Rationally designed targeted therapeutic approaches for NSCLC

合理设计NSCLC靶向治疗方法

• 批准号: 8191018
• 负责人: James V Degregori
• 金额: $ 29.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191018
• 关键词: Address; Advanced Malignant Neoplasm; Adverse effects; Algorithms; Animals; Cancer Biology; Cancer Etiology; Cancer cell line; Cell Survival; Cells; Cessation of life; Cetuximab; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Computational Biology; Computer Analysis; Data Set; Development; Diagnosis; Disease; Disease remission; Drug Delivery Systems; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Exhibits; Follow-Up Studies; Gefitinib; Gene Mutation; Genes; Goals; Human; In Vitro; Libraries; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Modification; Monoclonal Antibodies; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Polysomy; Process; Progression-Free Survivals; Proteins; Receptor Inhibition; Regimen; Relapse; Resistance; Role; Safety; Screening Result; Screening for cancer; Survival Rate; Tankyrase; Therapeutic; Validation; Xenograft procedure; cancer cell; cancer gene expression; cell killing; chemotherapy; clinical application; cytokine; design; disorder control; effective therapy; genome-wide; improved; in vivo; inhibitor/antagonist; killings; kinase inhibitor; mouse model; new therapeutic target; novel; research study; response; small hairpin RNA; small molecule; synergism; therapeutic target; tumor growth

DESCRIPTION (provided by applicant): Lung cancers are the leading cause of cancer deaths globally. In particular, non-small cell lung cancer (NSCLC) is a devastating disease, and is rarely curable. While targeted therapies, such as those using epidermal growth factor receptor (EGFR) inhibitors, have shown clinical promise, these therapies are rarely curative for advanced cancers. As lung cancers are typically diagnosed at advanced phases and appear to possess inherent or acquired survival mechanisms that can protect the cells from EGFR inhibition, the discovery of pathways that mediate these compensatory survival mechanisms could reveal novel therapeutic targets that render EGFR inhibition a more effective therapy for lung cancer. Using a genome-wide shRNA screen, we have identified gene products whose inhibition synergizes with the EGFR inhibitor gefitinib to eliminate NSCLC cells. This screen identified a number of druggable gene products and potential pathways, including Wnt/tankyrase/¿-catenin and NFAT/cytokine/STAT pathways. We refer to gene products whose inhibition sensitizes NSCLC cells to gefitinib treatment as 'SLuGs' for Synthetic Lethal upon Gefitinib. Follow up studies have shown that inhibition of these SLuG pathways potently synergizes with gefitinib to eliminate NSCLC cells. These studies will involve close collaborations between labs with expertise in genome-wide shRNA screens and cancer biology (DeGregori), computational biology (Tan), mouse models of NSCLC (Chan), and clinical application (Bunn). We will perform computational analysis and systematic validation of genome-wide shRNA screening results to reveal genes and pathways whose inhibition sensitizes NSCLC cells to EGFR inhibition. Further studies of the Wnt/tankyrase/¿-catenin and NFAT/cytokine/STAT pathways show reveal roles for these pathways in NSCLC cell survival during EGFR inhibition. Additional studies will determine whether inhibition of these pathways cooperates with gefitinib treatment to eliminate NSCLC in vivo using mouse models. The overarching goals of this project are 1) to identify novel drug targets or unanticipated combination therapies for NSCLC, 2) to reveal pathways and processes that maintain NSCLC cell survival in the face of EGFR inhibition, and 3) to uncover therapeutic approaches to make NSCLC, either highly or moderately EGFR-inhibitor sensitive, even more sensitive to these inhibitors, leading to longer remissions and better control of the disease. PUBLIC HEALTH RELEVANCE: Lung cancer is a devastating disease, and is rarely curable. While targeted therapies, such as through inhibition of the epidermal growth factor receptor (EGFR), have shown clinical promise, these therapies are rarely if ever curative for advanced cancers. Our screen has identified pathways that contribute to lung cancer cell survival during EGFR inhibition. By targeting multiple pathways, we hope to minimize the development of drug resistance and improve therapeutic outcomes. The proposed studies could provide the necessary justification for clinical trials to treat EGFR dependent lung cancers.

描述（由申请人提供）：肺癌是全球癌症死亡的主要原因。特别是，非小细胞肺癌（NSCLC）是一种毁灭性的疾病，并且很少能够治愈。虽然靶向治疗，如使用表皮生长因子受体（EGFR）抑制剂，已显示出临床前景，这些疗法很少治愈晚期癌症。由于肺癌通常在晚期诊断，并且似乎具有可以保护细胞免受EGFR抑制的固有或获得性生存机制，因此发现介导这些代偿性生存机制的途径可以揭示新的治疗靶点，使EGFR抑制成为肺癌的更有效疗法。使用全基因组shRNA筛选，我们已经鉴定了其抑制作用与EGFR抑制剂吉非替尼协同消除NSCLC细胞的基因产物。该筛选鉴定了许多可药物化的基因产物和潜在途径，包括Wnt/端锚聚合酶/β-连环蛋白和NFAT/细胞因子/STAT途径。我们将其抑制作用使NSCLC细胞对吉非替尼治疗敏感的基因产物称为吉非替尼合成致死的“SLuG”。后续研究表明，抑制这些SLuG途径与吉非替尼有效协同消除NSCLC细胞。 这些研究将涉及在全基因组shRNA筛选和癌症生物学（DeGregori）、计算生物学（Tan）、NSCLC小鼠模型（Chan）和临床应用（邦恩）方面具有专业知识的实验室之间的密切合作。我们将对全基因组shRNA筛选结果进行计算分析和系统验证，以揭示抑制NSCLC细胞对EGFR抑制敏感的基因和途径。对Wnt/端锚聚合酶/β-连环蛋白和NFAT/细胞因子/STAT通路的进一步研究显示，在EGFR抑制期间，这些通路在NSCLC细胞存活中的作用。其他研究将确定这些途径的抑制是否与吉非替尼治疗协同作用，以使用小鼠模型在体内消除NSCLC。该项目的总体目标是1）确定NSCLC的新型药物靶点或非预期联合治疗，2）揭示在EGFR抑制作用下维持NSCLC细胞存活的途径和过程，3）揭示使NSCLC对EGFR抑制剂高度或中度敏感的治疗方法，甚至对这些抑制剂更敏感，从而延长缓解期并更好地控制疾病。 公共卫生相关性：肺癌是一种毁灭性的疾病，很少能治愈。虽然靶向治疗，例如通过抑制表皮生长因子受体（EGFR），已显示出临床前景，但这些治疗很少能治愈晚期癌症。我们的筛选已经确定了在EGFR抑制期间有助于肺癌细胞存活的途径。通过靶向多个途径，我们希望最大限度地减少耐药性的发展并改善治疗结果。拟议的研究可以为治疗EGFR依赖性肺癌的临床试验提供必要的理由。