Use of Beta-lapachone for Lung Cancer Chemotherapy

描述（由申请人提供）：非小细胞肺癌（NSCLC）患者的五年生存率很低，约为15%。迫切需要靶向独特的蛋白质标记物以杀死NSCLC细胞（无论生长状态如何）并靶向原发性和转移性细胞的抗肿瘤药物。我们在之前的授权期内完成了所有拟定的目的，并阐明了单用拉帕酮（<$-lap）对NSCLC细胞的作用机制。<$-Lap对NSCLC选择性有效，其中>80%的肿瘤具有5至>100倍的NAD（P）H：醌氧化还原酶1（NQO 1）内源性过表达。<$-Lap通过NQO 1/ROS/Ca 2 +ER/PARP 1超活化途径杀死NSCLC细胞，导致<$-calpain细胞死亡。为了克服溶解度和正常组织毒性问题，开发了各种半腹腔镜给药方法。Arq 501（羟丙基-β-环糊精中的β-lap，Arqule Chem. Co.，MA）基于我们的工作进入了多个II期临床试验。几种新的纳米粒子胶束递送系统，将增加单独或与放射治疗相结合的<$-lap或pH敏感性<$-lap前药的疗效，将在这种竞争性更新中进行探索。我们假设，装载有<$-lap或<$-lap pH敏感性前药的癌症靶向pH敏感性纳米颗粒胶束可用于显著增加<$-lap单独使用以及与电离辐射（IR）治疗（XRT）联合使用的疗效。IR +？-lap协同作用是由于达到累积损伤阈值，这反过来又刺激NQO 1/ROS/Ca 2 +ER/PARP 1超活化途径，从而激活<$-钙蛋白酶，这是<$-lap细胞杀伤所特有的程序性坏死/凋亡途径。将完成三个目标：目标1。阐明？-lap作为放射增敏剂的作用机制。（1-5年级）。目标二：设计和开发负载有<$-lap或pH敏感性<$-lap前药的隐形、癌症靶向纳米粒子胶束，以有效治疗人NSCLC。（1-5年级）。目标3：阐明并优化单用和与XRT联合使用的负载有lap的纳米颗粒胶束对NSCLC作为异种移植物或原位模型的体内药代动力学和抗肿瘤活性（第1-5年）。这项资助的最终目标是开发一种由纳米粒子胶束递送的纳米-lap化合物平台，通过利用其独特的NQO 1过表达来有效治疗NSCLC。公共卫生相关性：非小细胞肺癌（NSCLC）患者治愈的希望很小，五年生存率仅为15%。这种竞争性的更新将建立在先前赠款的许多发现的基础上，包括：（一）评估和展示提高的（5- 100倍）NQO 1水平;（ii）阐明<$-lap的作用机制;（iii）开发新型<$-lap编码的纳米颗粒;（iv）开发pH敏感性<$-lap前药;（v）？-lap对A549 NSCLC的原位以及异种移植模型的有效抗肿瘤活性;以及（vi）开发能够靶向支配肿瘤新血管系统的血管生成内皮细胞的功能化纳米颗粒。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.