P1: Epigenetic Staging and Therapy for Lung Cancers

P1：肺癌的表观遗传分期和治疗

• 批准号: 7567913
• 负责人: JAMES G. HERMAN
• 金额: $ 42.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7567913
• 关键词: Adjuvant; Adjuvant Study; Adjuvant Therapy; Biological Markers; Biological Process; Blinded; Cancer Patient; Case-Control Studies; Cessation of life; Collaborations; Colorado; Controlled Clinical Trials; Country; Curative Surgery; DNA; DNA Methylation; Data; Development; Disease; Disease Progression; Disease-Free Survival; Epigenetic Process; Funding; Gene Silencing; Genes; Grant; Histologic; Histones; Human; Hypermethylation; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediastinal; Methylation; Molecular; Nested Case-Control Study; Non-Small-Cell Lung Carcinoma; Observational Study; Odds Ratio; Operative Surgical Procedures; Patients; Phase II Clinical Trials; Play; Population; Positioning Attribute; Prevention strategy; Prognostic Marker; Promoter Regions; Prospective Studies; Public Health; Recurrence; Recurrent disease; Reproduction spores; Resected; Role; Sputum; Staging; Staging System; System; Testing; Therapeutic; Time; United States; Work; effective therapy; gene discovery; high risk; improved; indexing; inhibitor/antagonist; leukemia; lymph nodes; novel; novel marker; promoter; prospective; response; success; therapeutic target; tumor

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.

我们的孢子已经在建立启动子区域DMA超甲基化和伴随的 异常基因沉默，在人类癌症的发展和进展中起关键作用，一般来说， 尤其是肺癌。在过去的融资周期中，我们明显地将这一概念提升到了一个高度 通过综合研究在肺癌管理方面的转化竞技场。这些包括 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启动子的效用， 区域DMA甲基化标记物作为将I期NSCLC重新分期为 三病。在上一个资助期，我们进行了一项盲法、回顾性、巢式病例对照研究， 167例I期肺癌根治性手术患者（40个月内复发51例; 116例未复发的对照组）。肿瘤组织中存在2个或2个以上的DMA高甲基化基因， 组织学上无肿瘤的纵隔淋巴结可以预测疾病复发，比值比高达25倍， 构成了肺癌分子分期的新范例。这些发现的重要性 本提案将探讨的重要影响。基因标记的沉默代表了 不仅是预后标志物，而且还可以作为一种独特的新辅助方法的潜在靶点， I.非小细胞肺癌（NSCLC），采用表观遗传学疗法使沉默基因重新表达。准备 为此，我们已经开始了一项对切除的I期肺癌的前瞻性研究，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，以改善这种分子测试。准备使用表观遗传学 治疗辅助方法，我们将继续已经启动的表观遗传治疗的2期试验， DNA甲基化和组蛋白去乙酰化酶的抑制剂，其中一个主要的反应已经是 办妥了一批最后，我们将启动这些药物的辅助试验，以确定是否靶向表观遗传 改变改善了切除肺癌患者的无病生存率和总生存率。成功，在这里 也会提出预防策略。 与公共卫生的相关性：肺癌是世界上癌症死亡人数最多的疾病。 美国和其他西方国家。早期肺癌的有效治疗将导致 提高生存率和减少肺癌死亡率。我们的研究应该有助于确定 早期肺癌患者手术后疾病复发的风险最高，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有效， 减少疾病复发。