RRM1 in the Management of Lung Cancer

描述（由申请人提供）：已知RRM 1基因作为核糖核苷酸还原酶（RR）的调节亚基。我们发现了RRM 1的新功能。它抑制致癌物诱导的肺肿瘤发生。RRM 1还抑制肿瘤进展，如通过降低体外细胞迁移和侵袭以及抑制同基因小鼠模型中的转移形成所证明的，从而导致动物存活率增加。在NSCLC患者中，高表达水平的患者的总生存期（OS）和无病生存期（DFS）明显长于低表达水平的患者。我们发现ERCC 1表达同样与OS和DFS显著相关，这些数据最近由一组独立的研究人员使用标准免疫组织化学（IHC）在一个非常大的独立数据集中证实。就其对治疗的影响而言，RRM 1是吉西他滨化疗疗效的主要细胞决定因素。我们已经在体外通过RRM 1表达的遗传操作和体内通过显示RRM 1表达与患者对吉西他滨/卡铂化疗的反应之间的负相关性直接证明了这一点。此外，我们观察到ERCC 1表达与肿瘤反应之间存在类似但不太令人信服的相关性。最后，我们已经完成了一项在晚期NSCLC患者中进行的单机构II期试验，其中化疗双联的决定是基于肿瘤RRM 1表达（是否使用吉西他滨）和ERCC 1表达（是否使用铂）。试验患者的结果非常令人鼓舞，1年生存率为59%。最近，我们发现肿瘤RRM 1和ERCC 1表达之间存在强有力的相关性。在我们对预后与两种基因表达之间的关联的最新分析中，两种基因高表达的患者组在手术切除后具有良好的预后。该组占所有早期NSCLC患者的30%。这些结果是我们假设RRM 1是NSCLC增殖、生存和治疗效果的重要调节因子的基础。该项目的主要重点是将RRM 1整合到当前的临床决策中，了解RRM 1和ERCC 1表达协调的机制，并生成优化RRM 1指导的治疗干预所需的工具。 公共卫生相关性：先前的工作已经证明了RRM 1和ERCC 1分别对切除的非小细胞肺癌患者的生存以及对吉西他滨和铂的疾病反应的预后和预测价值。该提案的目的是在切除患者的大数据集中验证这些数据，前瞻性地利用RRM 1和ERCC 1基因表达值进行治疗决策，并进行阐明基因表达和功能机制的研究。

DESCRIPTION (provided by applicant): The RRM1 gene has been known for its role as the regulatory subunit of ribonucleotide reductase (RR). We have discovered novel functions for RRM1. It suppresses carcinogen-induced lung tumorigenesis. RRM1 also suppresses tumor progression as demonstrated by decreased cellular migration and invasion in vitro and suppression of metastasis formation in a syngeneic mouse model resulting in increased animal survival. In patients with NSCLC, overall survival (OS) and disease-free survival (DFS) are substantially longer for those with high levels of expression as compared to those with low levels of expression. We had found that ERCC1 expression was likewise significantly associated with OS and DFS, and these data were recently confirmed in a very large independent dataset by a separate group of investigators using standard immunohistochemistry (IHC). In terms of its impact on therapy, RRM1 is the major cellular determinant of chemotherapeutic efficacy for gemcitabine. We have demonstrated this directly in vitro through genetic manipulation of RRM1 expression and in vivo through showing an inverse correlation between RRM1 expression and patients' response to gemcitabine/carboplatin chemotherapy. In addition, we observed a similar but less convincing association between ERCC1 expression and tumor response. Finally, we have completed a single institution phase II trial in patients with advanced NSCLC, where the decision on a chemotherapy doublet was based on tumoral RRM1 expression (whether or not gemcitabine was used) and ERCC1 expression (whether or not platinum was used). The outcome of patients on the trial was extremely encouraging with a 1-year survival of 59%. Most recently, we found a strong and convincing correlation between tumoral RRM1 and ERCC1 expression. In our latest analysis on an association between prognosis and expression of both genes, it was the group of patients with high expression of both genes that had a favorable outcome after surgical resection. This group accounts for 30% of all patients with early-stage NSCLC. These results are the basis for our hypothesis that RRM1 is an important regulator of proliferation, survival, and therapeutic efficacy in NSCLC. The primary focus of this project is to integrate RRM1 into current clinical decision-making, to understand the mechanism of coordinate RRM1 and ERCC1 expression, and to generate tools required for optimization of RRM1-directed therapeutic interventions. PUBLIC HEALTH RELEVANCE: Prior work has demonstrated the prognostic and predictive values of RRM1 and ERCC1 for survival of patients with resected non-small-cell lung cancer and for disease response to gemcitabine and platinum respectively. The purpose of this proposal to valid these data in large datasets of resected patients, to prospectively utilize RRM1 and ERCC1 gene expression values for therapeutic decisions, and to conduct studies elucidating the mechanism of gene expression and function.