Targeting Integrins in Lung Cancer

肺癌是美国退伍军人和全世界癌症相关死亡的最常见原因。分子 靶向治疗和免疫治疗是肺癌治疗中最近的两个主要突破， 已被证明可以延长生命并增加治愈率，但它们中的每一种都可以使约20%的非小细胞肺癌受益 （NSCLC）患者。需要新的治疗策略来确定新的治疗靶点并开发和 验证为分子靶向治疗和癌症选择合适患者的检测方法 免疫治疗和监测抗肿瘤反应。我们最近已经产生并表征了高亲和力的 用于靶向多个细胞表面上的肿瘤特异性和淋巴细胞特异性整联蛋白的肽配体 上皮癌类型，包括NSCLC和来源于特定细胞膜的微囊泡外泌体， 癌症或免疫细胞。我们假设这些高亲和性肽配体可用于改善细胞的免疫功能。 检测肺癌患者中肿瘤和免疫细胞特异性生物标志物的灵敏度。整体 本提案的目的是开发易于操作、低成本、灵敏的多重测定法，以改善 当前分子和免疫生物标志物检测的灵敏度，在单次抽血或胸腔穿刺中用于临床 癌症治疗选择和监测的决策。我们将使用收集的生物流体样本 在IRB批准的方案下，对晚期NSCLC患者进行研究，以优化我们的新型体外诊断 平台在具体的目标1中，我们开发了一种用于灵敏检测和富集肿瘤细胞的测定法， 使用LXY 30（对于α3β1整联蛋白）检测NSCLC患者的恶性体液。在具体目标2中，我们将制定一项 用于快速和简单分离肿瘤特异性外泌体的新型体外平台， 高质量的肿瘤DNA，以提高临床分子生物标志物测定的成功率。具体目标3： 开发一种新的体外平台，用于快速简单地分离血液中的功能性免疫细胞， NSCLC患者进行流式细胞术、T细胞受体多样性和单细胞基因组表征。我们 预期我们的新型、集成、简单、低成本的体外诊断平台在临床上的应用， 连续的非侵入性“液体活检”可以真实的时间为癌症患者选择最有效的治疗， 因此，它具有很大的潜力，可以促进癌症患者的个体护理，实现精准医疗的目标。

Lung cancer is the most common cause of cancer-related deaths in US veterans and worldwide. Molecularly targeted therapy and immunotherapy are two recent major breakthroughs in lung cancer treatment that have been shown to extend life and increase cure, but each of them benefits ~20% of non-small cell lung cancer (NSCLC) patients. Novel therapeutic strategies are needed to identify new treatment targets and develop and validate the assays that select the appropriate patients for molecularly targeted therapy and cancer immunotherapy and monitor antitumor responses. We have recently generated and characterized high-affinity peptide ligands for targeting tumor-specific and lymphocyte-specific integrins on the surface of multiple epithelial cancer types including NSCLC and microvesicle exosomes derived from the membranes of specific cancer or immune cells. We hypothesize that these high affinity peptide ligands can be used to improve the sensitivity of detecting tumor- and immune cell-specific biomarkers in lung cancer patients. The overall objective of this proposal is to develop easily operable, low cost, sensitive, multiplex assays to improve the sensitivity of current molecular and immune biomarker tests, in a single blood draw or thoracentesis for clinical decision-making in cancer treatment selection and monitoring. We will use biofluid samples collected from patients with advanced NSCLC under IRB-approved protocol to optimize our novel in vitro diagnostic platforms. In specific aim 1, we develop an assay for sensitive detection and enrichment of tumor cells from malignant body fluids of NSCLC patients using LXY30 (for α3β1 integrin). In specific aim 2, we will develop a novel in vitro platform for rapid and simple isolation of tumor-specific exosomes yielding high quantity and quality tumor DNA to increase the success of clinical molecular biomarker assays. In specific aim 3, we will develop a novel in vitro platform for rapid and simple isolation of functional immune cells in the blood from NSCLC patients for flow cytometry, T cell receptor diversity, and single cell genomic characterization. We anticipate that the clinical application of our novel, integrated, simple, low cost, in vitro diagnostic platform in a serial noninvasive “liquid biopsy” can select the most effective treatment for cancer patients in real time and thus has great potential to advance individual cancer patient care towards the goal of precision medicine.