HHSN2612012000151/HHSN2610006Base Contract Title: Preclinical Efficacy and Intermediate Biomarkers. Task Order Title: Modulation of miRNA Expression in Blood or Other Biological Fluids Compared wi

HHSN2612012000151/HHSN2610006基本合同标题：临床前功效和中间生物标志物。

• 批准号: 8947461
• 负责人: MARGIE CLAPPER
• 金额: $ 57.52万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2016-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8947461
• 关键词: A/J Mouse; Adenocarcinoma; Adverse effects; Aerosols; Apoptotic; Atomizer; Benign; Bexarotene; Biological; Biological Markers; Blood; Cell Proliferation; Chemopreventive Agent; Cholesterol; Contracts; Cutaneous; Cyclin D1; Drug Formulations; Drug Kinetics; Liquid substance; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lymphoid Cell; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Messenger RNA; MicroRNAs; Monitor; Non-Small-Cell Lung Carcinoma; Oral Administration; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma; Proliferation Marker; Refractory; Squamous cell carcinoma; Structure of parenchyma of lung; System; T-Cell Lymphoma; Testing; Toxic effect; Triglycerides; aerosolized; drug efficacy; mouse model; preclinical efficacy; tumor progression

The chemopreventive effect of an aerosolized rexinoid, bexarotene, and its efficacy in all subtypes of lung cancer, will be examined using a state-of-the-art (Collison atomizer) aerosol delivery system to lung to avoid the systematic side effects associated with oral administration of this agent. Bexarotene has been used clinically to treat cutaneous T cell lymphoma in patients who were refractory to any other medication. Bexarotene has also shown efficacy in a Phase 1/2 trial of non-small cell lung cancer (NSCLC). It is the only agent tested to date that is highly effective in mouse models of adenocarcinoma, squamous cell carcinoma (SCC), and SCLC. In B[a]P-induced lung tumors in A/J mice, aerosolized delivery of bexarotene retained lung tumor inhibitory effects without increasing plasma total cholesterol and triglyceride levels, compared with control. The proposed project will study aerosolized bexarotene in mouse models of both SCC and SCLC, as well as its effects on tumor progression (from benign to malignant tumors) in mouse models of lung adenocarcinoma, while closely monitoring side effects and toxicity. The project will also analyze changes in cell proliferation markers (cyclin D1 and Ki- 67), apoptotic activity, and infiltrating lymphoid cells, as well as mRNA changes in lung tumors and surrounding lung tissues.

雾化吸入类瑞辛素、贝沙罗汀的化学预防作用及其对所有患者的疗效 肺癌的亚型，将使用最先进的（Collison雾化器）气溶胶进行检查 以避免与口服给药相关的全身副作用 这个特工。贝沙罗汀已在临床上用于治疗皮肤T细胞淋巴瘤患者， 对其他任何药物都无效贝沙罗汀在一项1/2期临床试验中也显示出疗效， 非小细胞肺癌（NSCLC）。它是迄今为止测试过的唯一一种高效的药剂 在腺癌、鳞状细胞癌（SCC）和SCLC的小鼠模型中。在B[a] P诱导的肺中 在A/J小鼠中，贝沙罗汀的雾化递送保留了肺肿瘤抑制作用 而不增加血浆总胆固醇和甘油三酯水平。的 拟议的项目将研究雾化贝沙罗汀在SCC和SCLC小鼠模型，以及 其对小鼠肺模型中肿瘤进展（从良性肿瘤到恶性肿瘤）的影响 腺癌，同时密切监测副作用和毒性。该项目还将分析 细胞增殖标志物（细胞周期蛋白D1和Ki- 67）、凋亡活性和浸润性 淋巴样细胞，以及肺肿瘤中的mRNA变化， 周围的肺组织