Investigating apoptotic priming as a determinant of sensitivity to leukemia-directed therapies

研究细胞凋亡引发作为白血病定向治疗敏感性的决定因素

• 批准号: 10301504
• 负责人: Sheng Cai
• 金额: $ 25.5万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301504
• 关键词: Acute Myelocytic Leukemia; Address; Adopted; Amalgam; Apoptosis; Apoptotic; Attenuated; Azacitidine; BCL2 gene; BH3 Domain; Back; Bioinformatics; Biological; Biological Assay; Biological Markers; Biology; Blood; Cell Death; Cells; Cessation of life; Chromosomal Instability; Chromosome abnormality; Clinical; Clonal Evolution; Clonal Expansion; Combined Modality Therapy; Complex; Consequentialism; Cytogenetics; DNA Sequence Alteration; Data; Development Plans; Disease; Disease Progression; Disease remission; Dissection; Enterobacteria phage P1 Cre recombinase; Epigenetic Process; Erythroid; Event; Exhibits; FDA approved; Genetic; Genetic Transcription; Genomic Instability; Genotype; Goals; Hematologic Neoplasms; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Karyotype; Knowledge; Leukemic Cell; Maintenance; Malignant Neoplasms; Measures; Mediating; Megakaryocytes; Memorial Sloan-Kettering Cancer Center; Mentors; Mitochondria; Modeling; Molecular; Mus; Mutation; NPM1 gene; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Prediction of Response to Therapy; Randomized; Regimen; Relapse; Research; Research Personnel; Resistance; Risk; Role; Sampling; System; TP53 gene; TP53-mutant acute myeloid leukemia; Tertiary Protein Structure; Testing; Therapeutic; Time; Training; Validation; Work; Xenograft procedure; acute myeloid leukemia cell; aggressive therapy; base; biomarker validation; burden of illness; career development; chemotherapy; differential expression; drug sensitivity; high risk; individualized medicine; inhibitor/antagonist; interest; leukemia; leukemic transformation; loss of function; mortality; mouse model; mutant; novel; patient derived xenograft model; precision oncology; predict responsiveness; predictive test; progenitor; prognostic; programs; recombinase; relapse patients; response; restoration; standard of care; success; therapeutic biomarker; therapeutic target; therapy resistant; treatment planning; treatment response

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a lethal blood cancer characterized by a clonal expansion of precursor blood- forming cells. Intensive chemotherapy has been the mainstay of AML therapy for decades. Unfortunately, not all patients are fit enough to receive it and mortality due to relapse despite intensive treatment is common. Recently, the FDA approved a lower intensity regimen combining a hypomethylating agent, such as azacitidine (aza), with the BCL2 inhibitor venetoclax (ven), based on phase 3 randomized data showing an overall survival benefit and high response rates across AML prognostic subtypes. The success of aza/ven highlights the apoptotic pathway as an exciting therapeutic target. Venetoclax induces apoptosis by antagonizing the anti-apoptotic function of BCL2, one of many mitochondrial BH3-domain proteins that regulate the threshold at which an AML blast dies. This apoptotic threshold, or priming, in viable leukemic blasts can be measured via a functional cell death assay, called BH3 profiling. I have recently demonstrated that the cell of origin of leukemic transformation influences apoptotic priming and resultant therapeutic sensitivity via alterations in p53 activity. I am interested in understanding how AML cell state, whether established by AML genotype or apoptotic priming, can influence drug sensitivity and clinical outcomes in the context of attenuated p53 function. I hypothesize that BH3 profiling of AML patient samples can serve as a biomarker to predict treatment response to aza/ven. I also hypothesize that complex cytogenetic changes – ensuing from mutant TP53-induced genomic instability – promote AML progression and therapeutic resistance to aza/ven independent of mutant TP53. I believe that this work will address important biological questions with therapeutic implications: 1. Can BH3 profiling assays predict treatment response to aza/ven in xenograft mouse models? 2. Which transcriptional and epigenetic pathways are engaged in AML cells with low apoptotic priming and blunted responsiveness to aza/ven? 3. Is complex karyotype AML in the setting of TP53 loss of function a bystander phenomenon, or does it enhance leukemogenicity and/or resistance to therapies such as aza/ven and chemotherapy? Dr. Sheng Cai, an Assistant Attending at MSKCC, will conduct this study as part of his career development plan, dedicating 85% of his time to research. Dr. Cai is mentored by Dr. Ross Levine, a world expert in hematologic malignancies. He is also advised by Drs. Anthony Letai (who developed the BH3 profiling assay), Scott Lowe, Michael Kharas, Richard Koche, and Andriy Derkach. Dr. Cai's training will include gaining knowledge in biomarker validation and expertise in bioinformatics and genetic mouse models, with the long term goal of developing a research program as an independent investigator in hematologic malignancies developing functionalized biomarker assays for precision oncology.

项目摘要/摘要 急性髓样白血病（AML）是致命的血液癌，其特征是前体血液的克隆膨胀 形成细胞。数十年来，强化化疗一直是AML疗法的中流疗法。不幸的是，不是全部 患者足够适合接受它，并且由于缓解任务密集型治疗而导致的死亡率很常见。最近， FDA批准了较低的强度方案，该方案结合了甲基化剂，例如偶氮替丁（Aza）， Bcl2抑制剂Venetoclax（VEN），基于3阶段的随机数据，显示了总体生存益处和 AML预后亚型的高反应率。 Aza/Ven的成功突出了凋亡途径 作为令人兴奋的治疗目标。 Venetoclax通过拮抗抗凋亡功能，诱导凋亡 Bcl2，这是调节AML爆炸死亡阈值的许多线粒体BH3核蛋白之一。 可以通过功能性细胞死亡测定法测量这种凋亡性阈值或启动性的启动。 称为BH3分析。我最近证明了白血病转化的起源细胞会影响 通过改变p53活性的改变，凋亡启动和由此导致的治疗敏感性。我对 了解AML细胞状态如何通过AML基因型或凋亡启动是否可以影响 在p53功能减弱的背景下，药物敏感性和临床结果。我假设BH3分析 AML患者样品的生物标志物可以预测对AZA/VEN的治疗反应。我也假设 这种复杂的细胞遗传学变化 - 从突变体TP53诱导的基因组不稳定性随之而来的随之而来 - 促进AML 对AZA/VEN的进展和热阻力独立于突变体TP53。我相信这项工作会 解决重要的生物学问题具有治疗意义： 1。在Xenographic小鼠模型中，BH3分析测定可以预测对AZA/VEN的治疗反应吗？ 2。哪些转录和表观遗传途径在凋亡较低的AML细胞中参与 对Aza/ven的反应率钝了？ 3。在TP53功能丧失旁观者现象的情况下是复杂的核型AML，或者这样做 增强对AZA/VEN和化学疗法等疗法的白血病性和/或抗性？ 参加MSKCC的助理Sheng Cai博士将作为他的职业发展计划的一部分进行这项研究， 他的研究时间的85％。 CAI博士由血液学世界专家Ross Levine博士指导 恶性肿瘤。博士也建议他。安东尼·莱泰（Anthony Letai）（开发了BH3分析测定法），斯科特·洛（Scott Lowe）， 迈克尔·哈拉斯（Michael Kharas），理查德·科切（Richard Koche）和安德里（Andriy Derkach）。 CAI博士的培训将包括获得知识 生物标志物验证和生物信息学和遗传鼠标模型的专业知识，其长期目标的 作为血液系统恶性肿瘤的独立研究者制定研究计划 官能化的生物标志物测定精度肿瘤学。