Use of Beta-lapachone for Lung Cancer Chemotherapy

描述（由申请人提供）：非小细胞肺癌（NSCLC）患者的5年生存率约为15%。目前迫切需要针对独特的蛋白质标记物来杀死非小细胞肺癌细胞，无论其生长状态如何，以及针对原发和转移细胞的抗肿瘤药物。我们在之前的批准期内完成了所有提出的目的，并阐明了¿-lapachone（¿-lap）单独抗NSCLC细胞的作用机制。¿- lap对非小细胞肺癌选择性有效，其中80%的肿瘤内源性过表达NAD(P)H：醌氧化还原酶1 (NQO1) 5- 100倍。¿-Lap通过NQO1/ROS/Ca2+ER/PARP1超激活途径杀死NSCLC细胞，导致¿-calpain细胞死亡。为了克服溶解度和正常组织毒性问题，开发了各种搭接递送方法。Arq501 （-lap in hydroxypropyl- cyclodextrin, Arqule Chem.）基于我们的工作，公司进入了几个II期临床试验。在这一竞争更新中，将探索几种新的纳米颗粒胶束递送系统，这些系统将提高单独或与放射治疗联合使用的¿-lap或ph敏感的¿-lap前药的疗效。我们假设，携带¿-lap或¿-lap ph敏感前药的靶向ph敏感纳米颗粒胶束可用于显着提高¿-lap单独或与电离辐射（IR）治疗（XRT）联合的疗效。IR + -lap的协同作用是通过满足累积损伤阈值而产生的，这反过来刺激NQO1/ROS/ Ca2+ER/PARP1超激活途径，激活-calpain，这是一种程序性坏死/凋亡途径，是-lap细胞杀伤所特有的。完成三个目标：目标1。目的：阐明放射性增敏剂¿-lap的作用机理。(1 - 5)。目的2：设计和开发隐形的靶向癌症的纳米颗粒胶束，装载有-lap或pH敏感的-lap前药，以有效治疗人类非小细胞肺癌。(1 - 5)。目的3：阐明和优化纳米颗粒胶束单独和XRT作为非小细胞肺癌异种移植或原位模型的体内药代动力学和抗肿瘤活性（1-5年）。这项资助的最终目标是开发一个由纳米颗粒胶束递送的¿-lap化合物平台，通过利用其独特的NQO1过表达来有效治疗非小细胞肺癌。公共卫生相关性：非小细胞肺癌（NSCLC）患者治愈的希望渺茫，其5年生存率仅为15%。这一竞争性更新将建立在先前拨款的许多发现的基础上，包括：(i)评估和证明香港和纽约NSCLC人群中NQO1水平升高（5至100倍）；（ii）阐明-lap作用机制；（iii）新型¿-lap编码纳米颗粒的开发；（iv） pH敏感型¿-lap前药的研制；(v)¿-lap对A549非小细胞肺癌原位和异种移植模型的有效抗肿瘤活性；（六）功能化纳米颗粒的开发，可以靶向肿瘤新生血管的血管生成内皮细胞。这些研究的最终目标是开发一种纳米粒子平台，用于癌症靶向递送¿-lap及其ph敏感性前药，以根除非小细胞肺癌。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) patients have a dismal five year survival rate of ~15%. Antitumor agents that target unique protein markers to kill NSCLC cells irrespective of growth state, and target primary and metastatic cells, are desperately needed. We completed all the proposed Aims in the prior granting period and elucidated the mechanism of action of ¿-lapachone (¿-lap) alone against NSCLC cells. ¿-Lap was selectively efficacious for NSCLCs, in which >80% tumors had 5- to >100-fold endogenous overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1). ¿-Lap kills NSCLC cells through an NQO1/ROS/Ca2+ER/PARP1 hyperactivation pathway, leading to ¿-calpain cell death. To overcome solubility and normal tissue toxicity problems, various ¿-lap delivery methods were developed. Arq501 (¿-lap in hydroxypropyl-¿-cyclodextrin, Arqule Chem. Co., MA) entered several Phase II clinical trials based on our work. Several novel nanoparticle micelle delivery systems that will increased the efficacy of ¿-lap or pH-sensitive ¿-lap prodrugs alone, or in combination with radiation therapy, will be explored in this competitive renewal. We hypothesize that cancer-targeted, pH-sensitive nanoparticle micelles loaded with ¿-lap or ¿-lap pH-sensitive prodrugs can be used to significantly increase the efficacy of ¿-lap alone, and in combination with ionizing radiation (IR) therapy (XRT). IR + ¿-lap synergy results from meeting a accumulative damage threshold, that in turn stimulates the NQO1/ROS/ Ca2+ER/PARP1 hyperactivation pathway that activates ¿-calpain, a programmed necrotic/apoptotic pathway unique to ¿-lap cell killing. Three Aims will be completed: Aim 1. To elucidate the mechanism of action of ¿-lap as a radiosensitizer. (Years 1-5). Aim 2: To design and develop stealth, cancer-targeting nanoparticle micelles loaded with ¿-lap or pH- sensitive ¿-lap prodrugs to efficaciously treat human NSCLCs. (Years 1-5). Aim 3: To elucidate and optimize the pharmacokinetics and antitumor activity in vivo of ¿-lap-loaded nanoparticle micelles alone and with XRT against NSCLCs as xenograft or orthotopic models (Years 1-5). The ultimate goal of this grant is to develop a platform of ¿-lap compounds delivered by nanoparticle micelles that can efficacious treat NSCLC by exploiting their unique overexpression of NQO1. PUBLIC HEALTH RELEVANCE: Patients with nonsmall cell lung cancer (NSCLC) have little hope of being cured of their diseases, with five-year survival rates at only 15%. This competitive renewal will build on the many findings of the prior grant, including: (i) evaluation and demonstration of elevated (5- to 100-fold) NQO1 levels in NSCLC populations from Hong Kong and New York; (ii) elucidation of ¿-lap mechanism of action; (iii) development of novel ¿-lap-encoded nanoparticles; (iv) development of pH sensitive ¿-lap prodrugs; (v) efficacious antitumor activity of ¿-lap against orthotopic, as well as xenograft models of A549 NSCLCs; and (vi) development of functionalized nanoparticles that can target the angiogenic endothelial cells that innervate the tumor neovasculature. The ultimate goal of these studies is to develop a nanoparticle platform for the cancer-targeted delivery of ¿-lap and its pH-sensitive prodrugs for the eradication of nonsmall cell lung cancers.