Identification and targeting of the signaling pathways underlying lung cancer.

描述（由申请人提供）：肺癌是全球癌症死亡的主要原因，5年生存率<15%，这主要是由于缺乏对晚期疾病的有效治疗。在超过30%的肺腺癌中发现了K-ras基因的激活突变，这表明突变的K-ras是肺癌的驱动因素，也是治疗干预的重要靶标。然而，以前直接靶向突变K-ras的尝试几乎没有成功。因此，靶向激活的K-Ras信号传导的替代方法是必要的。我们的长期目标是确定突变K-Ras驱动的肿瘤发生所需的效应子，并开发针对这些分子和途径的治疗方法。我们的初步研究，沿着最近的发现，从其他人，表明Notch信号通路是潜在的重要的治疗目标，在非小细胞肺癌（NSCLC）。Notch家族由哺乳动物中的四种受体（Notch 1 -4）组成，并且目前的Notch抑制方法涉及使用γ-分泌酶抑制剂（GSI），其抑制所有四种受体的活化。不幸的是，由于整体Notch抑制导致的严重肠道毒性，GSI在患者中的使用受到限制。此外，最近的研究表明，不同的Notch受体在肿瘤发生中具有不同的和非重叠的功能，并且这些功能是细胞类型和时间依赖性的。这些发现表明，靶向Notch受体及其下游信号通路的抗癌疗法需要针对单个受体进行调整。鉴于先前的研究结果表明Notch 1是K-ras诱导的肿瘤发生所必需的，我们通过将条件诱导型K-rasG 12 D敲入小鼠模型与Notch 1条件敲除小鼠杂交，测试了Notch 1是否是体内突变型K-ras驱动的NSCLC发展所必需的。在这些小鼠中，Cre介导的重组同时激活K-rasG 12 D等位基因并使Notch 1失活。我们发现Notch 1的缺失显著降低了肿瘤的发生和总体肿瘤负荷，表明Notch 1是K-ras诱导的肺肿瘤发生所必需的。此外，我们的研究表明Notch 1通过抑制p53介导的凋亡而促进K-ras驱动的NSCLC。重要的是，这些结果确定了Notch 1活性与具有野生型p53的NSCLC患者（占所有NSCLC病例的50%）的不良预后之间相关性的分子基础。基于我们的研究结果，我们假设Notch 1通过其抑制肺肿瘤发生的能力， p53，并且靶向Notch 1和/或其下游效应物将抑制NSCLC的发展和/或维持。拟议的研究将检验这一假设，并确定K-Ras驱动的NSCLC中Notch 1需求的潜在机制。此外，我们还将检测Notch 1在由K-ras突变以外的致癌事件驱动的NSCLC中的作用，以确定Notch 1定向治疗是否会为广谱NSCLC患者提供获益。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths worldwide, with 5-year survival rates of <15%, and this is largely due to the lack of effective treatments for advanced disease. Activating mutations of the K-ras gene are found in more than 30% of lung adenocarcinoma, indicating that mutant K- ras is a driver of lung cancer and an important target for therapeutic intervention. However, previous attempts to directly target mutant K-ras have met with little success. Thus, alternative approaches to target activated K-Ras signaling are warranted. Our long-term goals are to identify effectors that are required for mutant K-Ras-driven tumorigenesis and to develop therapeutic approaches to targets these molecules and pathways. Our Preliminary Studies, along with recent findings from others, suggest that Notch signaling pathways are potentially important therapeutic targets in non-small cell lung cancer (NSCLC). The Notch family consists of four receptors in mammals (Notch1-4) and current approaches to Notch inhibition involve the use of γ-secretase inhibitors (GSIs), which inhibit the activation of all four receptors. Unfortunately, the use of GSIs in patients is limited due to severe intestinal toxicities that are a result of global Notch inhibition. In additin, recent studies indicate that the different Notch receptors have distinct and non-overlapping functions in tumorigenesis and that these functions are cell type and timing-dependent. These finding suggest that anti-cancer therapies targeting Notch receptors and their downstream signaling pathways need to be tailored to individual receptors. Given previous findings suggesting Notch1 is required for K-ras-induced tumorigenesis, we tested whether Notch1 is necessary for the development of mutant K-ras-driven NSCLC in vivo, by crossing the conditionally inducible K-rasG12D knock-in mouse model with a Notch1 conditional knockout mouse. In these mice, Cre-mediated recombination simultaneously activates the K-rasG12D allele and inactivates Notch1. We find that loss of Notch1 significantly reduced tumor initiation and overall tumor burden, indicating that Notch1 is required for K-ras-induced lung tumorigenesis. Moreover, our studies have shown that Notch1 contributes to K-ras-driven NSCLC by suppressing p53-mediated apoptosis. Importantly, these results identify the molecular basis for the documented correlation between Notch1 activity and poor prognosis in NSCLC patients having wild type p53, which represent 50% of all NSCLC cases. Based on our findings, we hypothesize that Notch1 is required for lung tumorigenesis via its ability to suppress p53, and that targeting Notch1 and/or its downstream effectors will inhibit the development and/or maintenance of NSCLC. The proposed studies will test this hypothesis and define the mechanisms underlying the requirement for Notch1 in K-Ras driven NSCLC. In addition, we will test the role of Notch1 in NSCLC driven by oncogenic events other than K-ras mutation, to determine if Notch1- directed therapies will provide benefit to a broad spectrum of NSCLC patients.