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.

应聘者：我很有能力成为一名独立的学术内科医生--科学家和 恶性血液病的代谢依赖性。我致力于提高治愈率和降低 我的儿科急性髓系白血病(AML)患者的治疗毒性驱使着我。我们已经这么做了 优化细胞毒化疗，使其耐受性达到极限。因此，为了有意义地改善儿童急性髓细胞白血病的预后- 这是一种死亡率约为50%的毁灭性疾病--我们必须识别并瞄准AML-BLAST依赖。我们的实验室 研究发现，经过验证、耐受性良好的药物阿托瓦酮(AQ)具有抗白血病作用。这让我想到了设计和 进行有限机构试验，以(1)评估如何将AQ纳入儿童急性髓系白血病的前期治疗 养生法和(2)收集生物杀虫剂用于我的AQ实验。这项试验也使刚刚开业的 儿童肿瘤学小组第三阶段试验，收集新诊断的AML患者使用AQ的数据。我的目标 就是找出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：我的数据显示AQ显著抑制急性髓系白血病细胞的氧化 磷酸化(OXPHOS)塑造了我的职业目标。我的导师团队和德克萨斯医疗中心的 丰富的资源，包括贝勒医学院(BCM)的研究生课程，将帮助我学习 精确靶向急性髓系白血病细胞的代谢紊乱。我将经常与我的主要导师Dr。 Sreekumar，审查我Aim 1a实验的数据，并与我的专家奖学金监督人员讨论结果 委员会审议阶段。我的二级导师雷德尔博士将继续帮助我在儿童肿瘤学小组的 很复杂。BCM和我的部门将在我的K08中提供75%受保护的研究时间和启动资金 这是该奖项的第四个年头。然后，我将争夺R01，专注于针对儿科AML原始细胞的失调代谢。 研究计划：我的工作表明，AQ通过抑制电子传递链诱导细胞凋亡 络合物III，从而抑制OXPHOS。我假设OXPHOS抑制触发了整合应激 导致细胞死亡的途径(ISR)。我们现在知道耐化疗的AML细胞 依赖于OXPHOS，服用AQ治疗肺炎的成年AML患者复发较少。为了测试 我的假设是，我将使用有针对性的技术来评估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来确定如何溶解 已知的促进化疗耐药的因子增加AQ诱导的细胞凋亡并更好地了解 哪些患者可能从针对OXPHOS依赖的治疗中受益最大。我会测量AQ诱导的 大样本队列中的细胞凋亡，并通过比较RNAseq-1确定AQ敏感性特征 生成了敏感和耐药样本转录本。了解急性髓系白血病原始细胞的代谢异常 将为我的事业奠定坚实的基础，并帮助为AML儿童找到更好的治疗方法。