P-3: Targeting Tumor Microenvironment in NSCLC

K-ras原癌基因的激活突变发生在30%的肺腺癌中， 非小细胞肺癌（NSCLC）的亚型。K-ras是一种膜相关的GT3， 多种激酶途径，其中几种在细胞模型中具有转化活性。哪些 K-ras的下游介质对肺肿瘤发生的作用尚未完全阐明。更没有 有效的方法可用于治疗K-ras突变型NSCLC。为了解决这个问题，我们 研究了小鼠模型（K-rasl_A1），该模型通过体细胞激活 致癌K-ras（G12 D）。我们观察到明显的炎症细胞（巨噬细胞和中性粒细胞）， 血管内皮细胞和细支气管肺泡干细胞（BASCs，肺的假定前体）。 腺癌细胞）浸润非典型肺泡增生（AAH）病变和腺瘤。这一发现 表明致癌K-ras诱导的间质反应伴随早期肺肿瘤形成。我们的全球 假设致癌K-ras诱导的肺肿瘤发生部分是由宿主对 存在转化的肺泡上皮细胞。这些细胞来源于BASCs并分泌趋化因子， 募集炎性细胞和内皮细胞，这些细胞又分泌趋化因子和生长因子， 促进BASC扩增，从而加速肺肿瘤发生。我们将测试这一假设， 有两个具体目标。在目标1中，我们将使用遗传方法（3-磷酸肌醇依赖性 激酶[PDK-1]，一种PI 3 K依赖性激酶）来证实我们发现， 信号传导（PX-866或CCI-779）足以阻断致癌Kras诱导的肺肿瘤发生， 我们将研究靶向肿瘤内内皮细胞的药物（中和CXCR-2）是否能抑制肿瘤内的内皮细胞， 抗体）和炎性细胞（CCI-779）具有协同抗肿瘤作用。在目标2中，我们将翻译 我们的研究结果在KrasLAI小鼠的临床上通过检查NSCLC患者是否具有K-ras突变肿瘤 CXCR 2配体的血清浓度增加，从而将CXCR 2 pos血细胞动员成 流通。我们已经建立了通过流式细胞术分析检测循环内皮细胞的能力， 细胞和CXCR 2 pos单核细胞群，我们将其作为治疗反应的生物标志物进行检查 在癌症患者的I期临床试验中使用中和抗CXCR 2抗体。

Activating mutations in the K-ras proto-oncogene occur in 30% of lung adenocarcinomas, the most common subtype of non-small cell lung cancer (NSCLC). K-ras is a membrane-associated GTPase that activates multiple kinase pathways, several of which have transforming activity in cellular models. Which of these downstream mediators of K-ras contribute to lung tumorigenesis has not been fully elucidated. Moreover, no effective approaches are available for the treatment of K-ras-mutant NSCLC. To address this problem, we investigated a mouse model (K-rasl_A1) that develops lung adenocarcinoma through somatic activation of oncogenic K-ras (G12D). We observed prominent inflammatory cells (macrophages and neutrophils), vascular endothelial cells, and bronchioalveolar stem cells (BASCs, the putative precursors of lung adenocarcinoma cells) infiltrating atypical alveolar hyperplasia (AAH) lesions and adenomas. This finding indicates that a stromal response induced by oncogenic K-ras accompanies early lung neoplasia. Our global hypothesis is that oncogenic K-ras-induced lung tumorigenesis is driven in part by a host response to the presence of transformed alveolar epithelial cells. These cells arise from BASCs and secrete chemokines that recruit inflammatory cells and endothelial cells, which, in turn, secrete chemokines and growth factors that promote BASC expansion, thereby accelerating lung tumorigenesis. We will test this hypothesis by carrying out two Specific Aims. In Aim 1, we will use a genetic approach (loss of 3-phosphoinositide-dependent kinase [PDK-1], a PI3K-dependent kinase) to confirm our finding that pharmacologic inhibition of PI3Kdependent signaling (PX-866 or CCI-779) is sufficient to block lung tumorigenesis induced by oncogenic Kras, and we will examine whether agents that target intra-tumoral endothelial cells (neutralizing CXCR-2 antibody) and inflammatory cells (CCI-779) have cooperative anti-tumor effects. In Aim 2, we will translate our findings in KrasLAI mice to the clinic by examining whether NSCLC patients with K-ras-mutant tumors have increased serum concentrations of CXCR2 ligands, which thereby mobilize CXCR2pos blood cells into the circulation. We have established the ability to detect by flow cytometric analysis circulating endothelial cell and CXCR2pos monocytic populations, which we will examine as biomarkers of response to treatment with a neutralizing anti-CXCR2 antibody in a Phase I clinical trial in cancer patients.