Notch and stem cells in lung cancer treated with erlotinib plus notch inhibitor.

用厄洛替尼加 Notch 抑制剂治疗肺癌中的 Notch 和干细胞。

• 批准号: 8234926
• 负责人: Don Lynn Gibbons
• 金额: $ 25.35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-02 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234926
• 关键词: Accounting; Biopsy; Cancer Patient; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erinaceidae; Erlotinib; Exposure to; Goals; Immunohistochemistry; Malignant neoplasm of lung; Mutation; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phase; Protein Array; Resistance; Signal Pathway; Stem cells; Therapeutic; Tissues; Tumor Markers; c-erbB-1 Proto-Oncogenes; inhibitor/antagonist; meetings; mutant; notch protein; prevent; public health relevance; resistance factors; secretase; tumor

DESCRIPTION (provided by applicant): We will conduct a preliminary assessment of whether efficacy of erlotinib in NSCLC is reduced if tumors have high Notch pathway and CSC marker expression, and whether addition of the 3-secretase inhibitor RO4929097 will abrogate the negative impact of high Notch/CSC marker expression. We will also assess whether Notch and CSC markers correlate with EMT and EGFR markers, and whether baseline marker signatures predict for efficacy of erlotinib alone or the RO4929097-erlotinib combination. We will assess whether exposure to erlotinib alone enriches tumors for Notch/CSC/EMT markers as a mechanism of acquired resistance, and whether addition of RO4929097 to erlotinib prevents this enrichment or alters impact of erlotinib on EGFR pathway signaling. We will assess impact of host Notch SNPs on tumor Notch/ CSC/ EMT/ EGFR marker expression and on efficacy of erlotinibRO4929097. We may also assess them as a secondary goal. Specifically, where tissue quantity and patient numbers permit, we will conduct preliminary assessments of: a) Notch/CSC/EMT marker expression in tumors with vs without other erlotinib resistance factors (eg, T790M mutation, IGF-1R activation, c-Met amplification); b) how Sonic Hedgehog (SHH) and Wnt pathway components modulate or augment the impact of the Notch pathway on EGFR TKI efficacy; c) Notch/CSC/EMT marker expression in EGFR-mutant vs -wild type tumors. Specific Aim 1: We will obtain pre-treatment biopsies from patients receiving erlotinib RO4929097 and will assess Notch pathway, CSC, EMT and EGFR pathway markers by immunohistochemistry (IHC) and reverse phase protein arrays (RPPAs). We will: a) correlate expression of Notch and CSC markers with each other and with EMT and EGFR markers; b) correlate marker expression with tumor shrinkage after RO4929097 initiation; c) correlate marker expression with tumor shrinkage after erlotinib initiation; d) compare marker expression in patients with vs without recent erlotinib exposure Specific Aim 2: We will obtain repeat NSCLC biopsies 6 weeks after initiating therapy with erlotinib RO4929097 and will compare change in Notch, CSC, EMT and EGFR marker expression in patients who received erlotinib alone to those who also received RO4929097. Specific Aim 3: We will assess how host Notch pathway SNPs (assessed in peripheral blood mononuclear cells [PBMCs]) correlate with: a) tumor expression of Notch, CSC, EMT and EGFR markers; b) change in tumor markers with erlotinib RO4929097; c) efficacy of erlotinib RO4929097. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. About 10% of NSCLCs have activating mutations of the epidermal growth factor receptor (EGFR) gene, and tumors with these mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib. We are conducting an NCI-sponsored trial in which erlotinib-resistant NSCLC patients have the 3-secretase/ Notch inhibitor RO4929097 added to their erlotinib. While erlotinib is less effective vs EGFR wild type tumors, therapeutic benefit is nevertheless seen.

描述（由申请方提供）：我们将进行初步评估，如果肿瘤具有高Notch途径和CSC标志物表达，厄洛替尼在NSCLC中的疗效是否会降低，以及添加3-分泌酶抑制剂RO 4929097是否会消除高Notch/CSC标志物表达的负面影响。我们还将评估Notch和CSC标志物是否与EMT和EGFR标志物相关，以及基线标志物特征是否预测厄洛替尼单独或RO 4929097-厄洛替尼组合的疗效。我们将评估单独暴露于厄洛替尼是否会使肿瘤富集Notch/CSC/EMT标志物作为获得性耐药的机制，以及向厄洛替尼中添加RO 4929097是否会阻止这种富集或改变厄洛替尼对EGFR通路信号传导的影响。我们将评估宿主Notch SNP对肿瘤Notch/ CSC/ EMT/ EGFR标志物表达和厄洛替尼RO 4929097疗效的影响。我们也可以将其作为次要目标进行评估。具体而言，在组织数量和患者数量允许的情况下，我们将进行以下初步评估：a）Notch/CSC/EMT标记物在具有与不具有其他厄洛替尼耐药因子的肿瘤中的表达（例如，T790 M突变、IGF-1 R活化、c-Met扩增）; B）Sonic Hedgehog（SHH）和Wnt途径组分如何调节或增强Notch途径对EGFR TKI功效的影响; c）EGFR突变体与野生型肿瘤中的Notch/CSC/EMT标志物表达。具体目标1：我们将从接受厄洛替尼RO 4929097的患者中获得治疗前活检，并将通过免疫组织化学（IHC）和反相蛋白阵列（RPPA）评估Notch途径、CSC、EMT和EGFR途径标志物。我们将：a）将Notch和CSC标志物的表达相互关联并与EMT和EGFR标志物关联; B）将标志物表达与RO 4929097开始后的肿瘤缩小关联; c）将标志物表达与厄洛替尼开始后的肿瘤缩小关联; d）比较最近暴露于厄洛替尼与没有暴露于厄洛替尼的患者中的标志物表达。我们将在开始厄洛替尼RO 4929097治疗后6周获得重复NSCLC活检，并将比较单独接受厄洛替尼治疗的患者与同时接受RO 4929097治疗的患者中Notch、CSC、EMT和EGFR标志物表达的变化。具体目标3：我们将评估宿主Notch途径SNP（在外周血单核细胞[PBMC]中评估）如何与以下各项相关：a）Notch、CSC、EMT和EGFR标志物的肿瘤表达; B）厄洛替尼RO 4929097的肿瘤标志物变化; c）厄洛替尼RO 4929097的疗效。 非小细胞肺癌（NSCLC）占肺癌病例的85%。约10%的NSCLC具有表皮生长因子受体（EGFR）基因的激活突变，并且具有这些突变的肿瘤对EGFR酪氨酸激酶抑制剂（TKI）如厄洛替尼敏感。我们正在进行一项由美国国家癌症研究所（NCI-Sponsored Trial）发起的试验，在厄洛替尼耐药的NSCLC患者中，将3-分泌酶/ Notch抑制剂RO 4929097添加到厄洛替尼中。虽然厄洛替尼与EGFR野生型肿瘤相比效果较差，但仍观察到治疗益处。