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.

项目概要/摘要 急性髓系白血病 (AML) 是一种致命的血液癌症，其特征是前体血液细胞的克隆扩增。 几十年来，强化化疗一直是 AML 治疗的支柱，但不幸的是，并非所有治疗都如此。 患者的健康状况足以接受治疗，尽管进行了强化治疗，但由于复发而导致的死亡最近很常见。 FDA 批准了一种较低强度的治疗方案，将低甲基化剂（如阿扎胞苷 (aza)）与 BCL2 抑制剂 Venetoclax (ven)，基于 3 期随机数据，显示总体生存获益，并且 跨 AML 预后亚型的高反应率 aza/ven 的成功凸显了细胞凋亡途径。 Venetoclax 作为一个令人兴奋的治疗靶点，通过拮抗其抗凋亡功能来诱导细胞凋亡。 BCL2 是多种线粒体 BH3 结构域蛋白之一，可调节 AML 原始细胞死亡的阈值。 活白血病细胞中的凋亡阈值或启动可以通过功能性细胞死亡测定来测量， 称为 BH3 分析，我最近证明了白血病转化的细胞来源。 我对 p53 活性改变引起的细胞凋亡引发和由此产生的治疗敏感性感兴趣。 了解 AML 细胞状态（无论是由 AML 基因型还是凋亡引发建立）如何影响 p53 功能减弱情况下的药物敏感性和临床结果。 AML 患者样本可以作为生物标志物来预测对 aza/ven 的治疗反应。 由突变 TP53 诱导的基因组不稳定性引起的复杂的细胞遗传学变化促进了 AML 我相信这项工作将独立于突变体 TP53。 解决具有治疗意义的重要生物学问题： 1. BH3 分析检测能否预测异种移植小鼠模型对 aza/ven 的治疗反应？ 2. 哪些转录和表观遗传途径参与低凋亡启动和低凋亡的 AML 细胞？ 对 aza/ven 的反应迟钝？ 3. TP53功能丧失情况下的复杂核型AML是旁观者现象吗？ 增强致白血病性和/或对 aza/ven 和化疗等疗法的耐药性？ MSKCC 的助理蔡胜博士将进行这项研究，作为其职业发展计划的一部分， 蔡博士将 85% 的时间用于研究，并得到世界血液学专家 Ross Levine 博士的指导。 他还得到了 Anthony Letai 博士（BH3 分析检测的开发者）、Scott Lowe 的建议。 Michael Kharas、Richard Koche 和 Andriy Derkach 的培训内容包括获取以下方面的知识。 生物标志物验证以及生物信息学和遗传小鼠模型方面的专业知识，长期目标是 作为血液恶性肿瘤的独立研究者制定研究计划 用于精准肿瘤学的功能化生物标志物测定。