Foxa2 and C/EBP transcription factors in the pathogenesis and treatment of lung c

尽管非小细胞肺癌(NSCLC)的诊断和治疗最近取得了进展，但生存率 仍然是贫穷的。更好地理解导致肺癌和其他疾病的分子机制 恶性肿瘤是当务之急。在过去的十年中，大多数关于肺癌的研究都集中在 关于致癌基因，如本孢子提交的项目3、4和5所强调的。然而，关于以下方面的研究 参与肺癌的肿瘤抑制基因已经滞后，而且没有针对性的治疗方法 这些基因的出现是为了帮助患者。自从2002年最初的肺癌孢子提案以来，我们 我研究了两个可能作为肿瘤抑制因子的特定基因，这两个基因可能是正常肺发育所必需的 肺癌中的基因。这些是转录因子C/EBPalpha和Foxa2。我们小组的工作已经完成 表明这两个因子在许多肺癌中普遍下调的途径中起作用，并进一步 实验将加强对其临床后果的理解。这项研究的目标是 最终设计出可以重新建立其诱导分化和抑制肿瘤的治疗方法 途径，这可能扩大治疗和化学预防这种恶性肿瘤的选择。因此， 根据2003至2007年的新发现，我们建议进一步扩大对这些问题的研究。 转录因子并使途径和潜在靶点更接近有效的临床应用 呼吸道上皮恶性肿瘤的具体目标如下：1)建立主要发病机制 Foxa2在肺癌中的失活及其下游靶点(15-PGDH)及其预后意义 建立诱导C/EBPbeta作为肺癌治疗的新策略；3)评价 合成三萜类化合物(CDDO及其衍生物)，作为能够诱导C/EBPβ和有效的化合物 肺癌的治疗选择。这些研究的可预见的临床潜力是确定 早期非小细胞肺癌(FOXA2)的新预后标记物和口服的合理介绍 目前正在进行人类I期临床试验的化合物(CDDO-Me就是这种情况)-可以重新激活 C/EBP在非小细胞肺癌中具有重要的肺分化途径和抑制增殖、诱导细胞凋亡的作用。 这些研究很可能是未来对这种恶性肿瘤患者进行临床试验的跳板。

Despite recent progress in diagnosis and treatment of non-small cell lung cancer (NSCLC), survival continues to be poor. Better understanding of the molecular mechanisms that lead to lung cancer and other malignancies are urgently necessary. Most of the research over the last decade in lung cancer has focused on oncogenes, as highlighted in Projects 3, 4, and 5 of this SPORE submission. However research regarding tumor suppressor genes involved in lung cancer has lagged behind, and no specific therapies targeting these genes have emerged to help patients. Since the original Lung Cancer SPORE proposal in 2002, we have studied two specific genes necessary for normal lung development that may act as tumor suppressor genes in lung cancer. These are the transcription factors C/EBPalpha and Foxa2. Our groups' work has demonstrated that both factors act in a pathway commonly downregulated in many lung cancers and further experiments will enhance understanding of their clinical consequences. The goal of this research is to eventually devise therapies that can re-establish their differentiation-inducing and tumor suppressive pathways, which may expand the therapeutic and chemopreventive options for this malignancy. Therefore, based on the novel findings obtained in 2003 to 2007, we propose to further expand our studies of these transcription factors and move the pathways and potential targets closer to effective clinical applications in malignancies of the airway epithelium with the following Specific Aims: 1) To establish the main mechanisms of inactivation of Foxa2 in lung cancer, its downstream targets (15-PGDH) and prognostic significance; 2} To establish the induction of C/EBPbeta as a novel strategy for lung cancer treatment; 3) To evaluate the synthetic triterpenoids (CDDO and derivatives) as compounds capable of inducing C/EBPbeta and as potent therapeutic options for lung cancer. The foreseeable clinical potential of these studies are the identification of novel prognostic markers in early stage non-small cell lung cancer (Foxa2) and the sound introduction of oral compounds - currently in human phase I clinical trials (as is the case of CDDO-Me) - that can re-activate the crucial C/EBP lung differentiation pathway and halt proliferation as well as induce apoptosis in NSCLC. These studies will likely be the springboard to future clinical trials in patients with this malignancy.