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

描述(申请人提供)：我们将进行初步评估，如果肿瘤有Notch通路和CSC标记物的高表达，厄洛替尼治疗非小细胞肺癌的疗效是否会降低，以及加入3-分泌酶抑制剂RO4929097是否会消除Notch/CSC标记物高表达的负面影响。我们还将评估Notch和CSC标记物是否与EMT和EGFR标记物相关，以及基线标记物签名是否预测厄洛替尼单独或RO4929097-erlotinib联合治疗的疗效。我们将评估单独暴露于erlotinib是否使肿瘤的Notch/CSC/EMT标记丰富作为获得性耐药的一种机制，以及将RO4929097添加到erlotinib是否阻止这种丰富或改变erlotinib对EGFR途径信号的影响。我们将评估宿主Notch SNPs对肿瘤Notch/CSC/EMT/EGFR标记物表达的影响以及对erlotinibRO4929097疗效的影响。我们也可以把它们作为次要目标来评估。具体地说，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标记物在有或没有其他erlotinib耐药因子(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通路组件如何调节或增强Notch通路对EGFR TKI疗效的影响；c)Notch/CSC/EMT标记物在EGFR突变的VS野生型肿瘤中的表达。具体目标1：我们将获得接受厄洛替尼RO4929097治疗前的活检组织，并将通过免疫组织化学(IHC)和反相蛋白阵列(RPPA)检测Notch通路、CSC、EMT和EGFR通路标志物。我们将：a)将Notch和CSC标记物彼此之间以及与EMT和EGFR标记物的表达相关联；b)将标记物的表达与RO4929097启动后的肿瘤缩小相关联；c)将标记物的表达与erlotinib启动后的肿瘤缩小相关联；d)比较有或没有最近应用erlotinib的患者中的标记物的表达；特定目标2：我们将在使用erlotinib RO4929097开始治疗6周后再次进行非小细胞肺癌活检，并将单用erlotinib治疗的患者与同时接受RO4929097治疗的患者的Notch、CSC、EMT和EGFR标记物的表达变化进行比较。具体目标3：我们将评估宿主Notch途径SNPs(在外周血单核细胞中评估)如何与：a)Notch、CSC、EMT和EGFR标记物的肿瘤表达；b)与erlotinib RO4929097的肿瘤标记物的变化；c)erlotinib RO4929097的疗效。 公共卫生相关性：非小细胞肺癌(NSCLC)占肺癌病例的85%。大约10%的NSCLC存在表皮生长因子受体(EGFR)基因的激活突变，具有这些突变的肿瘤对EGFR酪氨酸激酶抑制剂(TKIs)如厄洛替尼敏感。我们正在进行一项由NCI赞助的试验，在该试验中，对厄洛替尼耐药的非小细胞肺癌患者在他们的厄洛替尼中加入了3-分泌酶/Notch抑制剂RO4929097。虽然厄洛替尼与EGFR野生型肿瘤相比效果较差，但治疗上仍有好处。

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.