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儿童急性髓细胞白血病（AML）患者的预后， 部分是通过开发更好的方法来检测残留疾病，从而能够早期识别 并对那些复发风险最高的患者进行干预。我作为一名儿科肿瘤学家的临床经验 专门从事骨髓恶性肿瘤的治疗通知我在这一领域的转化研究重点。这 导师职业发展奖将促进我发展成为一个独立的翻译医生- 科学家通过提供工资支持和保护时间，以提高我的技术技能，知识基础， 在数字PCR（dPCR）检测开发和验证方面的个人发展，双重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 指导团队由克雷格乔丹博士（主要导师），丹波利耶博士，迈克Verneris博士和博士。 Chris Hourigan都是各自领域的领导者，在培养学员和 初级教师成功的学术生涯。安舒茨医疗资源丰富的环境 校园的科罗拉多大学和接触患者样本提供了我的COG骨髓 委员会进一步为拟议的以患者为导向的研究的成功概率高作出贡献。AML 占儿童白血病相关发病率和死亡率的比例不成比例， 复发是这些患者死亡的主要原因。可测量残留病（MRD）已在 AML和其他血液恶性肿瘤是复发的单一最有价值的治疗后预测因子， 但是现有的MRD临床测定具有显著的局限性， 最终死于复发性AML的患者实际上是治疗后MRD阴性。我们假设 将分子MRD检测应用于儿童AML疾病监测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 在儿童AML中通过基于突变和基于嵌合体的dPCR测定法确定复发与MRD阳性之间的关系 患者一般或移植后，分别;（2）回顾性评估之间的相关性 在儿童AML患者中通过定制双链体NGS组检测复发和MRD阳性;和（3）前瞻性 验证双链体NGS作为儿科AML中新型MRD模式的复发预测价值。成功 该项目的完成将为发展dPCR和duplex等分子工具铺平道路 NGS作为改进的MRD模式，将增强临床医生识别最高风险患者的能力。 复发和干预，以防止其发生。这将提高儿科患者的生存率 患有骨髓性白血病