Inhaled DNA demethylating therapy for lung cancer and bronchial premalignancy

吸入 DNA 去甲基化疗法治疗肺癌和支气管癌前病变

• 批准号: 8230467
• 负责人: ROMAN PEREZ-SOLER
• 金额: $ 40.26万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230467
• 关键词: Azacitidine; Biological; Breathing; Cancer Etiology; Cancer Model; Cessation of life; Characteristics; Chronic; Clinical; DNA; Development; Disease; Dose; Dysmyelopoietic Syndromes; Early Diagnosis; Early treatment; Epigenetic Process; Exhalation; Experimental Models; Failure; Gene Silencing; Genes; Human; Hypermethylation; Individual; Inhalation Therapy; Intervention; Laboratories; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Modeling; Mus; Non-Small-Cell Lung Carcinoma; Nude Mice; Patients; Pattern; Pharmacodynamics; Phase; Play; Population; Precancerous Conditions; Process; Property; Research; Risk; Route; Safety; Secondary to; Staging; Surface; System; Therapeutic; Therapeutic Index; Time; Tissue Sample; Tissues; Tobacco; Tobacco-Associated Carcinogen; Toxic effect; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vision; Xenograft Model; base; bronchial epithelium; carcinogenesis; clinical efficacy; cytotoxic; human study; lung cancer prevention; man; neoplastic cell; novel; phase 1 study; phase 2 study; positional cloning; preclinical study; prevent; programs; promoter; public health relevance; therapeutic development; tool; treatment strategy

DESCRIPTION (provided by applicant): Tumor suppressor silencing secondary to promoter hypermethylation plays a key role in the bronchial carcinogenesis process. The demethylating agent 5-azacytidine has demonstrated clinical efficacy in the treatment of the preleukemic condition myelodysplasia. Preliminary studies in our laboratory have demonstrated a 75-fold increase in the therapeutic index of 5-azacytidine when the intratracheal route of administration is used against orthotopic human lung cancer models in nude mice. In this application we propose to perform preclinical studies and the first human study of 5-azacytidine by inhalation. Our basic therapeutic strategy consists of exploiting the demethylaring properties of 5-azacytidine while avoiding its cytotoxic effects by using demethylating, non-cytotoxic doses, directly delivered to the target tissue, the bronchial epithelium, by inhalation over long periods of time. Before we initiate the proposed clinical Phase I study of inhaled 5-azacytidine we will determine the minimal effective dose as well as the lung toxicity of inhaled 5-azacytitine in a relevant murine model of lung premalignancy. These preclinical studies will allow us to rationally determine the starting dose that is likely to be both safe and therapeutic in man. We then propose to perform a feasibility and proof of principle Phase I study aimed at determining the optimal biological dose of inhaled 5-azacytidine using tumor suppressor gene reexpression in the target tissue as the pharmacodynamic endpoint. The specific aims are: 1. To determine the optimal dose of inhaled 5- azacytidine in mice exposed to tobacco carcinogens intratracheally (years 1 and 2). Endpoints will be: lung toxicity, efficacy in delaying lung tumor development, and tumor suppressor gene reexpression in the bronchial epithelium. 2. To perform a Phase I feasibility and proof of principle study of inhaled 5-azacytidine in patients with advanced NSCLC after failure of standard therapy (years 3-5). Endpoints will be: tolerability and toxicity with special emphasis on lung toxicity, tumor suppressor gene reexpression in the bronchial epithelium, and changes in methylation patterns in the bronchial epithelium. This proposal represents the first step of a long term program aimed at developing targeted epigenetic strategies for the treatment of advanced bronchial premalignancy and eventually the prevention of lung cancer. If successful, this strategy will provide clinical benefit to the very large population of individuals at risk of developing and dying from the most common cause of cancer-related death. PUBLIC HEALTH RELEVANCE: Lung cancer remains the number one cause of cancer-related death because of lack of effective early detection and intervention strategies. For many years, the disease remains confined to the airway surface. We propose to start exploring clinically a new early intervention strategy consisting on delivering by inhalation an agent, 5 azacytidine that has the potential of reversing the genetic damage produced by tobacco in the normal lung. If successful, such intervention may postpone or effectively prevent the occurrence of lung cancer in the large population of individuals at risk.

描述（由申请人提供）：继发于启动子超甲基化的肿瘤抑制子沉默在支气管癌的发生过程中起着关键作用。去甲基化剂5-氮杂胞苷在治疗白血病前期骨髓异常增生中已被证明具有临床疗效。我们实验室的初步研究表明，当气管内给药时，5-氮杂胞苷的治疗指数增加了75倍，用于裸鼠原位人肺癌模型。在这个申请中，我们建议进行临床前研究和首次吸入5-氮杂胞苷的人体研究。我们的基本治疗策略包括利用5-氮扎胞苷的去甲基化特性，同时通过使用去甲基化，非细胞毒性剂量，通过长时间吸入直接递送到目标组织，支气管上皮，避免其细胞毒性作用。在我们启动拟议的吸入5-阿扎胞苷临床I期研究之前，我们将在相关的肺恶性肿瘤小鼠模型中确定吸入5-阿扎胞苷的最小有效剂量和肺毒性。这些临床前研究将使我们能够合理地确定可能对人类既安全又有治疗作用的起始剂量。然后，我们建议进行可行性和原则性的I期研究，以肿瘤抑制基因在靶组织中的重新表达为药效学终点，旨在确定吸入5-氮杂胞苷的最佳生物剂量。具体目标是：1。确定经气管接触烟草致癌物的小鼠吸入5-氮扎胞苷的最佳剂量（1年和2年）。终点将是：肺毒性，延缓肺肿瘤发展的功效，以及支气管上皮中肿瘤抑制基因的重新表达。2. 在标准治疗失败（3-5年）的晚期NSCLC患者中进行吸入5-氮杂胞苷的I期可行性和原理证明研究。终点将是：耐受性和毒性，特别强调肺毒性，支气管上皮中肿瘤抑制基因的重新表达，以及支气管上皮中甲基化模式的变化。这一建议代表了一个长期项目的第一步，该项目旨在开发有针对性的表观遗传策略，以治疗晚期支气管恶性肿瘤，并最终预防肺癌。如果成功，这一战略将为大量面临癌症相关死亡最常见原因的患病和死亡风险的个体提供临床益处。