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.

项目摘要/摘要 我的长期职业目标是改善急性髓性白血病（AML）的儿科患者的结局 通过发展改善模态的部分来检测残留疾病，从而允许早期识别 以及那些患有最高复发风险的患者的干预。我作为儿科肿瘤学家的临床经验 专门治疗髓样恶性肿瘤，可以将我在这一领域的转化研究重点介绍。这 指导的职业发展奖将使我成为独立的翻译医师的发展 - 科学家提供薪水支持和保护时间，以提高我的技术技能，知识库和 数字PCR（DPCR）测定开发和验证的个人发展，双工NGS技术，NGS 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 指导团队由Craig Jordan博士（主要导师），Dan Pollyea博士，Mike Verneris博士和博士组成。 克里斯·霍尼根（Chris Hourigan）都是各自领域的领导者，并具有促进学员和 成功学术职业的初级教师。 Anschutz医疗的资源丰富的环境 科罗拉多大学的校园以及COG髓样的进入病人样品的机会 委员会进一步为拟议的面向患者的研究带来了很高的成功可能性。 AML 儿童中与白血病相关的发病率和死亡率的比例不成比例 复发这些患者的主要死亡原因。可测量的残留疾病（MRD）已显示 AML和其他血液学恶性肿瘤是最有价值的后处理后复发预测指标， 但是MRD的现有临床测定法具有重大局限性，因此很大比例的儿童 最终屈服于复发的AML实际上是MRD负面处理。我们假设这一点 分子MRD测定在儿科AML疾病监测中的应用将是敏感的预测指标 疾病负担和复发。在接下来的5年中，我建议（1）回顾性评估相关性 基于突变的基于突变和基于嵌合主义的DPCR分析在小儿AML中的复发和MRD阳性之间 患者通常或移植后分别； （2）回顾性评估 小儿AML患者的自定义双工NGS面板复发和MRD积极性； （3）前瞻性 验证双链NG的复发预测值是小儿AML中新型的MRD模态。成功的 该项目的完成将铺平开发分子工具（例如DPCR和双工）的方式 NGS作为改善的MRD模式，将增强临床医生识别具有最高风险的患者的能力 复发和干预以防止其发生。这将导致小儿患者的生存率提高 患有髓样白血病。