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: 8444289
• 负责人: ROMAN PEREZ-SOLER
• 金额: $ 47.27万
• 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/8444289
• 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 Intervention; 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.

描述（由申请人提供）：继发于启动子高甲基化的肿瘤抑制基因沉默在支气管癌发生过程中起关键作用。去甲基化剂5-氮杂胞苷已被证明在治疗白血病前期条件骨髓增生异常的临床疗效。在我们实验室的初步研究表明，在治疗指数增加75倍的5-氮杂胞苷时，使用的皮下给药途径是对裸鼠原位人肺癌模型。在本申请中，我们建议进行临床前研究和首次人体吸入5-氮杂胞苷研究。我们的基本治疗策略包括利用5-氮杂胞苷的去甲基化特性，同时通过长时间吸入直接递送至靶组织（支气管上皮）的去甲基化、非细胞毒性剂量来避免其细胞毒性作用。在我们开始拟定的吸入5-氮杂胞苷的临床I期研究之前，我们将确定吸入5-氮杂胞苷在肺癌前病变相关小鼠模型中的最小有效剂量以及肺毒性。这些临床前研究将使我们能够合理地确定起始剂量，这可能是安全和治疗man. We然后建议进行一项可行性和证明的原则I期研究，旨在确定吸入5-氮胞苷的最佳生物剂量，使用肿瘤抑制基因在靶组织中的再表达作为药效学终点。具体目标是：1.确定吸入5-氮杂胞苷的最佳剂量，小鼠气管内暴露于烟草致癌物（1年和2年）。终点为：肺毒性、延缓肺肿瘤发展的疗效和支气管上皮中肿瘤抑制基因的再表达。2.在标准治疗失败后（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、支气管上皮中的肿瘤抑制基因再表达和支气管上皮中甲基化模式的变化。该提案代表了长期计划的第一步，该计划旨在开发针对晚期支气管癌前病变治疗并最终预防肺癌的靶向表观遗传策略。如果成功的话，这一策略将为大量有发展和死于最常见的癌症相关死亡原因风险的个体提供临床益处。