Use of Beta-lapachone for Lung Cancer Chemotherapy

描述(申请人提供)：非小细胞肺癌(NSCLC)患者的五年生存率令人沮丧，约为15%。迫切需要以独特的蛋白质标记为靶点，无论生长状态如何都能杀死非小细胞肺癌细胞，并以原发和转移细胞为靶点的抗肿瘤药物。我们在之前的授权期内完成了所有建议的目标，并阐明了拉帕酮(LAP)单独对非小细胞肺癌细胞的作用机制。β-LAP对非小细胞肺癌有选择性治疗作用，其中80%的肿瘤内源性NAD(P)H：Q氧化还原酶1(NQO1)高表达5~100倍。？-Lap通过NQO1/ROS/Ca~(2+)-ER/PARP1过度激活途径杀死NSCLC细胞，导致？-calain细胞死亡。为了克服溶解性和正常的组织毒性问题，开发了各种不同的LAP给药方法。Arq501(羟丙基-β-环糊精，ArQule Chem.)Co.，MA)根据我们的工作进入了几个第二阶段临床试验。在这次竞争更新中，将探索几种新型纳米粒子胶束递送系统，这些系统将单独或与放射治疗结合使用，提高LAP或pH敏感前药的疗效。我们假设，携带pH敏感前药的癌症靶向、pH敏感纳米胶束可用于显著提高单独使用或与电离辐射(IR)治疗(XRT)联合使用的疗效。IR+？-LAP的协同作用源于达到累积损伤阈值，进而刺激NQO1/ROS/Ca~(2+)ER/PARP1过度激活途径，激活？-calain，这是？-Lap细胞杀伤所特有的程序性坏死/凋亡途径。将完成三个目标：目的1.阐明-LAP作为放射增敏剂的作用机制。(1-5年级)。目的2：设计和开发隐形、肿瘤靶向的纳米胶束，载药或pH敏感的前药，以有效治疗人非小细胞肺癌。(1-5年级)。目的：阐明和优化载药纳米胶束的体内药代动力学和体内抗肿瘤活性，并将其作为异种或原位移植模型(1-5年)。这笔赠款的最终目标是开发一个由纳米粒子胶束提供的化合物平台，该平台可以通过利用NQO1的独特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)患者被治愈的希望微乎其微，五年生存率仅为15%。这一竞争性更新将基于先前拨款的许多结果，包括：(I)评估和展示香港和纽约非小细胞肺癌人群中NQO1水平升高(5至100倍)；(Ii)阐明？-LAP的作用机制；(Iii)开发新型？-LAP编码的纳米颗粒；(Iv)开发对pH敏感的？-LAP前体药物；(V)？-LAP对原位和A549非小细胞肺癌移植模型的有效抗肿瘤活性；以及(Vi)开发能够靶向肿瘤新生血管生成的血管生成内皮细胞的功能性纳米颗粒。这些研究的最终目标是开发一种纳米颗粒平台，用于癌症靶向传递-LAP及其pH敏感的前药，用于根除非小细胞肺癌。

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.