Biomarkers to Assess Selenium Chemoprevention for NSCLC

描述（由申请人提供）：美国国立卫生研究院宣布恢复法案资金的竞争性修订申请的可用性。肺癌是美国癌症相关死亡的主要原因，并将很快在全球范围内达到流行水平。通过识别高风险个体和实施有效的治疗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了由异常CpG岛甲基化失活的基因作为肺癌早期检测的候选生物标志物。这项竞争性补充的母基金，“评估非小细胞肺癌硒化学预防的生物标志物”，重点是确定通过痰液或血浆中基因启动子甲基化失活的一组基因的能力，以预测参与评估L-硒代蛋氨酸的III期化学预防试验的切除I期肺癌患者对治疗的反应和癌症复发。在这一竞争性补充中提出的研究将以几种方式补充和扩展父母补助金中的工作。基因启动子高甲基化已成为癌症发生和发展的主要机制，通过药物逆转其可能为初级和辅助（二级预防）癌症治疗提供有效策略。通过组合脱甲基化剂如5-氮杂胞苷和组蛋白脱乙酰酶抑制剂（例如，MS 275）现在被FDA批准用于治疗骨髓增生异常综合征和急性白血病。最重要的是，在晚期肺癌的I/II期临床试验中看到了令人兴奋的反应。这项竞争性补充的研究将使用经验证的原位裸大鼠肺癌模型来确定表观遗传治疗对影响具有特定致癌突变和携带数百个甲基化基因的肿瘤生长的疗效。治疗和载体肿瘤的甲基化和表达阵列将鉴定生物标志物（去甲基化和重新表达的基因），这些生物标志物最终可用于人体试验，以预测肺癌辅助和主要表观遗传治疗的反应者。这些研究还将确定表观遗传疗法疗效的关键机制是否是靶向和清除自我更新的肿瘤细胞。最后，我们将讨论表观遗传治疗与标准治疗细胞毒性治疗（基于铂）的组合是否可以进一步影响肿瘤生长。 公共卫生相关性：这些研究将使用经验证的原位裸大鼠肺癌模型来确定表观遗传疗法对影响具有特定致癌突变和携带数百个甲基化基因的肺肿瘤生长的功效。治疗和载体肿瘤的甲基化和表达阵列将鉴定生物标志物（去甲基化和重新表达的基因），这些生物标志物最终可用于人体试验，以预测肺癌辅助和主要表观遗传治疗的反应者。这一应用的研究可以通过提供关键的新见解来指导和促进肺癌治疗和预防的人类临床试验的发展，使表观遗传疗法更接近管理最具破坏性的癌症形式的最前沿。

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.