Phospho-sulindac for Lung Cancer Treatment

简介(申请人提供)：肺癌是癌症死亡的主要原因，5年生存率为15%。这一令人担忧的预后清楚地表明，迫切需要新的有效药物来治疗它。我们开发的一种新型化合物--磷酸-舒林酸(PS)对肺癌移植瘤的生长有87-103%的抑制作用，在一项研究中消除了3/7的肺癌肿瘤。除了显著的疗效外，PS还具有特殊的安全性。因此，PS有很强的潜力成为治疗肺癌的有效药物。我们的初步数据表明，PS的抗癌作用机制是通过其 实质如下：PS诱导氧化应激，激活氧化还原敏感的信号级联反应，进而阻断细胞周期进程，抑制细胞增殖，诱导细胞凋亡，最终抑制肿瘤生长。PS引起的氧化应激是由于：a)NADPH氧化酶的激活，产生自由基超氧阴离子；b)抑制细胞抗氧化系统的几个成员，包括酶(硫氧还蛋白系统、过氧化还蛋白、细胞球蛋白、超氧化物歧化酶)和化学物质(谷胱甘肽)。这些效应迅速增加了细胞内活性氧物种(ROS)的水平，使氧化还原平衡转向氧化应激。在体内，抗氧化剂N-乙酰半胱氨酸和PS联合应用可抑制氧化应激，并消除PS对肺癌移植瘤的抗癌作用。我们的假设是PS是一种治疗肺癌的高效和安全的药物，其作用主要是通过诱导氧化应激来发挥作用。为了评估这一假设，我们提出了以下具体目标：1)在动物肿瘤模型中评估PS对肺癌的疗效：我们将扩大疗效研究，包括反映肺癌遗传亚型的额外细胞系的异种移植和肺癌的转基因模型。2)验证患者来源的肺癌异种移植的疗效。它们提供了对人类药物疗效的极好预测；我们将研究具有KRAS或EGFR突变的肿瘤。3)体外和体内研究PS诱导氧化应激的分子靶点及介导其抗癌作用的下游信号通路。我们将评估氧化应激的主要贡献者和氧化应激下游的信号通路。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths, with a 5-year survival rate of <15%. This alarming prognosis makes clear the urgent need for new efficacious agents for its treatment. Phospho-sulindac (PS), a novel compound developed by us, inhibits the growth of lung cancer xenografts by 87-103%, eliminating, in one study, 3/7 lung cancer tumors. In addition to its remarkable efficacy, PS has an exceptional safety profile. Thus PS has a strong potential of becoming an efficacious agent for the treatment of lung cancer. Our preliminary data indicate that the mechanism of the anti-cancer effect of PS is, in its essence, the following: PS induces oxidative stress, which activates redox-sensitive signaling cascades, which in turn block cell cycle progression, inhibit proliferation and induce apoptosis; the end result is inhibition of tumor growth. The development of oxidative stress by PS is due to: a) activation of NADPH oxidase, which generates the free radical superoxide anion; and b) suppression of several members of the antioxidant system of the cell, both enzymatic (the thioredoxin system, peroxiredoxin, cytoglobin, superoxide dismutase) and chemical (glutathione).These effects increase rapidly the cellular levels of reactive oxygen species (ROS) shifting the redox balance towards oxidative stress. In vivo, co-administration of the antioxidant N-acetyl-cysteine and PS suppresses oxidative stress and eliminates the anticancer effect of PS on lung cancer xenografts. Our hypothesis is that PS is a highly effective and safe agent for the treatment of lung cancer acting predominantly by inducing oxidative stress. To evaluate this hypothesis, we propose the following specific aims: 1) Assess the efficacy of PS against lung cancer in animal tumor models: We will expand the efficacy studies to include xenografts of additional cell lines mirroring the genetic subtypes of lung cancer and a transgenic model of lung cancer. 2) Validate efficacy results in patient-derived lung cancer xenografts. They provide excellent prediction of drug efficacy in humans; we will study tumors with KRAS or EGFR mutations. And 3) Study in vitro and in vivo the molecular targets involved in the induction of oxidative stress by PS and the downstream signaling pathways that mediate its anticancer effect. We will evaluate the main contributors to oxidative stress and signaling pathways downstream of oxidative stress.