Novel COX-2 and PGE2-dependent pathways in lung cancer

肺癌中新的 COX-2 和 PGE2 依赖性途径

• 批准号: 7561013
• 负责人: Steven M. Dubinett
• 金额: $ 23.97万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-17 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561013
• 关键词: Address; Attention; Cancer Patient; Cell physiology; Cells; Dinoprostone; Disease; Dose; Eligibility Determination; Enrollment; Environment; Evaluation; Excision; Goals; Human; Immune; Immune response; Immunosuppressive Agents; Intervention; Knowledge; Lymphocyte; Malignant neoplasm of lung; Mediating; Neoadjuvant Therapy; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Pathway interactions; Patients; Peripheral Blood Lymphocyte; Phase I Clinical Trials; Pilot Projects; Prostaglandins; Proteins; Randomized; Research; Research Personnel; Resectable; Role; Specimen; Staging; Survival Rate; T-Lymphocyte; Tissues; Tumor-Infiltrating Lymphocytes; Urine; base; celecoxib; cohort; conventional therapy; cyclooxygenase 2; improved; in vitro activity; novel; overexpression; progesterone 11-hemisuccinate-(2-iodohistamine); programs; receptor; statistics; tumor

Despite focused research in conventional therapies, the five-year survival rate for lung cancer remains only 14 percent and has improved only minimally in the past 25 years. These dismal statistics have led us to explore the lung cancer-induced immunosuppressive environment and to develop novel targeted therapies based on this new knowledge. Tumor-reactive T cells have been shown to accumulate in lung cancer tissues but fail to respond. In fact, a high proportion of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TIL)are CD4+CD25hi9h T regulatory (T reg)cells. In previous studies we found an immune suppressive network in NSCLC that is due to overexpression of tumor cyclooxygenase 2 (COX-2). The current proposal focuses particular attention on defining the pathways whereby the COX-2 and its metabolite prostaglandin E2 (PGE2) inhibit immune responses in lung cancer by promoting T regulatory cell activity. The specific aims will: 1) determine the role of COX-2/PGE2-dependent modulation of T reg cell function. We will determine the pathways whereby COX-2 and PGE2 modulate human T reg cell functional activity in vitro and 2) determine the effect of COX-2 inhibition on T regulatory cells in NSCLC two pilot studies will be conducted in patients with advanced and surgically resectable disease. In the first study, we will conduct a two-center, non-randomized, dose-escalation phase I clinical trial to evaluate the effects of COX-2 inhibition on T regulatory cells in stage NIB and IV NSCLC patients. We will enroll 24 subjects in three escalating dose-cohorts to establish the optimal biologic dose (OBD) of celecoxib for decreasing T reg cells in advanced NSCLC. The second pilot study will evaluate subjects with early stage, resectable NSCLC. Forty eligible subjects will be randomly assigned to receive celecoxib at the OBD determined above or no intervention for a 7-day period prior to surgical resection. The overall goal of these studies is to determine the role of COX-2 and PGE2 inhibition in modulation of CD4+CD25high T regulatory (T reg)cells in NSCLC.

尽管对传统疗法进行了重点研究，但肺癌的五年生存率仍然只有 14%，在过去的25年里只有很小的改善。这些令人沮丧的统计数据使我们 探索肺癌诱导的免疫抑制环境并开发新的靶向治疗 基于这些新知识。肿瘤反应性T细胞已被证明在肺癌中积聚 组织，但没有反应。事实上，高比例的非小细胞肺癌（NSCLC）肿瘤浸润性 淋巴细胞（TIL）是CD 4 + CD 25 hi 9 h T调节（T reg）细胞。在以前的研究中，我们发现免疫系统 NSCLC中的抑制网络是由于肿瘤环氧化酶2（考克斯-2）的过表达。的 目前的建议特别关注于确定考克斯-2及其代谢产物 前列腺素E2（PGE 2）通过促进调节性T细胞活性抑制肺癌免疫应答。 具体的目标是：1）确定T reg细胞功能的考克斯-2/PGE 2依赖性调节的作用。 我们将确定考克斯-2和PGE 2调节人T reg细胞功能活性的途径， 体外和2）确定考克斯-2抑制对NSCLC中T调节细胞的影响， 在晚期和可手术切除的疾病患者中进行。在第一项研究中，我们将进行一项 评价考克斯-2抑制作用的双中心、非随机、剂量递增I期临床试验 对NIB期和IV期NSCLC患者的T调节细胞的影响。我们将招募24名受试者， 剂量队列，以确定塞来昔布降低T reg细胞的最佳生物剂量（OBD）， 晚期NSCLC。第二项初步研究将评价早期可切除NSCLC受试者。四十 合格的受试者将被随机分配接受塞来昔布治疗， 在手术切除之前进行为期7天的干预。这些研究的总体目标是确定 抑制考克斯-2和PGE 2在调节NSCLC中CD 4 + CD 25 high T调节（T reg）细胞中的作用。