RRM1 in the Management of Lung Cancer

描述（由申请人提供）：RRM1基因以其作为核糖核苷酸还原酶（RR）的调控亚基的作用而闻名。我们发现了RRM1的新功能。它抑制致癌物诱导的肺肿瘤发生。在同基因小鼠模型中，RRM1还抑制肿瘤进展，减少细胞在体外的迁移和侵袭，抑制转移形成，从而提高动物存活率。在NSCLC患者中，与低表达水平的患者相比，高表达水平的患者的总生存期（OS）和无病生存期（DFS）明显更长。我们发现ERCC1表达同样与OS和DFS显著相关，这些数据最近由一个独立的研究小组使用标准免疫组织化学（IHC）在一个非常大的独立数据集中得到证实。就其对治疗的影响而言，RRM1是吉西他滨化疗疗效的主要细胞决定因素。我们在体外通过基因操作RRM1表达直接证明了这一点，在体内通过显示RRM1表达与患者对吉西他滨/卡铂化疗的反应呈负相关。此外，我们观察到ERCC1表达与肿瘤反应之间存在类似但不那么令人信服的关联。最后，我们在晚期非小细胞肺癌患者中完成了一项单机构II期试验，其中化疗双药的决定是基于肿瘤RRM1表达（是否使用吉西他滨）和ERCC1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RRM1和ERCC1表达之间存在强烈且令人信服的相关性。在我们最新的关于两种基因表达与预后之间关系的分析中，两种基因高表达的患者在手术切除后预后良好。这一群体占所有早期NSCLC患者的30%。这些结果为我们假设RRM1是非小细胞肺癌增殖、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RRM1整合到当前的临床决策中，了解RRM1和ERCC1协调表达的机制，并生成优化RRM1导向治疗干预所需的工具。

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.