Investigating the link between cancer and neurodegenerative disease

研究癌症和神经退行性疾病之间的联系

基本信息

批准号：
9336844
负责人：
JANE A DRIVER
金额：
--
依托单位：
VA BOSTON HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336844
关键词：
Address Adriamycin PFS Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Antineoplastic Agents Bioinformatics Biological Biological Process Biology Cancer Patient Cancer Survivor Cell Cycle Cell Cycle Progression Cell Death Cessation of life Chemoprevention Clinical Trials Code Comorbidity Complex DNA Damage Data Data Set Databases Dementia Diabetes Mellitus Diagnosis Diagnostic Disease Epidemic Epidemiology Framingham Heart Study Gene Expression Genes Genetic Healthcare Systems Incidence Individual Inflammation Information Centers Interdisciplinary Study Interruption Lead Limes Link Macular degeneration Malignant Neoplasms Massachusetts Medicare Meta-Analysis Metabolic Metformin Methods Microtubule Stabilization Natural Language Processing Neurodegenerative Disorders Neurofibrillary Tangles Observational Study Outcome Oxidative Stress Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Pharmacoepidemiology Play Prevention approach Prostate Public Health Schools Publishing Quantitative Trait Loci Recording of previous events Research Research Personnel Resources Retrieval Risk Risk Factors Role Source Stabilizing Agents Survivors Techniques Variant Veterans Work cancer chemoprevention cancer diagnosis cancer risk cancer therapy cancer type chemotherapy cohort design effective therapy epidemiology study genetic association genetic variant genome wide association study genome-wide improved outcome insight mouse model neoplasm registry neuron apoptosis neuron loss new therapeutic target novel novel strategies novel therapeutics prevent protective effect public health relevance tau aggregation taxane

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is among the most devastating conditions that affect older Veterans today, and despite decades of intense research, there is still no effective treatment. Convincing epidemiologic evidence suggests that cancer survivors have a lower risk of AD, and that people with AD have a lower risk of cancer. In this proposal, we pursue the hypothesis that this inverse association may hold the key to new approaches to prevention and treatment of AD. Our pilot data in a national cohort of Veterans shows that survivors of many cancer types have a decreased risk of AD that is independent of cancer treatment, and that those who receive chemotherapy have an even lower risk. The protective effect of chemotherapy did not seem to be explained by earlier death or less frequent diagnosis of other conditions among cancer patients. It is quite plausible that anti-cancer treatments could decrease AD risk, since some common drugs are known to improve outcomes in mouse models of AD through multiple mechanisms including stabilization of microtubules and dissolution of tangles. Other cancer drugs interrupt the cell cycle in its early stages, and may thus prevent neuronal cell death. Furthermore, cancer and AD share many key pathophysiologic features, including oxidative stress, metabolic dysregulation, DNA damage, and inflammation. Agents that suppress these pathways might be used as chemoprevention for both diseases. One example is the diabetes drug metformin, for which there is emerging evidence of both anti-neoplastic and neuroprotective effects. In this proposal, our multidisciplinary research team will further explore the epidemiologic and biological link between AD and cancer using the rich resources of the Massachusetts Veterans Epidemiology Research and Information Center and the Department of Statistical Genetics at the Harvard School of Public Health. In Aim 1 we will investigate the association between 20 different cancer types and AD in our national dataset of over 3.5 million Veterans. We will refine our pilot analyses by validating a more accurate definition of AD, confirming the cancer diagnosis through the VA Cancer Registry, and requesting linked Medicare data. In Aim 2, we will examine the relationship between particular classes of anti-neoplastic therapy and the risk of AD in both the national VA dataset and our more detailed pharmaco-epidemiology database. We will also determine whether regular users of metformin have a lower risk of AD. In Aim 3, we will perform genome-wide meta- analyses of published studies on cancer and AD to identify shared genetic variants of both diseases. We will gain insight into common biological pathways using novel techniques such as gene-set enrichment, pathway and network analysis. Successful completion of these studies will generate important hypotheses about drugs that could be repositioned as treatment or chemoprevention for AD, and lead to clinical trials that would directly benefit US Veterans. Characterization of the biological overlap between cancer and AD will likely yield new pathophysiologic insights and could identify new targets for therapy.

描述（由申请人提供）：阿尔茨海默氏病（AD）是影响当今老年退伍军人的最具破坏性的疾病之一，尽管进行了数十年的深入研究，但仍然没有有效的治疗方法。令人信服的流行病学证据表明，癌症幸存者的AD风险较低，并且AD患者患癌症的风险较低。在该提案中，我们提出了这样的假设：这种反相关可能是预防和治疗AD的新方法的关键。我们在全国退伍军人队列中的飞行员数据表明，许多癌症类型的幸存者的AD风险降低，与癌症治疗无关，而接受化疗的人的风险甚至更低。化学疗法的保护作用似乎并未通过早期死亡或对癌症患者中其他疾病的频繁诊断的解释。抗癌处理可能会降低AD风险是非常合理的，因为已知某些常见药物通过多种机制（包括稳定微管和缠结的溶解）来改善AD小鼠模型的预后。其他癌症药物在早期阶段中断细胞周期，因此可能预防神经元细胞死亡。此外，癌症和AD具有许多关键的病理生理特征，包括氧化应激，代谢失调，DNA损伤和炎症。抑制这些途径的药物可以用作两种疾病的化学预防。一个例子是糖尿病药物二甲双胍，有抗塑性和神经保护作用的新证据。在此提案中，我们的多学科研究团队将进一步探索马萨诸塞州退伍军人流行病学研究和信息中心的丰富资源以及哈佛大学公共卫生学院的统计遗传学系，AD与癌症之间的流行病学和生物学联系。在AIM 1中，我们将在国家数据集中研究20种不同的癌症类型和AD之间的关联，其中350万退伍军人。我们将通过验证对AD的更准确的定义，通过VA癌症注册表确认癌症诊断，并要求链接的Medicare数据来完善我们的试点分析。在AIM 2中，我们将研究特定类别的抗塑性疗法与国家VA数据集中的AD风险之间的关系，而我们更详细的Pharmaco-EpideMiology数据库之间的关系。我们还将确定二甲双胍的常规用户是否具有较低的AD风险。在AIM 3中，我们将对癌症和AD的已发表研究进行全基因组的元分析，以鉴定两种疾病的共享遗传变异。我们将使用新型技术（例如基因富集，途径和网络分析）来深入了解常见的生物途径。这些研究的成功完成将产生有关药物的重要假设，这些假设可以重新定位为AD的治疗或化学预防，并导致临床试验直接使美国退伍军人受益。癌症和AD之间生物重叠的表征可能会产生新的病理生理见解，并可以鉴定出新的治疗靶标。