Mitigating Long-term Treatment-related Morbidity in Childhood Cancer Survivors

减轻儿童癌症幸存者的长期治疗相关发病率

基本信息

批准号：
10682635
负责人：
SMITA BHATIA
金额：
$ 86.83万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682635
关键词：
Acceleration Age Alabama American American Society of Clinical Oncology Anthracycline Award Cancer Patient Cancer Survivorship Charge Chronic Clinical Trials Cooperative Group Collaborations Coupled Development Dose Epidemiology Funding Future Genetic Genetic Predisposition to Disease Goals Health Incidence Infrastructure Intervention Life Malignant Childhood Neoplasm Malignant Neoplasms Modeling Molecular Molecular Biology Morbidity - disease rate Myocardial dysfunction Neoplasms Newly Diagnosed Oncology Outcome Outcomes Research Pathogenesis Patients Pediatric Oncology Pediatric Oncology Group Peer Review Pharmacogenomics Physicians Population Premature Mortality Prevention Publications Qualifying Radiation Research Research Personnel Risk Role Shapes Societies Therapeutic Therapeutic Agents Universities anticancer research childhood cancer survivor clinical investigation cohort experience genetic signature high risk improved indexing inter-individual variation interpatient variability leukemia/lymphoma member novel personalized management response risk prediction risk prediction model survivorship treatment risk

项目摘要

Cancer Relevance and Scientific Rationale: Childhood cancer survivors are at a life-long risk of chronic health conditions; by age 50, the cumulative incidence of life-threatening/fatal chronic health conditions is 53%. The two leading causes of premature mortality in childhood cancer survivors are radiation-related subsequent neoplasms (SNs) and anthracycline-related cardiac dysfunction (CD). Radiation and anthracyclines are both used in >60% of children with cancer, and there are no plans in the foreseeable future to eliminate these agents. Although there is a dose-response relation between radiation and SN and between anthracyclines and CD (regardless of the underlying primary cancer), there is significant inter-patient variability in the risk, suggesting the moderating role of genetic predisposition. The high burden of morbidity coupled with the inter-individual variability in risk, suggests a need and an opportunity to identify patients at highest risk for treatment-related morbidity, such that targeted interventions can be instituted. Broad Plan: This application harnesses and merges novel concepts from the field of molecular biology, pharmacogenomics and cancer survivorship to identify cancer patients by their personal risk of SN or CD. This award also attempts to understand the molecular pathogenesis of these complications to inform future development of targeted prevention/therapeutic strategies. The necessary infrastructure for the proposed research, including banked, annotated biospecimens (n=13,450) and pre-existing collaborations with the necessary expertise will be leveraged in this application. The goals are to: i) develop a risk prediction model for radiation-related SN and anthracycline-related CD in childhood cancer survivors; ii) replicate the optimized model in an independent cohort of childhood cancer survivors; iii) apply the optimized model to newly-diagnosed children with cancer to predict the risk of incident SN/CD; iv) determine the functional relevance of the genetic signatures. Qualifications: I am the founding Director of the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham. I have over 20y of experience conducting cancer outcomes research that bridges the fields of oncology, epidemiology and genetics. Since 2000, I have been charged with shaping the pediatric oncology survivorship research agenda within the Children's Oncology Group – an NCI-supported clinical trials group, devoted exclusively to pediatric cancer research across 220 centers. I am currently serving as chair-elect for the ASCO survivorship committee. I am a Leukemia Lymphoma Scholar, a recipient of the Frank H Oski award, and am an elected member of the American Society of Clinical Investigation, and the Association for American Physicians. I have been continuously funded by NCI since 2000. With over 235 peer-reviewed publications and 15,220 citations (9,300 since 2012), my Google Scholar H-INDEX is 66 (54 since 2012) and my i10-index is 182 (167 since 2012). I am fully committed to improving the long-term health of our childhood cancer survivors, and I strongly believe that findings from this application will accelerate the pace to reduce the burden of morbidity in this population.

癌症相关性和科学依据：儿童癌症幸存者终生面临慢性健康风险到 50 岁时，危及生命/致命的慢性健康状况的累积发生率为 53%。儿童癌症幸存者过早死亡的两个主要原因与辐射有关肿瘤（SN）和蒽环类药物相关的心脏功能障碍（CD）放射和蒽环类药物均属于此类。用于超过 60% 的癌症儿童，并且在可预见的将来没有计划消除这些药物。尽管辐射与 SN 之间以及蒽环类药物与 CD 之间存在剂量反应关系（无论潜在的原发癌症是什么），患者之间的风险存在显着差异，表明遗传易感性的调节作用。高发病率加上个体间的差异。风险的可变性表明需要和机会来识别治疗相关风险最高的患者发病率，以便可以制定有针对性的干预措施：该应用程序利用和合并。来自分子生物学、药物基因组学和癌症生存领域的新概念来识别癌症该奖项还试图了解患者的 SN 或 CD 的分子发病机制。这些并发症的信息可为未来制定有针对性的预防/治疗策略提供信息。拟议研究的基础设施，包括存储的、带注释的生物样本（n = 13,450）和预先存在的该应用程序将利用与必要专业知识的合作，目标是： i) 开发一个儿童癌症幸存者中辐射相关 SN 和蒽环类药物相关 CD 的风险预测模型 ii) 在独立的儿童癌症幸存者队列中复制优化模型；iii) 应用优化模型；为新诊断的癌症儿童建立模型来预测 SN/CD 事件的风险 iv) 确定功能；遗传特征的相关性资格：我是癌症研究所的创始主任。我在阿拉巴马大学伯明翰分校的成果和生存方面拥有 20 多年的经验。开展癌症结果研究，将肿瘤学、流行病学和遗传学领域联系起来。 2000 年，我负责制定儿科肿瘤生存研究议程儿童肿瘤学小组——NCI 支持的临床试验小组，专门致力于儿童癌症研究我目前担任 ASCO 幸存者委员会的候任主席。白血病淋巴瘤学者，Frank H Oski 奖获得者，美国癌症协会当选会员临床研究协会和美国医师协会持续资助我。自 2000 年起被 NCI 评为。我的论文发表超过 235 篇同行评审出版物和 15,220 次引用（自 2012 年以来为 9,300 次） Google Scholar H-INDEX 为 66（自 2012 年以来为 54），我的 i10 指数为 182（自 2012 年以来为 167）。改善我们儿童癌症幸存者的长期健康，我坚信这一发现应用将加快减轻这一人群发病负担的步伐。