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

基本信息

批准号：
10041004
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10041004
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

项目摘要

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.

项目摘要为了改善癌症的患者预后，迫切需要更好的方法来测量治疗反应并检测早期复发。在急性髓样白血病（AML）中，50％的缓解患者将复发2 年。当前的方法缺乏检测所有最小残留疾病（MRD）的敏感性和普遍性那些患者。多路复用精确的敏感定量（MASQ）既敏感又一般。它可以定位至50个患者特异性突变，序列错误率降低到100万中的1个，并计算突变体DNA 具有分子标签的分子。在一项针对AML的试点研究中，MASQ检测 100万至100万分之一的1分之一，复发的患者的突变频率较高。也有关键需要解释在美食前克隆造血和进化的背景下的最小残留疾病白血病细胞。复发可能是由耐药性白血病细胞，遗传差异的亚克隆或A 白血病前干细胞的储层。在此建议中，我应用并改善了创新的基因组工具来衡量治疗反应，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跟踪患者特异性白血病相关在疾病过程中采集的血液样本的变体。 AIM 1将分析亚克隆治疗反应以及通过跟踪与白血病相关的变体等位基因频率的复发动力学。 AIM 2意志建立个性化，高度敏感和定量测试的预后价值，以实现残留疾病 AML。 AIM 3提议隔离带有白血病相关变体的稀有残留细胞与缓解血液样本以确定可能提供进一步生物学和临床的基因组和转录谱。对疾病的洞察力。我提出了一项量身定制的职业发展计划，这将使我为过渡到独立做准备。经过博士后奖学金培训，我的目标是成为一名专业的独立终身教授研究大学。冷春港实验室（CSHL）的培训环境可通往世界知名会议和课程，以及大量具有癌症专业知识和定量专业知识的调查员生物学。我的专业发展活动集中于指导，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，癌症生物学和液体活检；并在我的导师迈克尔·威格勒（Michael Wigler）博士和我的共同指导下指导了研究目标导师Dan Levy博士。我已经组建了一个包括Dr.的其他科学顾问和合作者团队。来自CSHL的David Tuveson和Christopher Vakoc博士以及Northwell Health的Steven Allen博士。