P1: Epigenetic Staging and Therapy for Lung Cancers

我们孢子在建立启动子区DMA超甲基化和伴随 异常基因沉默在人类癌症的发生和发展中起着关键作用，通常， 尤其是肺癌。在过去的资金周期中，我们明显地将这一概念转变为高度 通过综合研究，在肺癌治疗方面的翻译领域。这些措施包括 肺癌异常甲基化新基因的发现及其定位和生物学功能 在疾病的发展过程中。最重要的是，我们现在已经定义了一组推动者的效用 区域DNA甲基化标记作为I期NSCLC再分期的潜在分子系统 三病。在过去的资助期间，我们进行了一项盲法、回溯性、嵌套病例对照研究 167例接受根治性手术的I期肺癌患者(51例在40个月内复发； 未复发的116名对照)。肿瘤中2个或2个以上DMA高甲基化基因的发现 组织学上无肿瘤的纵隔淋巴结可以预测复发的疾病，优势比高达25倍， 构成了肺癌分子分期的新范式。这些发现的意义在于 将在当前提案中探讨的重要影响。基因标记的沉默代表着 不仅是预后标志物，而且也是一种独特的分期新辅助方法的潜在靶点。 I非小细胞肺癌(NSCLC)采用表观遗传疗法重新表达沉默基因。做好准备 为此，我们已经开始了对切除的I期非小细胞肺癌的前瞻性研究，以验证我们的上述工作。 这表明DNA甲基化的变化可以预测疾病的复发和死亡。我们还将使用新的 发现了启动子甲基化的变化，以改进这一分子测试。为使用表观遗传学做准备 治疗辅助方法，我们将继续已经启动的表观遗传治疗的第二阶段试验 DNA甲基化和组蛋白脱乙酰酶的抑制剂，其中主要的反应已经是 已实现。最后，我们将用这些药物启动一项佐剂试验，以确定靶向表观遗传学 改变改善了肺癌切除患者的无病和总体存活率。成功，在这里 也将提出预防策略。 与公共卫生相关：肺癌是世界上导致癌症死亡人数最多的 美国和其他西方国家。早期肺癌的有效治疗将导致 提高存活率，减少肺癌死亡。我们的研究应该有助于确定 早期肺癌患者术后复发的风险最高，因此需要 额外的治疗。此外，我们将确定针对这些变化的治疗是否在 减少疾病复发。

Our SPORE has been instrumental in establishing that promoter region DMA hypermethylation, and attendant abnormal gene silencing, play a key role in the development and progression of human cancer, in general, and lung cancer, in particular. During the past funding cycle, we markedly moved this concept to a highly translational arena in terms of lung cancer management through a synthesis of studies. These include discovery of new genes aberrantly methylated in lung cancer and defining their position and biological function in the progression of the disease. Most importantly, we now have defined the utility of a panel of promoter region DMAmethylation markers as a robust potential molecular system for re-staging stage I NSCLC to stage III disease. During the last funding period, we performed a blinded, retrospective, nested case control study of 167 patients who underwent curative surgery for stage I lung cancer (51 cases who recurred within 40 months; 116 controls who did not recur). The finding that 2 or more DMA hypermethylated genes in tumor plus histologically tumor-free mediastinal nodes can predict recurrent disease with odds ratios up to 25-fold, constitutes a new paradigm for the molecular staging of lung cancer. The significance of these discoveries has important implications which will be explored in the current proposal. Silencing of the gene markers represent not only prognostic markers, but also serve as a potential target for a unique new adjuvant approach for stage I non-small cell lung cancer (NSCLC) using epigenetic therapy to re-express the silenced genes. To prepare for this, we have started a prospective study of resected stage I lung NSCLC to validate our above work indicating that changes in DNA methylation can predict disease recurrence and death. We will also use newly discovered changes in promoter methylation to improve this molecular test. To prepare for use of epigenetic therapy adjuvant approaches, we will continue an already initiated Phase 2 trial of epigenetic therapy with inhibitors of DNAmethylation and histone deacetylases, in which a major response has already been achieved. Finally we will initiate an adjuvant trial with these agents, to determine if targeting epigenetic changes improves the disease free and overall survival of patients with resected lung cancer. Successes, here will suggest prevention strategies as well. Relevance to Public Health: Lung Cancer is responsible for the greatest number of cancer deaths in the United States and other western countries. Effective treatment of early stage lung cancer would result in improvements in survival and reduction in death from lung cancer. Our studies should help define which patients with early lung cancer are at highest risk for disease recurrence after surgery, and therefore need additional therapy. In addition, we will determine whether therapy directed at these changes proves effective in reducing disease recurrence.