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

• 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
• 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

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.

癌症相关性和科学原理：儿童癌症的存活率有终身慢性健康的风险 状况;到50岁时，威胁生命/致命的慢性健康状况的累积事件为53％。这 儿童癌症存活中过早死亡的两个主要原因是与辐射有关的随后序列 肿瘤（SNS）和与蒽环类有关的心脏功能障碍（CD）。辐射和蒽环类药物都是 > 60％的癌症儿童使用，并且在可预见的将来没有计划来消除这些药物。 尽管辐射与SN之间以及蒽环类药物和CD之间存在剂量反应关系 （不管基本的原发性癌症如何），风险的患者间差异很大，表明 遗传倾向的调节作用。高燃烧发病率与个体间 风险的变异性表明需要和有机会识别与治疗相关风险最高风险的患者 发病率，因此可以采取有针对性的干预措施。广泛计划：本申请利用和合并 来自分子生物学，药物基因组学和癌症生存领域的新概念，以鉴定癌症 患者以SN或CD的个人风险。该奖项还试图理解分子发病机理 这些并发症为有针对性的预防/治疗策略的未来发展提供了信息。必要的 拟议研究的基础设施，包括库存的，带注释的生物测量（n = 13,450）和现有的 与必要的专业知识的合作将在此应用程序中利用。目标是：i）开发 儿童癌症存活中与辐射相关的SN和与蒽环类有关的CD的风险预测模型； ii） 在独立的儿童癌症存活中复制优化模型； iii）应用优化 与新诊断的癌症儿童的模型，以预测发生SN/CD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 伯明翰阿拉巴马大学的成果和生存。我有20岁以上的经验 进行癌症结果研究，桥接肿瘤学，流行病学和遗传学领域。自从 2000年，我被指控塑造儿科肿瘤学生存研究议程 儿童肿瘤学组 - 一个由NCI支持的临床试验组，专门用于儿科癌症 跨220个中心的研究。我目前是ASCO表面委员会的当选主席。我是一个 白血病淋巴瘤学者，弗兰克·奥斯基奖的获得者，是美国当选成员 临床研究协会和美国医师协会。我一直被资助 NCI自2000年以来。 Google Scholar H-Index为66（自2012年以来为54），我的i10索引是182（自2012年以来167）。我完全投入 为了改善我们儿童期癌症生存的长期健康，我坚信从中的发现 应用将加快速度以减少该人群中发病率的燃烧。