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 原癌基因的激活突变发生在 30% 的肺腺癌中，这是最常见的肺腺癌非小细胞肺癌（NSCLC）的亚型。 K-ras 是一种膜相关 GTP 酶，可激活多种激酶途径，其中一些在细胞模型中具有转化活性。其中哪一个 K-ras 下游介质对肺肿瘤发生的贡献尚未完全阐明。而且，没有 K-ras 突变 NSCLC 的治疗有有效的方法。为了解决这个问题，我们研究了一种小鼠模型（K-rasl_A1），该模型通过体细胞激活发展为肺腺癌致癌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，假定的肺细胞前体）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 诱导的肺肿瘤发生部分是由宿主对转化的肺泡上皮细胞的存在。这些细胞由 BASC 产生并分泌趋化因子募集炎症细胞和内皮细胞，进而分泌趋化因子和生长因子促进 BASC 扩张，从而加速肺部肿瘤发生。我们将通过携带来检验这个假设提出两个具体目标。在目标 1 中，我们将使用遗传方法（失去 3-磷酸肌醇依赖性激酶 [PDK-1]，一种 PI3K 依赖性激酶）来证实我们的发现，PI3K 依赖性药物抑制信号传导（PX-866 或 CCI-779）足以阻止致癌 Kras 诱导的肺部肿瘤发生，我们将检查是否有针对肿瘤内内皮细胞的药物（中和 CXCR-2）抗体）和炎症细胞（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 小鼠中的发现通过检查 NSCLC 患者是否患有 K-ras 突变肿瘤而推向临床 CXCR2 配体的血清浓度增加，从而动员 CXCR2pos 血细胞流通。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 CXCR2pos 单核细胞群，我们将检查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。