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

描述（由申请人提供）：我们将初步评估如果肿瘤具有高Notch通路和CSC标记物表达，是否会降低erlotinib在NSCLC中的疗效，以及添加3-secretase inhibitor RO4929097是否会消除高Notch/CSC标记物表达的负面影响。我们还将评估Notch和CSC标记物是否与EMT和EGFR标记物相关，以及基线标记物特征是否预测厄洛替尼单独或ro4929097 -厄洛替尼联合治疗的疗效。我们将评估单独暴露于厄洛替尼是否会使肿瘤的Notch/CSC/EMT标志物富集作为获得性耐药的机制，以及RO4929097加入厄洛替尼是否会阻止这种富集或改变厄洛替尼对EGFR通路信号的影响。我们将评估宿主Notch snp对肿瘤Notch/ CSC/ EMT/ EGFR标记物表达的影响以及erlotinibRO4929097的疗效。我们也可以把它们作为次要目标来评估。具体而言，在组织数量和患者数量允许的情况下，我们将进行初步评估：a) Notch/CSC/EMT标记物在有或没有其他埃洛替尼耐药因子（例如，T790M突变、IGF-1R激活、c-Met扩增）的肿瘤中的表达；b) Sonic Hedgehog （SHH）和Wnt通路组分如何调节或增强Notch通路对EGFR TKI疗效的影响；c) Notch/CSC/EMT标记物在egfr突变型与野生型肿瘤中的表达。具体目标1：我们将对接受erlotinib RO4929097治疗的患者进行治疗前活检，并通过免疫组化（IHC）和逆相蛋白阵列（RPPAs）评估Notch通路、CSC、EMT和EGFR通路标志物。我们将：a)将Notch和CSC标记相互之间以及与EMT和EGFR标记的表达关联起来；b)启动RO4929097后标志物表达与肿瘤缩小相关；C)厄洛替尼启动后标志物表达与肿瘤缩小相关；d)比较近期接触厄洛替尼与未接触厄洛替尼患者的标志物表达特异性目的2：我们将在开始厄洛替尼RO4929097治疗后6周进行重复NSCLC活检，并将比较单独接受厄洛替尼与同时接受RO4929097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通路snp（在外周血单个核细胞[PBMCs]中评估）如何与：a) Notch、CSC、EMT和EGFR标记物的肿瘤表达；b)厄洛替尼RO4929097治疗后肿瘤标志物的变化；c)厄洛替尼RO4929097的疗效。

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.