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

癌症相关性和科学依据：儿童癌症幸存者面临终身慢性健康风险 到50岁时，危及生命/致命的慢性健康状况的累积发病率为53%。的 儿童癌症幸存者过早死亡的两个主要原因是与辐射有关的随后死亡。 肿瘤（SN）和蒽环类药物相关的心功能障碍（CD）。辐射和蒽环类药物 在>60%的癌症儿童中使用，并且在可预见的未来没有计划消除这些药物。 虽然放射与SN、蒽环类药物与CD之间存在剂量-反应关系， （不考虑潜在的原发性癌症），风险存在显著的患者间差异，表明 遗传倾向的调节作用。高发病率负担加上个体间 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，这样就可以采取有针对性的干预措施。Broad Plan：此应用程序利用和合并 从分子生物学、药物基因组学和癌症存活率领域来识别癌症的新概念 患者的SN或CD个人风险。该奖项还试图了解分子发病机制 这些并发症，为今后制定有针对性的预防/治疗策略提供信息。必要的 拟议研究的基础设施，包括库存、注释生物标本（n= 13，450）和预先存在的 在这一应用中将利用与必要的专门知识的协作。目标是：（一）制定一个 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） 在儿童癌症幸存者的独立队列中复制优化的模型; iii）应用优化的模型， 模型，以预测事件SN/CD的风险; iv）确定功能性 基因特征的相关性资格：我是癌症研究所的创始主任 结果和生存在伯明翰的亚拉巴马大学。我有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。以来 2000年，我被任命为制定儿科肿瘤生存研究议程， 儿童肿瘤学小组-一个由美国国家癌症研究所支持的临床试验小组，专门致力于儿科癌症 在220个中心进行研究。我目前担任ASCO幸存者委员会的当选主席。我是一个 白血病淋巴瘤学者，弗兰克H奥斯基奖的获得者，是美国 临床研究学会和美国医师协会。我一直得到资助 自2000年以来，NCI超过235篇同行评议的出版物和15，220次引用（自2012年以来有9，300次），我的 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）。我完全致力 改善我们儿童癌症幸存者的长期健康，我坚信， 这一应用将加快步伐，减轻这一人群的发病负担。

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.