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.

雾化类rexinoid贝沙罗汀的化学预防作用及其在所有疾病中的功效 肺癌的亚型，将使用最先进的（Collison雾化器）气雾剂进行检查 输送系统至肺部，以避免与口服给药相关的系统副作用 这个代理。贝沙罗汀已在临床上用于治疗以下患者的皮肤 T 细胞淋巴瘤： 对任何其他药物都无效。 Bexarotene 还在 1/2 期试验中显示出疗效 非小细胞肺癌（NSCLC）。它是迄今为止经过测试的唯一高效药剂 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 A/J 小鼠肿瘤中，雾化给药贝沙罗汀保留了肺肿瘤抑制作用 与对照相比，不增加血浆总胆固醇和甘油三酯水平。这 拟议的项目将研究 SCC 和 SCLC 小鼠模型中的雾化贝沙罗汀，以及 它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）、凋亡活性和浸润的变化 淋巴样细胞，以及肺部肿瘤和 mRNA 的变化 周围的肺组织。