Biomarkers to Assess Selenium Chemoprevention for NSCLC

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资金。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病水平。通过识别高危人群，实施有效的治疗措施，防止肿瘤切除后肺癌复发，可以降低本病的死亡率。我们的研究已经确定了被异常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“评估NSCLC硒化学预防的生物标志物”的资助重点是确定通过痰或血浆中基因启动子甲基化灭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。这项竞争性补编中提出的研究将在几个方面补充和扩大父母补助金方面的工作。基因启动子超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。通过结合去甲基化剂（如5-氮杂胞苷）和组蛋白去乙酰化酶抑制剂（如MS275）的表观遗传疗法现已被FDA批准用于骨髓增生异常综合征和急性白血病的治疗。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。这项竞争性补充研究将使用经过验证的原位裸鼠肺癌模型来确定表观遗传疗法对具有特定致癌突变和包含数百个甲基化基因的肿瘤生长的影响。治疗肿瘤和载体肿瘤的甲基化和表达阵列将识别生物标志物（基因去甲基化和重新表达），最终可用于人体试验，以预测肺癌辅助和原发性表观遗传治疗的反应。这些研究还将确定表观遗传治疗有效性的关键机制是否是靶向和去除自我更新的肿瘤细胞。最后，我们将讨论是否结合表观遗传治疗与标准护理细胞毒性治疗（铂基）可以进一步影响肿瘤生长。

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.