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可用于竞争性修订申请。肺癌是美国癌症相关死亡的主要原因，很快将在全球范围内达到流行水平。这种疾病的死亡率可以通过识别高危个体和实施有效的治疗措施来降低，以防止肺癌在肿瘤切除后复发。我们的研究已经确定CpG岛异常甲基化失活的基因可以作为肺癌早期检测的候选生物标记物。这一竞争性补充剂的父母拨款为“评估非小细胞肺癌硒化学预防的生物标记物”，重点是确定一组通过痰或血浆中基因启动子甲基化而失活的基因，以预测参与评估L-硒蛋氨酸化学预防试验第三阶段的I期肺癌患者的治疗反应和癌症复发的能力。本竞争性补编中提出的研究将在几个方面补充和扩展家长补助金中的工作。基因启动子高甲基化已成为肿瘤发生发展的主要机制，药物逆转基因启动子甲基化可能为肿瘤的初级和辅助(二级预防)治疗提供有效的策略。表观遗传疗法通过联合去甲基化药物如5-氮杂胞苷和组蛋白去乙酰化酶抑制剂(如MS275)现已被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，人们看到了令人兴奋的反应。在这份竞争性补充材料中的研究将使用经过验证的裸鼠原位肺癌模型来确定表观遗传治疗对具有特定致癌基因突变和含有数百个甲基化基因的肿瘤生长的影响的有效性。治疗肿瘤和载体肿瘤的甲基化和表达阵列将识别生物标记物(去甲基化和重新表达的基因)，这些生物标记物最终可能用于人体试验，以预测肺癌辅助和初级表观遗传治疗的应答者。这些研究还将确定表观遗传疗法疗效的关键机制是否为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疗法与标准护理细胞毒疗法(以铂为基础)的结合是否会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裸鼠原位肺癌模型来确定表观遗传学治疗对具有特定致癌基因突变和含有数百个甲基化基因的肺癌生长的影响的有效性。治疗肿瘤和载体肿瘤的甲基化和表达阵列将识别生物标记物(去甲基化和重新表达的基因)，这些生物标记物最终可能用于人体试验，以预测肺癌辅助和初级表观遗传治疗的应答者。这一应用的研究可以通过提供关键的新见解来指导和进一步发展治疗和预防肺癌的人类临床试验，从而使表观遗传疗法更接近于管理最具破坏性的癌症形式的前沿。

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.