P-3: Targeting Tumor Microenvironment in NSCLC

P-3：针对 NSCLC 中的肿瘤微环境

基本信息

批准号：
8118986
负责人：
Jonathan M Kurie
金额：
$ 25.11万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8118986
关键词：
1-Phosphatidylinositol 3-Kinase Address Adenocarcinoma Adenocarcinoma Cell Affect Aftercare Alleles Alveolar Antibodies Apoptosis Attenuated Bioinformatics Biological Assay Biological Markers Blood Blood Cells Blood Circulation Blood specimen CCI-779 CXCL1 gene Cancer Model Cancer Patient Cell Line Cell model Cells Clinic Clinical Investigator Clinical Trials Design Combined Modality Therapy Endothelial Cells Epithelial Cells Figs - dietary Flow Cytometry Gene Expression Profile Genetic Genotype Goals Growth Factor Guanosine Triphosphate Phosphohydrolases Histologic Human Hyperplasia IL8RB gene Immune response Inflammatory Lesion Ligands Lung Lung Adenocarcinoma Lung Neoplasms Malignant Epithelial Cell Malignant neoplasm of lung Maximum Tolerated Dose Measures Mediator of activation protein Membrane Mus Mutation Neoplasms Non-Small-Cell Lung Carcinoma Oncogenic Partner in relationship Pathology Pathway interactions Phase I Clinical Trials Phosphatidylinositols Phosphotransferases Population Process Proto-Oncogenes Recruitment Activity Reproduction spores Safety Scanning Serum Signal Transduction Stem cells Structure of parenchyma of lung Testing Toxic effect Translating Vascular Endothelial Cell X-Ray Computed Tomography adenoma antiangiogenesis therapy base cell type chemokine chemokine receptor cytokine human FRAP1 protein inhibitor/antagonist kinase inhibitor lung tumorigenesis mRNA Expression mTOR Inhibitor macrophage monocyte mouse model mutant neoplastic cell neutralizing antibody neutrophil research study response small molecule synthetic polymer Bioplex tumor

项目摘要

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.

K-RAS原型癌中的激活突变发生在30％的肺腺癌中，是最常见的非小细胞肺癌（NSCLC）的亚型。 K-RAS是一种激活膜相关的GTPase 多个激酶途径，其中几种在细胞模型中具有转化活性。其中哪一个 K-RAS的下游介体有助于肺部肿瘤发生。而且，不有效的方法可用于治疗K-Ras突变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而发展为肺腺癌致癌K-Ras（G12D）。我们观察到明显的炎症细胞（巨噬细胞和中性粒细胞），血管内皮细胞和支气管肺泡干细胞（BASC，肺的假定前体腺癌细胞）浸润非典型的肺泡增生（AAH）病变和腺瘤。这个发现表明致癌K-RAS诱导的基质反应伴随着早期肺肿瘤。我们的全球假设是致癌K-RAS诱导的肺肿瘤发生的部分原因是宿主对存在转化的肺泡上皮细胞。这些细胞来自BASC和分泌趋化因子募集炎性细胞和内皮细胞，而这些细胞又分泌趋化因子和生长因子促进BASC扩张，从而加速肺部肿瘤。我们将通过携带来检验这一假设淘汰两个具体的目标。在AIM 1中，我们将使用一种遗传方法（依赖3-磷酸肌醇的丧失激酶[PDK-1]，一种依赖PI3K 信号传导（PX-866或CCI-779）足以阻止致癌性KRAS诱导的肺肿瘤发生，我们将检查靶向肿瘤内内皮细胞的试剂（中和CXCR-2 抗体）和炎症细胞（CCI-779）具有合作的抗肿瘤作用。在AIM 2中，我们将翻译我们在Kraslai小鼠到诊所的发现，通过检查NSCLC是否患有K-Ras突变肿瘤的患者 CXCR2配体的血清浓度升高，从而动员CXCR2POS血细胞进入循环。我们已经确定了通过流式细胞仪分析循环内皮检测的能力细胞和CXCR2POS单核细胞种群，我们将研究作为对治疗反应的生物标志物在癌症患者的I期临床试验中，具有中和抗CXCR2抗体。