Measuring treatment response and residual disease in leukemia with personalized, sensitive, and quantitative genomic methods

使用个性化、灵敏和定量的基因组方法测量白血病的治疗反应和残留疾病

• 批准号: 10197045
• 负责人: Andrea Moffitt
• 金额: $ 12.47万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-10-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197045
• 关键词: Acute Myelocytic Leukemia; Aftercare; Algorithmic Analysis; Benchmarking; Biological; Biology; Blood; Blood specimen; Cancer Biology; Cancer Patient; Cells; Clinical; Clinical Markers; Clinical Research; Communication; Computational algorithm; DNA; DNA Sequence Alteration; Data; Development; Development Plans; Diagnosis; Disease; Disease remission; Doctor of Philosophy; Drug resistance; Early Diagnosis; Educational process of instructing; Environment; Evaluation; Evolution; Fellowship; Frequencies; Future; Gene Frequency; Genetic; Genetic Heterogeneity; Genetic study; Genome; Genomics; Goals; Health; Hematopoiesis; Heterogeneity; In complete remission; Informatics; Intervention; Intervention Studies; Knowledge; Laboratories; Lead; Leukemic Cell; Long-Term Survivors; Lymphoma; Malignant Neoplasms; Measurement; Measures; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Biology; Monitor; Mutation; Nature; Neoplasm Circulating Cells; Nucleic Acids; Occupations; Paper; Patient-Focused Outcomes; Patients; Phenotype; Pilot Projects; Population; Property; Relapse; Research; Research Personnel; Residual Neoplasm; Residual Tumors; Residual state; Sampling; Sensitivity and Specificity; Techniques; Testing; Time; Training; Treatment Efficacy; Universities; Variant; Visit; Work; base; burden of illness; cancer genomics; cancer type; career development; cell free DNA; cell type; clinical translation; cost; disease heterogeneity; experience; follow-up; genetic variant; genomic data; genomic profiles; genomic tools; improved; innovation; insight; leukemia; liquid biopsy; meetings; mutant; precision genetics; predict clinical outcome; professor; prognostic value; single cell analysis; single cell technology; skills; stem cells; success; symposium; tenure track; transcriptomics; translational genomics; translational study; treatment response; whole genome

Project Summary To improve patient outcome in cancer, better methods are urgently needed to measure therapeutic response and detect early relapse. In acute myeloid leukemia (AML), 50% of patients in remission will relapse within 2 years. Current methods lack the sensitivity and generality to detect minimal residual disease (MRD) in all of those patients. Multiplex Accurate Sensitive Quantitation (MASQ), is both sensitive and general. It can target up to 50 patient-specific mutations, with sequence error rates reduced to 1 in 1 million, and count mutant DNA molecules with molecular tags. In a pilot study of AML, MASQ detected somatic variants at levels ranging from 1 in 100 to nearly 1 in 1 million, with higher mutation frequencies in patients who relapsed. There is also a critical need to interpret minimal residual disease in the context of pre-leukemic clonal hematopoiesis and the evolution of leukemic cells. Relapse may arise from drug-resistant leukemic cells, a genetically diverged subclone, or a reservoir of pre-leukemic stem cells. In this proposal, I apply and improve innovative genomic tools for measuring treatment response, predicting clinical outcome, and investigating the nature of residual cells in AML. This project utilizes a large observational clinical study of AML to track patient-specific leukemia-associated variants in blood samples taken over the course of the disease. Aim 1 will analyze subclonal treatment response and the dynamics of relapse by tracking leukemia-associated variant allele frequencies across time. Aim 2 will establish the prognostic value of a personalized, highly sensitive, and quantitative test for residual disease in AML. Aim 3 proposes to isolate the rare residual cells harboring leukemia-associated variants from a remission blood sample to determine the genomic and transcriptomic profiles that may provide further biological and clinical insight into the disease. I have proposed a tailored career development plan that will prepare me for my transition to independence. Following my postdoctoral fellowship training, I aim to be an independent tenure-track professor at a major research university. The training environment at Cold Spring Harbor Laboratory (CSHL) provides access to world-renowned meetings and courses, and a plethora of investigators with expertise in cancer and quantitative biology. My professional development activities center around mentorship, communication, teaching, lab management, and preparing for the academic job search. My training will also include coursework in clinical translation and single cell analysis; presentations at conferences in genome informatics, cancer biology, and liquid biopsy; and mentored research goals under the guidance of my mentor Dr. Michael Wigler and my co- mentor Dr. Dan Levy. I have assembled a team of additional scientific advisors and collaborators including Dr. David Tuveson and Dr. Christopher Vakoc from CSHL and Dr. Steven Allen from Northwell Health.

项目概要 为了改善癌症患者的治疗效果，迫切需要更好的方法来测量治疗反应 并发现早期复发。在急性髓系白血病 (AML) 中，50% 的缓解期患者会在 2 年内复发 年。目前的方法缺乏检测所有微小残留病 (MRD) 的敏感性和通用性。 那些病人。多重精确灵敏定量 (MASQ) 既灵敏又通用。它可以瞄准 多达 50 个患者特异性突变，序列错误率降至百万分之一，并对突变 DNA 进行计数 带有分子标签的分子。在 AML 的一项试点研究中，MASQ 检测到的体细胞变异水平为 百分之一到近百万分之一，复发患者的突变频率更高。还有一个关键 需要在白血病前克隆造血和进化的背景下解释微小残留病 白血病细胞。复发可能由耐药白血病细胞、基因分化的亚克隆或 白血病前期干细胞的储存库。在这个提案中，我应用并改进了创新的基因组工具来测量 治疗反应、预测临床结果并研究 AML 中残留细胞的性质。 该项目利用 AML 的大型观察性临床研究来追踪患者特异性白血病相关的 疾病过程中采集的血液样本中的变异。目标 1 将分析亚克隆治疗反应 以及通过随时间追踪白血病相关变异等位基因频率来了解复发的动态。目标2将 建立针对残余疾病的个性化、高灵敏度和定量检测的预后价值 反洗钱。目标 3 提出从缓解期分离出含有白血病相关变异的罕见残留细胞 血液样本以确定基因组和转录组图谱，从而提供进一步的生物学和临床信息 对疾病的深入了解。 我提出了一份量身定制的职业发展计划，为我向独立的过渡做好准备。 在完成博士后研究金培训后，我的目标是成为一个专业的独立终身教授 研究型大学。冷泉港实验室 (CSHL) 的培训环境提供了访问 世界知名的会议和课程，以及大量具有癌症和定量专业知识的研究人员 生物学。我的专业发展活动围绕指导、沟通、教学、实验室 管理，并为学术求职做准备。我的培训还将包括临床课程 翻译和单细胞分析；在基因组信息学、癌症生物学等会议上发表演讲 液体活检；并在我的导师 Michael Wigler 博士和我的同事的指导下指导研究目标 导师丹·利维博士。我组建了一个由其他科学顾问和合作者组成的团队，其中包括博士。 CSHL 的 David Tuveson 和 Christopher Vakoc 博士以及 Northwell Health 的 Steven Allen 博士。

项目成果

Recruiting women faculty through inclusive, family-friendly practices.

通过包容性、家庭友好的做法招聘女教师。

• DOI: 10.1016/j.tibs.2023.01.003
• 发表时间: 2023
• 期刊: Trends in biochemical sciences
• 影响因子: 13.8
• 作者: SanMartin,Rebeca;Moffitt,Andrea;Loveless,Theresa;Brixius-Anderko,Simone
• 通讯作者: Brixius-Anderko,Simone