E2F's impact on Therapeutic Efficacy

E2F对治疗效果的影响

• 批准号: 7923278
• 负责人: Doug Cress
• 金额: $ 30.16万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7923278
• 关键词: Address; Apoptosis; Apoptosis Promoter; Binding; Cancer Patient; Carboplatin; Cell Culture Techniques; Cell Cycle; Cell Death; Cell Line; Cell Survival; Cessation of life; Cisplatin; Clinical; Clinical Research; Clinical Trials; Community Clinical Oncology Program; Contrast Media; Cytotoxic agent; Data; Deacetylase; Drug usage; E2F1 gene; Etoposide; Evaluation; Family; Family member; Feedback; Future; Histone Deacetylase; Immunohistochemistry; In Vitro; Induction of Apoptosis; Intervention; Lead; Malignant neoplasm of lung; Measures; Mediating; Modeling; Molecular; Molecular Analysis; Non-Small-Cell Lung Carcinoma; Outcome; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Process; Prognostic Marker; Proteins; Publishing; RNA Interference; Reagent; Reproduction spores; Resistance; Retrospective Studies; Role; Sampling; Signal Transduction; Specimen; Therapeutic; Thoracic Oncology; Tissue Microarray; Treatment Efficacy; Variant; Vinorelbine; base; cancer cell; chemotherapeutic agent; chemotherapy; cytotoxic; docetaxel; gemcitabine; high throughput screening; improved; in vivo; member; novel; polypeptide; preclinical study; prospective; research study; response; small molecule libraries; tissue culture

The majority of drugs currently used for advanced NSCLC induce cell cycle alterations and apoptosis. Apoptosis induction by these drugs appears dependent upon the E2F1 pathway. Specifically, we find these drugs induce E2F1 at the protein level and that E2F1 deficiency protects NSCLC cells from death induced by such agents. However, we have identified SirT1 as a novel negative regular of E2F1 that restricts E2F1-mediated induction of apoptosis by cytotoxic agents in a negative feedback loop. Preliminary data suggest that interference of this negative feedback significantly increases the sensitivity of NSCLC lines to drug-induced apoptosis. These results suggest the hypothesis that the E2F1/SirT1 pathway is crucial for efficacy of chemotherapeutic agents in NSCLC and provide proof-ofprinciple that targeting the E2F1/SirT1 pathway will have therapeutic benefit. This project will address three specific aims. Thus far results suggest that E2F1 activates SirT1 and that SirT1, in turn, limits E2F1-induced cell death. Preliminary data also would suggest that the E2F1/E2F4 ratio may play an important role in drug-induce apoptosis. However, we do fully understand whether other E2F family members play any significant roles in this process. Thus, the first specific aim will define the molecular interactions between SirT1 and members of the E2F family in NSCLC and will define the roles of different E2F family members in drug-induced apoptosis. This first aim will primarily address experimentation in tissue culture using NSCLC lines. The second specific aim will determine the contribution of the E2F1-SirT1 pathway to clinical outcome and therapeutic efficacy in lung cancer patients in ongoing clinical studies administered by the Thoracic Oncology Program. The purpose of this aim will be to understand whether the pathway that we have define in cell culture are applicable to the patient and whether E2F1, E2F4 or SirT1 will serve a prognostic markers in NSCLC. The third specific aim will seek to generate and characterize reagents that will disrupt the E2F/SirT1 pathway and define the functional consequences of this disruption in NSCLC chemotherapeutic interventions. We hypothesize that these agents will result in increased apoptosis in response to chemotherapeutic drugs and could ultimately have significant therapeutic value in NSCLC. The drugs used in the treatment of lung cancer could be highly effective; however, lung cancer cells have mechanisms that allow them to avoid death induced by these drugs. This project has discovered a new way cancer cells avoid death and proposes several ways to counterattack this process.

目前用于晚期NSCLC的大多数药物诱导细胞周期改变和细胞凋亡。 这些药物诱导的细胞凋亡似乎依赖于E2 F1途径。具体来说，我们发现 这些药物在蛋白质水平诱导E2 F1，E2 F1缺乏可保护非小细胞肺癌细胞免于死亡 由这些代理商。然而，我们已经确定SirT 1是E2 F1的一种新的负规则， 在负反馈环中限制细胞毒性剂对E2 F1介导的细胞凋亡的诱导。 初步数据表明，这种负反馈的干扰显着增加了 NSCLC细胞系对药物诱导凋亡的敏感性。这些结果表明， E2 F1/SirT 1通路对NSCLC化疗药物的疗效至关重要，并提供了原理性证据 靶向E2 F1/SirT 1通路将具有治疗益处。 该项目将实现三个具体目标。到目前为止的结果表明，E2 F1激活SirT 1， SirT 1反过来又限制了E2 F1诱导的细胞死亡。初步数据还表明， E2 F1/E2 F4比值可能在药物诱导细胞凋亡中起重要作用。不过，我们完全理解 其他E2 F家族成员是否在这一过程中发挥重要作用。第一个具体目标 将定义NSCLC中SirT 1和E2 F家族成员之间的分子相互作用， 定义不同E2 F家族成员在药物诱导的细胞凋亡中的作用。第一个目标主要是 解决了使用NSCLC细胞系进行组织培养的实验。第二个具体目标将决定 E2 F1-SirT 1通路对肺癌临床结局和治疗效果的贡献 正在进行的胸部肿瘤项目临床研究中的患者。这样做的目的 目的是了解我们在细胞培养中定义的途径是否适用于 患者以及E2 F1、E2 F4或SirT 1是否将作为NSCLC的预后标志物。第三特定 目的是寻求产生和表征能够破坏E2 F/SirT 1途径的试剂，并确定 这种破坏在NSCLC化疗干预中的功能后果。我们 假设这些药物将导致对化疗药物应答的细胞凋亡增加 并最终可能对NSCLC具有显著的治疗价值。 治疗肺癌的药物可能非常有效;然而，肺癌细胞 有机制使他们避免这些药物引起的死亡。这个项目发现了一个 癌细胞避免死亡的新方法，并提出了几种反击这一过程的方法。