Combination molecular therapeutics for lung cancer

描述（由申请人提供）：肺癌是美国癌症死亡的主要原因，估计每年有> 160，000例死亡和> 200，000例新诊断病例。尽管在肺癌的治疗中使用了手术、化疗和放疗，但患者的生存率仍然极低（5年内约为15%），并且在过去20年中，这一生存率没有明显变化。在肺癌的靶向治疗中，有靶向表皮生长因子受体（EGFR）的小分子抑制剂。吉非替尼（Iressa，Astra-Zeneca）和厄洛替尼（Tarceva，OSI Pharmaceuticals，Genentech）是EGFR酪氨酸激酶抑制剂（TKI），已获得美国食品药品监督管理局（FDA）批准用于治疗既往常规化疗失败后的非小细胞肺癌（NSCLC）患者。然而，临床试验表明，这些治疗剂在肺癌的治疗中缺乏足够的功效，无论是作为单一药剂还是与常规化疗方案组合。吉非替尼或厄洛替尼缺乏临床成功的原因是存在或发展了由其他分子决定因素控制的原发性和继发性耐药。Asuragen是从Ambion分拆出来的，目的是专注于RNA技术的医学应用。该提案旨在开发基于微小RNA（miRNA）的新型肺癌治疗剂，微小RNA是最近发现的一类内源性调节RNA分子。我们已经鉴定了在肺癌细胞中诱导抑制反应的miRNA。这些miRNAs在肺癌中经常失调，并可能控制对EGFR抑制剂的敏感性。因此，我们假设miRNA和EGFR-TKI的组合使用将有助于对EGFR-TKI的治疗反应并减少和/或预防EGFR-TKI抗性。该I期提案旨在鉴定在具有原发性或继发性耐药的肺癌细胞中与EGFR-TKI协同作用的miRNA。结合EGFR-TKI，我们将评估我们以前鉴定的miRNA的活性。此外，我们将使用我们独特的DiscovArray微阵列在具有获得性耐药的细胞中进行全面的miRNA微阵列分析，该微阵列分析了最全面的miRNA含量。我们将使用这些特征来鉴定介导耐药性并能使肺癌细胞对EGFR-TKI敏感的新型miRNA。公共卫生相关性：本申请中提出的研究和开发将通过使用新发现的一类调节RNA改善肺癌治疗来促进人类健康。基础技术将广泛应用于其他癌症和非癌症疾病。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths in the United States with an estimated >160,000 deaths and >200,000 newly diagnosed cases each year. Despite the use of surgery, chemotherapy and radiation in the treatment of lung cancer, the survival rate for patients remains extremely poor (~15% over 5 years) and this survival rate has not changed appreciably over the past 20 years. Among the targeted therapies for lung cancer are small molecule inhibitors that target epidermal growth factor receptor (EGFR). Gefitinib (Iressa, Astra-Zeneca) and erlotinib (Tarceva, OSI Pharmaceuticals, Genentech) are EGFR tyrosine kinase inhibitors (TKIs) that received approval by the US Food and Drug Administration (FDA) for the treatment of patients with non-small cell lung cancer (NSCLC) after failure of prior conventional chemotherapy. However, clinical trials demonstrated that these therapeutics lack sufficient efficacy in the treatment of lung cancer, either as single agents or in combination with conventional chemotherapeutic regimes. The lack of clinical success with gefitinib or erlotinib has been explained by the existence or development of primary and secondary resistance which are governed by other molecular determinants. Asuragen was spun out of Ambion in order to focus on the medical application of RNA technologies. This proposal aims to develop novel lung cancer therapeutics based on microRNAs (miRNAs), a recently- discovered class of endogenous regulatory RNA molecules. We have identified miRNAs that induce an inhibitory response in lung cancer cells. These miRNAs are frequently deregulated in lung cancer and may govern the sensitivity to EGFR inhibitors. Therefore, we hypothesize that the combinatorial use of miRNAs and EGFR-TKIs will aid in the therapeutic response to EGFR-TKIs and diminish and/or prevent EGFR-TKI resistance. This Phase I proposal seeks to identify miRNAs that function synergistically with EGFR-TKIs in lung cancer cells with primary or secondary resistance. In combination with EGFR-TKIs, we will assess the activity of miRNAs that we have identified previously. In addition, we will perform a comprehensive miRNA microarray analysis in cells with acquired resistance using our unique DiscovArray microarrays, which profile the most comprehensive miRNA content available. We will use these profiles to identify novel miRNAs that mediate resistance and can sensitize lung cancer cells to EGFR-TKIs. PUBLIC HEALTH RELEVANCE: The research and development proposed in this application will advance human health by improving therapies for lung cancer using a newly discovered class of regulatory RNAs. The underlying technology will have broad application to other cancers and non-cancerous diseases.