我们现在知道耐化疗的AML细胞 取决于Oxphos和为肺炎服用AQ的成年AML患者的继电器较少。测试 我的假设，我将使用集中技术来评估AML-Cells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衍生的Xenographictics来确定如何溶解 已知促进化学疗法增强AQ引起的凋亡并更好地理解的因素 哪些患者可能会受益于针对OXPHOS依赖性的治疗方法。我将测量AQ引起的 大型患者样品队列中的凋亡，并通过比较rnaseq-识别AQ敏感性特征 产生敏感和抗性样本的转录组。了解AML爆炸的代谢失调 将构成建立我的职业并帮助AML儿童更好地治疗的基础。