Pharmacogenomic factors associated with severe acute toxicities and survival in pediatric Latino patients with acute lymphoblastic leukemia

与患有急性淋巴细胞白血病的拉丁裔儿童患者的严重急性毒性和生存相关的药物基因组因素

• 批准号: 10449744
• 负责人: Melanie Brooke Bernhardt
• 金额: $ 23.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449744
• 关键词: Accounting; Acute; Acute Lymphocytic Leukemia; Acute leukemia; Adolescent; African American population; Award; Biological; Biology; Black race; Characteristics; Child; Child Care; Childhood; Childhood Acute Lymphocytic Leukemia; Clinical; Clinical Trials; Cohort Analysis; Computerized Medical Record; Data; Data Set; Development; Diagnosis; Disease; Disease-Free Survival; Drug Exposure; Drug toxicity; Electronic Medical Records and Genomics Network; Enrollment; Environment; Epidemiology; Ethnic Origin; Ethnic group; Event; Exhibits; Foundations; Frequencies; Funding; Gene Frequency; Genetic; Genome; Genomics; Genotype; Goals; Health Occupations; Health Sciences; Hematology; Hospitals; Human Genetics; Human Genome; Incidence; Individual; Inferior; Joints; Knowledge; Latino; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical; Medicine; Mentors; Mentorship; Methodology; Methotrexate; Mexican; Minor; Minority Groups; Modeling; Modification; Molecular Epidemiology; Multicenter Studies; Native American Ancestry; Outcome; Patient Care; Patients; Pattern; Pediatric Hematology; Pediatric Oncology; Pediatric cohort; Pegaspargase; Pharmacists; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Phenotype; Population; Populations at Risk; Prevalence; Prospective cohort; Quality of life; Race; Relapse; Research; Research Activity; Research Personnel; Research Project Grants; Research Training; Retrospective cohort study; Risk; Risk Factors; Role; Sampling; Science; Scientist; Self-Direction; Shoulder; Students; Subgroup; Survival Rate; Testing; Texas; Therapeutic; Time; Toxic effect; Training; Translating; Treatment outcome; Treatment-related toxicity; United States; United States National Institutes of Health; Variant; Work; acute toxicity; career development; clinical decision-making; clinical risk; clinically relevant; cohort; college; database of Genotypes and Phenotypes; drug clearance; effective therapy; ethnic disparity; experience; genome sciences; genome wide association study; genome-wide; genomic signature; high risk; improved; insight; leukemia treatment; medical schools; meetings; molecular pathology; mortality; multi-ethnic; neurotoxicity; novel; peer; predictive signature; prognostic; programs; prospective; racial and ethnic; relapse risk; research and development; risk variant; success; training opportunity; translational approach; treatment risk

1 PROJECT SUMMARY/ABSTRACT 2 Research Project: Latino children have the highest risk of developing acute lymphoblastic leukemia (ALL), a 3 higher cumulative incidence of relapse, and lower survival rates. We hypothesize that Latino children with ALL 4 will exhibit more severe acute toxicities and a unique pattern of drug toxicity clusters. We also believe that these 5 toxicities and clusters are more prevalent in Latino patients, are related to pharmacogenomic factors and are 6 associated with an increased risk of relapse and reduced event-free survival. To demonstrate these points, we 7 will validate prior work with pegaspargase-related toxicity clusters, then apply this approach to describe toxicity 8 clusters for other agents used throughout ALL treatment. We will define the relationship between severe acute 9 toxicities and toxicity clusters on the risk of relapse and event-free survival and examine the pharmacogenomics 10 of toxicities and clusters using candidate and genome-wide association studies. Lastly, we will describe the 11 frequency of variant risk alleles from our cohorts by analyzing other pharmacogenomic datasets. 12 Candidate plan and goals: Dr. Bernhardt aspires to be a leading, independent, clinician-scientist in the field of 13 clinical pharmacogenomics. Her overarching goal is to improve the care of children with cancer by translating 14 genomic science to clinical decision-making at the bedside. This goal will be accomplished by developing 15 knowledge and research expertise in clinical pharmacogenomics. Dr. Bernhardt will participate in formal and 16 informal training relevant to her research, including didactic and hands-on experiences in pharmacogenomics, 17 translational biology, and epidemiology. She will be mentored by Drs. Michael Scheurer and Richard Gibbs, 18 renowned investigators in molecular epidemiology and human genetics (respectfully). Dr. Bernhardt’s advisory 19 committee will guide her research and career development during formal meetings and one-on-one interactions. 20 Baylor College of Medicine (BCM) has invested in Dr. Bernhardt’s career development by assuring 75% 21 protected time as described in this application, and commitment to her success in the long-term. 22 The Environment: Career development and research activities will be conducted at BCM and Texas Children's 23 Hospital (TCH). BCM is a premiere medical school and academic health science center, highly ranked in funding 24 from the National Institutes of Health and the National Science Foundation. BCM actively trains more than 3,000 25 medical, graduate, and health professions students and fellows. Texas Children’s Cancer and Hematology 26 Centers, a joint BCM/TCH program, is the largest pediatric cancer and hematology program in the United States. 27 Research and training opportunities will occur within the TXCH Epidemiology Program, BCM Human Genome 28 Sequencing Center, and TCH Molecular Pathology programs. Programs at BCM and TCH offer extensive 29 opportunities for mentored and self-directed training, didactic coursework, peer interactions, and ongoing 30 professional development across multiple scientific domains.

