An agent for the treatment of lung cancer

描述（由申请人提供）：肺癌是美国和全球癌症死亡的主要原因。鉴于其流行率、发病率和死亡率，显然在治疗方面，“肺癌问题”远未解决;迫切需要新的药物。我们的初步数据表明，新化合物磷酸-舒林酸（PS）对肺癌具有潜在的高度有效性。我们的假设是，PS是一种安全和高效的抗肺癌药物。为了验证这一假说，我们提出了以下具体目标：1）确定PS在肺癌动物模型中的疗效和作用机制。PS将给予具有代表主要临床亚类的人肺癌细胞异种移植物的裸鼠和具有原位异种移植肺癌的裸鼠，并评估已经概述的信号传导途径的体内变化。2)进行PS毒性研究。我们将确定PS的遗传毒性、最大耐受剂量和重复剂量/器官毒性。3)研究PS的代谢、药代动力学和药效学。这些目标将评估对PS临床前开发至关重要的参数：药物疗效、药物安全性、药物代谢、药代动力学和药效学。预期结果将为完成PS的临床前评价铺平道路。 公共卫生相关性：肺癌是美国和全球癌症死亡的主要原因。鉴于其患病率、发病率和死亡率，显然在治疗方面，“肺癌问题”远未解决，迫切需要新的药剂。我们正在计划开发一种新型化合物，磷酸舒林酸，它可能对肺癌非常有效。预期的结果将为完成磷酸-舒林酸的临床前评估铺平道路，这是在人体测试之前的一个必要步骤。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths in the US and worldwide. Given its prevalence, morbidity and mortality, it is clear that in terms of treatment, the "lung cancer problem" is far from solved; and that new agents are urgently needed. Our preliminary data indicate that the novel compound phospho-sulindac (PS) is potentially highly effective against lung cancer. Our hypothesis is that PS is a safe and highly effective agent against lung cancer. To evaluate this hypothesis, we propose the following specific aims: 1) Determine the efficacy and mechanism of action of PS in animal models of lung cancer. PS will be administered to nude mice with xenografts of human lung cancer cells representing the major clinical subcategories and to nude rats with orthotopic xenografted lung cancer and assess the in vivo changes of the signaling pathways already outlined. 2) Perform toxicity studies of PS. We will determine the genotoxicity, maximum tolerated dose and repeated dose/organ toxicity of PS. 3) Study the metabolism, pharmacokinetics and pharmacodynamics of PS. These aims will assess parameters that are essential to the preclinical development of PS: drug efficacy; drug safety; drug metabolism; pharmacokinetics; and pharmacodynamics. The expected results will pave the way towards the completion of PS's preclinical evaluation. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths in the US and worldwide. Given its prevalence, morbidity and mortality, it is clear that in terms of treatment, the "lung cancer problem" is far from solved and that new agents are urgently needed. We are proposing to develop a novel compound, phospho-sulindac, which is potentially highly effective against lung cancer. The expected results will pave the way towards the completion of phospho-sulindac's preclinical evaluation, a required step prior to its testing in humans.