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

项目摘要/摘要 我的长期职业目标是改善儿童急性髓系白血病(AML)患者的预后 部分是通过开发改进的模式来检测残留病，从而使早期识别成为可能 并对复发风险最高的患者进行干预。我作为儿科肿瘤学家的临床经验 专门从事髓系恶性肿瘤的治疗是我在这一领域的翻译研究重点。这 导师职业发展奖将促进我发展成为一名独立的翻译医生- 通过提供工资支持和有保障的时间来增强我的技术技能、知识基础和 个人在数字聚合酶链式反应(DPCR)分析开发和验证、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 指导团队由克雷格·乔丹博士(主要导师)、丹·波利亚博士、迈克·弗纳里斯博士和迈克尔·韦尔内里斯博士组成。 Chris Hourigan都是各自领域的领导者，在培养学员和 从初级教员到成功的学术生涯。安舒茨医疗资源丰富的环境 科罗拉多大学校园和COG髓样体提供给我的患者样本 委员会进一步为拟议的以患者为中心的研究提供了很高的成功机会。急性髓细胞白血病 在儿童白血病相关发病率和死亡率中占不成比例的比例， 复发是这些患者的主要死亡原因。可测量的残留病(MRD)已在 急性髓细胞白血病和其他血液系统恶性肿瘤是治疗后最有价值的复发预测指标， 但现有的MRD临床检测方法有很大的局限性，因此有很高比例的儿童 最终死于复发的AML其实都是MRD阴性的治疗后。我们假设 将分子MRD检测应用于儿童AML疾病监测将是一项敏感的预测指标 疾病负担和复发。在接下来的5年里，我建议(1)回顾评估这种相关性 基于突变和基于嵌合体的dPCR检测儿童AML复发与MRD阳性之间的关系 患者一般情况下或移植后分别为；(2)回顾评估两者之间的相关性 儿童AML患者的复发率和MRD阳性；以及(3)前瞻性 验证双链NGS作为一种新的MRD手段在儿童AML中的复发预测价值。成功 该项目的完成将为dPCR和DUPLEX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高危患者的能力 复发，并进行干预，防止其发生。这将提高儿科患者的存活率。 患有髓系白血病。

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.