Biomarkers to Assess Selenium Chemoprevention for NSCLC

评估硒化学预防非小细胞肺癌的生物标志物

• 批准号: 7808538
• 负责人: Steven A Belinsky
• 金额: $ 121.26万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808538
• 关键词: Acute leukemia; Address; Adjuvant; Affect; Aftercare; Agar; Amino Acids; Azacitidine; Biological Markers; CD44 gene; Cancer Etiology; Cancer Model; Cancer Patient; Caring; Cell Line; Cell Survival; Cessation of life; Chemoprevention; Cisplatin; Clinical Treatment; Clinical Trials; Complement; CpG Islands; Cytosine; Cytotoxic Chemotherapy; Development; Disease; Dysmyelopoietic Syndromes; Effectiveness; Epidemic; Epigenetic Process; Excision; FDA approved; Functional disorder; Funding; Gene Mutation; Gene Silencing; Genes; Genetic Transcription; Genome; Growth; Heterogeneity; Histone Deacetylase Inhibitor; Histones; Human; Human Development; Hypermethylation; Individual; L-Selenomethionine; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Modification; Molecular; Molecular Profiling; Mutation; Non-Small-Cell Lung Carcinoma; Nude Mice; Nude Rats; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phase; Plasma; Platinum; Population; Promoter Regions; Rattus; Recovery; Recurrence; Resected; Resistance; Secondary Prevention; Selenium; Sputum; Staging; Stem cells; Tumor Burden; Tumor Suppressor Genes; Tumor-Derived; United States National Institutes of Health; Work; base; cancer cell; cancer recurrence; cancer therapy; chemotherapy; effective therapy; established cell line; high risk; improved; insight; lung cancer prevention; lung cancer screening; mortality; neoplastic cell; parent grant; prevent; promoter; public health relevance; response; self renewing cell; self-renewal; tumor; tumor growth

DESCRIPTION (provided by applicant): NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Lung cancer is the leading cause of cancer-related death in the U.S. and will soon reach epidemic levels worldwide. Mortality from this disease could be reduced through the identification of high-risk individuals and the implementation of effective therapies to prevent recurrence of lung cancer after tumor resection. Our studies have identified genes inactivated by aberrant CpG island methylation as candidate biomarkers for early detection of lung cancer. The parent grant to this competitive supplement, "Biomarkers to Assess Selenium Chemoprevention for NSCLC," is focused on determining the ability of a panel of genes inactivated through gene promoter methylation in sputum or plasma to predict response to therapy and the recurrence of cancer for resected Stage I lung cancer patients participating in a Phase III Chemoprevention trial evaluating L- selenomethionine. The studies proposed in this competitive supplement will complement and extend the work in the parent grant in several ways. Gene promoter hypermethylation has emerged as a major mechanism in the initiation and development of cancer and its reversal by pharmacological agents may offer an effective strategy for primary and adjuvant (secondary prevention) cancer therapy. Epigenetic therapy through combining a demethylating agent such as 5-azacytidine and an inhibitor of histone deacetylase (e.g., MS275) is now approved by the FDA for treatment of myelodysplastic syndrome and acute leukemia. Most important, exciting responses are being seen in a Phase I/II clinical trial for advanced lung cancer. Studies in this competitive supplement will use a validated orthotopic nude rat lung cancer model to define the efficacy of epigenetic therapy for affecting growth of tumors with specific oncogenic mutations and harboring hundreds of methylated genes. Methylation and expression arrays on treated and vehicle tumors will identify biomarkers (genes demethylated and re-expressed) that could ultimately be used in human trials to predict responders to adjuvant and primary epigenetic therapy for lung cancer. These studies will also define whether a key mechanism for the efficacy of epigenetic therapy is targeting and removal of self-renewing tumor cells. Finally, we will address whether combining epigenetic therapy with standard-of-care cytotoxic therapy (platinum- based) can further impact tumor growth. PUBLIC HEALTH RELEVANCE: These studies will use a validated orthotopic nude rat lung cancer model to define the efficacy of epigenetic therapy for affecting growth of lung tumors with specific oncogenic mutations and harboring hundreds of methylated genes. Methylation and expression arrays on treated and vehicle tumors will identify biomarkers (genes demethylated and re-expressed) that could ultimately be used in human trials to predict responders to adjuvant and primary epigenetic therapy for lung cancer. Studies in this application could bring epigenetic therapy closer to the forefront of managing the most devastating form of cancer by providing key new insights to guide and further the development of human clinical trials for treatment and prevention of lung cancer.

描述（由申请人提供）：NIH宣布为竞争性修订申请提供恢复法案的可用性。肺癌是美国与癌症相关的主要原因，并将很快在全球范围内达到流行病。通过鉴定高风险个体和实施有效的疗法以防止肿瘤切除后肺癌复发，可以降低这种疾病的死亡率。我们的研究已经确定，异常CpG岛甲基化灭活的基因是早期发现肺癌的候选生物标志物。父母对这种竞争性补充的授予“评估NSCLC化学预防的生物标志物”的重点是确定通过基因启动子在痰液或等离子体中灭活基因的能力，以预测治疗反应的反应以及对癌症患者的癌症复发的反应和阶段III阶段III III III III III III III III III III III III III III III III III III III。在这种竞争补充剂中提出的研究将以几种方式补充和扩展父母赠款中的工作。基因启动子高甲基化已成为癌症开始和发展的主要机制，药理学剂的逆转可能为原发性和辅助（辅助预防）癌症治疗提供有效的策略。通过结合脱甲基化剂，例如5-氮杂丁胺和组蛋白脱乙酰基酶的抑制剂（例如MS275），FDA现在批准了脱乙酰脱乙酰基酶的抑制剂（例如5-氮杂剂和组蛋白脱乙酰基酶的抑制剂），用于治疗骨髓增生性综合征和急性白血病。最重要的是，在晚期肺癌的I/II期临床试验中正在看到令人兴奋的反应。该竞争性补充剂的研究将使用经过验证的原位裸大鼠肺癌模型来定义表观遗传疗法对影响特异性致癌突变并含有数百种甲基化基因的肿瘤生长的疗效。治疗和车辆肿瘤上的甲基化和表达阵列将鉴定生物标志物（基因脱甲基化和重新表达），最终可以在人类试验中使用，以预测对肺癌辅助和原发性表观遗传疗法的反应者。这些研究还将定义表观遗传疗法有效性的关键机制是靶向和去除自我更新的肿瘤细胞。最后，我们将解决将表观遗传疗法与护理标准细胞毒性疗法（基于铂）结合起来是否可以进一步影响肿瘤的生长。 公共卫生相关性：这些研究将使用经过验证的原始裸大鼠肺癌模型来定义表观遗传疗法对影响肺部肿瘤生长的功效，并具有特定的致癌基因并含有数百种甲基化基因。治疗和车辆肿瘤上的甲基化和表达阵列将鉴定生物标志物（基因脱甲基化和重新表达），最终可以在人类试验中使用，以预测对肺癌辅助和原发性表观遗传疗法的反应者。该应用中的研究可以通过提供关键的新见解来指导和进一步开发人类临床试验以治疗和预防肺癌，从而使表观遗传疗法更接近管理癌症的最前沿。