Preclinical Validation of Personalized Molecular Assays for Measurable Residual Disease Monitoring in Pediatric AML

用于儿科 AML 可测量残留疾病监测的个性化分子检测的临床前验证

• 批准号: 10643568
• 负责人: Amanda C Winters
• 金额: $ 22.79万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643568
• 关键词: Acute Myelocytic Leukemia; Adolescent and Young Adult; Adult Acute Lymphocytic Leukemia; Adult Acute Myeloblastic Leukemia; Aftercare; Allogenic; American Society of Hematology; Area; Bioinformatics; Biological Assay; Biological Sciences; Bone Marrow; Bone Marrow Transplantation; CBFA2T1 gene; Cause of Death; Child; Childhood; Childhood Acute Myeloid Leukemia; Chimerism; Clinical; Clinical Trials Design; Collaborations; Colorado; Custom; Data Analyses; Detection; Development; Diagnostic; Disease; Disease Marker; Disease Outcome; Disease remission; Early Intervention; Early identification; Environment; Faculty; Flow Cytometry; Fostering; Foundations; Frequencies; Genes; Goals; Hematologic Neoplasms; Incidence; Jordan; K-Series Research Career Programs; Measurable; Measures; Medical; Mentors; Modality; Molecular; Monitor; Morbidity - disease rate; Morphology; Mutation; Mutation Detection; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; NPM1 gene; Observational Study; Patients; Pediatric Hospitals; Pediatric Oncologist; Pediatric Oncology Group; Pediatric cohort; Physicians; Population; Predictive Value; Probability; Prospective cohort; RUNX1 gene; Relapse; Research; Residual Neoplasm; Resources; Retrospective cohort; Sampling; Scientist; Stem cell transplant; Survival Rate; Technical Expertise; Technology; Testing; Time; Translational Research; Transplantation; Universities; Validation; Wages; Work; adolescent patient; assay development; burden of illness; career; chemotherapy; cohort; design; digital; digital measure; experience; high risk; improved; improved outcome; knowledge base; leukemia; meetings; mortality; mutation assay; next generation sequencing; novel; patient oriented research; pediatric patients; post-transplant; pre-clinical; prevent; prospective; relapse patients; relapse prediction; relapse risk; research clinical testing; success; tool; translational physician; tumor

PROJECT SUMMARY/ABSTRACT My long-term career goal is to improve outcomes for pediatric patients with acute myeloid leukemia (AML), in part through development of improved modalities to detect residual disease and thus allow early identification and intervention for those patients at highest risk of relapse. My clinical experience as a pediatric oncologist specializing in treatment of myeloid malignancies informs my translational research focus in this area. This mentored career development award will facilitate my development into an independent translational physician- scientist by providing salary support and protected time to enhance my technical skills, knowledge base, and personal development in digital PCR (dPCR) assay development and validation, duplex NGS technology, NGS data analysis and bioinformatics, clinical trial design and development, networking, and collaboration. My mentoring team comprised of Dr. Craig Jordan (primary mentor), Dr. Dan Pollyea, Dr. Mike Verneris, and Dr. Chris Hourigan are all leaders in their respective fields and have a proven track record of fostering trainees and junior faculty to successful academic careers. The resource-rich environment on the Anschutz Medical Campus of the University of Colorado and the access to patient samples afforded me by the COG Myeloid Committee further contribute to a high probability of success for the proposed patient-oriented research. AML accounts for a disproportionate percentage of leukemia-associated morbidity and mortality in children, with relapse the leading cause of death in these patients. Measurable residual disease (MRD) has been shown in AML and other hematologic malignancies to be the single most valuable post-treatment predictor of relapse, but the existing clinical assays for MRD have significant limitations such that a high proportion of children who ultimately succumb to relapsed AML are actually MRD negative post-treatment. We hypothesize that application of molecular MRD assays to pediatric AML disease monitoring will be a sensitive predictor of disease burden and relapse. During the next 5 years I propose (1) to retrospectively evaluate the correlation between relapse and MRD positivity by mutation-based and chimerism-based dPCR assays in pediatric AML patients generally or post-transplant, respectively; (2) to retrospectively evaluate the correlation between relapse and MRD positivity by custom duplex NGS panels in pediatric AML patients; and (3) to prospectively validate the relapse predictive value of duplex NGS as a novel MRD modality in pediatric AML. Successful completion of this project will pave the way toward development of molecular tools such as dPCR and duplex NGS as improved MRD modalities that will enhance clinicians' ability to identify patients at highest risk of relapse and intervene to prevent its occurrence. This will lead to improved survival in pediatric patients suffering from myeloid leukemia.

项目概要/摘要 我的长期职业目标是改善急性髓系白血病 (AML) 儿科患者的治疗结果， 部分是通过开发改进的方法来检测残留疾病，从而实现早期识别 以及对复发风险最高的患者进行干预。我作为儿科肿瘤科医生的临床经验 专门研究骨髓恶性肿瘤的治疗为我在该领域的转化研究提供了重点。这 指导职业发展奖将促进我发展成为一名独立的转化医生- 科学家通过提供薪资支持和受保护的时间来提高我的技术技能、知识基础和 数字 PCR (dPCR) 检测开发和验证、双工 NGS 技术、NGS 方面的个人发展 数据分析和生物信息学、临床试验设计和开发、网络和协作。我的 导师团队由 Craig Jordan 博士（主要导师）、Dan Pollyea 博士、Mike Verneris 博士和 Dr. Chris Hourigan 都是各自领域的领导者，在培养学员和 初级教师走向成功的学术生涯。安舒茨医疗资源丰富的环境 科罗拉多大学校园和 COG Myeloid 为我提供了获取患者样本的机会 委员会进一步为拟议的以患者为导向的研究取得成功的可能性做出了贡献。反洗钱 在儿童白血病相关发病率和死亡率中所占比例过高，其中 复发是这些患者死亡的主要原因。可测量残留病灶 (MRD) 已显示在 AML 和其他血液恶性肿瘤是治疗后最有价值的复发预测因子， 但现有的 MRD 临床检测有很大的局限性，因此很大一部分儿童 最终死于复发性 AML 的患者实际上是治疗后 MRD 阴性的患者。我们假设 分子 MRD 检测在儿科 AML 疾病监测中的应用将是一个敏感的预测因子 疾病负担和复发。在接下来的5年里，我建议（1）回顾性评估相关性 通过基于突变和嵌合的 dPCR 检测儿童 AML 的复发和 MRD 阳性之间的关系 一般患者或移植后患者； (2) 回顾性评估之间的相关性 通过定制双工 NGS 组合检测儿童 AML 患者的复发和 MRD 阳性； (3) 前瞻性地 验证双工 NGS 作为儿童 AML 的新型 MRD 模式的复发预测价值。成功的 该项目的完成将为 dPCR 和双链体等分子工具的开发铺平道路 NGS 作为改进的 MRD 模式，将增强临床医生识别具有最高风险的患者的能力 复发并进行干预以防止其发生。这将提高儿科患者的生存率 患有粒细胞白血病。