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

基本信息

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
项目类别：
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

项目摘要

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继发的肿瘤抑制沉默在支气管致癌过程中起关键作用。脱甲基化剂5-氮杂丁胺在治疗前脑发育不全方面表现出临床功效。当我们实验室的初步研究表明，当气管内给药途径用于裸体小鼠的原位人体肺癌模型时，5-余苷的治疗指数增加了75倍。在此应用中，我们建议通过吸入进行临床前研究和对5-氮杂替丁的首次人类研究。我们的基本治疗策略包括利用5-氮杂丁胺的脱甲基化特性，同时通过使用脱甲基化的，非胞毒性剂量来避免其细胞毒性作用，直接通过长时间的吸收来直接递送到靶组织，即支气管上皮细胞。在我们启动对吸入5-氮杂丁丁的I阶段研究的临床研究之前，我们将在相关的肺预现态鼠模型中确定吸入的5-齐丁替氨酸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人类可能既安全又治疗的起始剂量。然后，我们建议在旨在确定吸入5-余丁胺的最佳生物学剂量的可行性和原理I期研究证明，该研究使用靶向组织中的肿瘤抑制基因重新表达作为药效终点。具体目的是：1。确定暴露于烟叶肿瘤的小鼠中吸入的5-偶氮丁丁的最佳剂量（1和2年）。终点将是：肺毒性，延迟肺部肿瘤发育的功效以及支气管上皮的肿瘤抑制基因表达。 2。在标准疗法失败后，对患有晚期NSCLC的患者进行I阶段的可行性和原理研究证明（3-5年）。终点将是：耐受性和毒性，特别着重于肺毒性，支气管上皮中的肿瘤抑制基因表达，以及支气管上皮的甲基化模式的变化。该提案是长期计划的第一步，旨在制定针对性的表观遗传策略，用于治疗晚期支气管预现态，并最终预防肺癌。如果成功，该策略将为有癌症相关死亡的最常见原因的风险和死亡风险的人群提供临床益处。