1 项目概要/摘要 2 研究项目：拉丁裔儿童患急性淋巴细胞白血病 (ALL) 的风险最高，这是一种 3.累积复发率较高，生存率较低。我们假设患有 ALL 的拉丁裔儿童 4将表现出更严重的急性毒性和独特的药物毒性簇模式。我们也相信，这些 5 种毒性和集群现象在拉丁裔患者中更为常见，与药物基因组因素相关，并且 6 与复发风险增加和无事件生存期减少相关。为了证明这些观点，我们 7 将验证先前与培门冬酶相关的毒性簇的工作，然后应用此方法来描述毒性 8 个集群用于整个 ALL 治疗过程中使用的其他药物。我们将定义严重急性发作之间的关系 关于复发风险和无事件生存的 9 个毒性和毒性簇并检查药物基因组学 使用候选和全基因组关联研究的 10 种毒性和集群。最后，我们将描述 通过分析其他药物基因组数据集，我们得到了 11 个队列中变异风险等位基因的频率。 12 候选人计划和目标：Bernhardt 博士渴望成为以下领域的领先、独立的临床医生科学家 13.临床药物基因组学。她的首要目标是通过翻译来改善癌症儿童的护理 14 基因组科学与床边临床决策的关系。这一目标将通过开发来实现 15 临床药物基因组学知识和研究专长。 Bernhardt 博士将参加正式和 16 次与她的研究相关的非正式培训，包括药物基因组学的教学和实践经验， 17 转化生物学和流行病学。她将受到博士的指导。迈克尔·舍勒和理查德·吉布斯， 18 位分子流行病学和人类遗传学领域的著名研究者（尊敬的）。伯恩哈特博士的建议 19委员会将在正式会议和一对一互动期间指导她的研究和职业发展。 20 贝勒医学院 (BCM) 对 Bernhardt 博士的职业发展进行了投资，确保 75% 21 保护本申请中所述的时间，并致力于她的长期成功。 22 环境：职业发展和研究活动将在 BCM 和德克萨斯儿童医院进行 23 医院（TCH）。 BCM 是一流的医学院和学术健康科学中心，在资金方面排名靠前 24 来自美国国立卫生研究院和国家科学基金会。 BCM积极培训超过3000人 25 名医学、研究生和卫生专业的学生和研究员。德克萨斯州儿童癌症和血液学 26 中心是 BCM/TCH 联合项目，是美国最大的儿科癌症和血液学项目。 27 研究和培训机会将在 TXCH 流行病学计划、BCM 人类基因组范围内提供 28 测序中心和 TCH 分子病理学项目。 BCM 和 TCH 的课程提供广泛的 29 个指导和自我指导培训、教学课程、同伴互动和持续的机会 跨多个科学领域的 30 项专业发展。