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，这是最常见的 非小细胞肺癌(NSCLC)亚型。K-ras是一种膜相关的GTP酶，它能激活 多条激酶通路，其中几条在细胞模型中具有转化活性。这些中的哪一个 K-ras下游调节因子在肺肿瘤发生中的作用尚未完全阐明。此外，没有 治疗K-ras基因突变的NSCLC是一种有效的方法。为了解决这个问题，我们 建立小鼠肺腺癌模型(K-RASL_A1) 致癌K-ras(G12D)。我们观察到显著的炎症细胞(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)，推测为肺的前体 腺癌细胞)浸润性不典型肺泡增生(AAH)病变和腺瘤。这一发现 提示致癌K-ras诱导的间质反应伴随早期肺肿瘤。我们的全球 假说认为致癌K-ras诱导的肺肿瘤发生部分是由宿主对 出现转化的肺泡上皮细胞。这些细胞起源于BASCs，并分泌趋化因子 招募炎症细胞和内皮细胞，它们反过来分泌趋化因子和生长因子，从而 促进BASC的扩张，从而加速肺癌的发生。我们将通过以下方式验证这一假设 提出了两个具体目标。在目标1中，我们将使用遗传方法(丢失3-磷酸肌醇依赖 激酶[PDK-1]，一种依赖PI3K的激酶)来证实我们的发现，药物抑制依赖的PI3K 信号(PX-866或CCI-779)足以阻断致癌Kras诱导的肺肿瘤形成， 我们将检查靶向肿瘤内皮细胞(中和CXCR-2)的药物 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 我们在Kraslai小鼠身上的发现通过检测非小细胞肺癌患者是否存在K-ras突变肿瘤来临床 增加CXCR2配体的血清浓度，从而动员CXCR2pos血细胞进入 发行量。我们已经建立了通过流式细胞仪分析检测循环内皮细胞的能力 细胞和CXCR2pos单核细胞群，我们将考察它们作为治疗反应的生物标志物 在癌症患者的I期临床试验中使用中和抗CXCR2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.