Tumor-selective radiosensitization of NSCLC using NQO1 bioactivatable drugs

布斯曼，地区检察官 摘要 在非小细胞肺癌(NSCLC)中，80%的肿瘤NQO1水平升高5-200倍 高于相关的正常组织，而过氧化氢酶水平在 NSCLC与体内所有正常组织进行比较。我们展示了独特而新颖的NQO1 生物活性药物？拉帕酮(临床试验中的ARQ761)和一种新药， 异丁基脱氧苯二酚(IB-DNQ)被NQO1激活，导致大量的过氧化氢诱导， 脱嘧啶/无嘌呤(AP)位点和DNA单链断裂介导的聚(ADP- 核糖基)聚合酶1(PARP1)，导致NAD+/ATP急剧丧失。Be-Lapachone也是一个 针对过表达NQO1的癌细胞的极佳放射增敏剂。我们假设暴露于 NQO1+NSCLC低剂量电离辐射(IR)，紧随其后的是无毒 NQO1生物活性药物(？？拉帕酮或IB-DNQ，作用2小时)将导致DNA水平升高 在过度表达NQO1的细胞中过度激活PARP活性的病变。低剂量的IR或？ 雷帕酮单独不能导致显著水平的DNA损伤来过度激活PARP， 将一起使用。由于IR会导致DSB迅速修复，因此必须交付该试剂 在NQO1生物活性药物之前或同时使用，18，19然后必须至少申请2 H对最大DNA损伤形成、PARP过度激活和代谢改变7、8、12具有抑制作用 DSB对NQO1+NSCLC细胞的修复和协同杀伤作用。将实现三个目标： 目的1：确定DNA修复抑制效应(对同源重组和非DNA修复)的影响 同源末端连接(NHEJ))。(0-5岁)。前提：非致命性、低剂量 可用于引起DSB和PARP过度激活，从而耗尽NAD+/ATP水平 并抑制DSB修复(NHEJ和HR)，从而增强对非小细胞肺癌的疗效。 目的2：确定对碳代谢的抑制(糖酵解和三氯乙酸循环抑制 NAD+/ATP损失)在IR+？拉帕酮(0-5岁)后。前提：PARP过度激活导致戏剧性 NAD+/ATP丢失，极大地抑制了LDH的糖酵解(通过抑制GAPDH)和TCA循环 抑制和其他NAD(P)H依赖的途径，以最大限度地发挥对NQO1+NSCLC的疗效。 目的3：阐明IR+NQO1生物活性药物组合的最有效用法 对NQO1+NSCLC。(0-5岁)。前提：IR+NQO1生物活性药物会诱发DSB+ DNA损伤过度激活PARP，导致显著的NAD+/ATP丢失，极大地抑制DSB修复 抑制糖酵解和TCA循环代谢，导致肿瘤选择性程序性坏死。 一个优秀的研究小组将探索IR+NQO1生物活性药物对DSB的影响 针对非小细胞肺癌异种移植模型的修复、代谢和疗效，导致在3-5年内进行临床试验。

Boothman, DA Abstract In non-small cell lung cancer (NSCLC), >80% tumors have elevated NQO1 levels 5- to 200-fold above associated normal tissues, while Catalase levels are expressed at extremely low levels in NSCLCs compared to all normal tissue in the body. We showed that unique and novel NQO1 bioactivatable drugs, ß-lapachone (ARQ761 in clinical trials) and a new drug, isobutyldeoxynyboquinone (IB-DNQ), are `bioactivated' by NQO1, resulting in massive H2O2-induced, apyrimidinic/apurinic (AP) site- and DNA single-strand break-mediated hyperactivation of poly(ADP- ribosyl) polymerase 1 (PARP1) that causes dramatic NAD+/ATP losses. ß-Lapachone is also an excellent radiosensitizer against cancer cells overexpressing NQO1. We hypothesize that exposure of NQO1+ NSCLC cancers with low dose ionizing radiation (IR), followed immediately with nontoxic NQO1 bioactivatable drugs (ß-lapachone or IB-DNQ for 2 h) will cause an elevated level of DNA lesions that hyperactivate PARP activity in cells that over-express NQO1. Low doses of IR or ß- lapachone, which are not able alone to cause a significant level of DNA lesions to hyperactivate PARP, will be used together. Since IR causes DSBs that are quickly repaired, this agent must be delivered before or at the same time as NQO1 bioactivatable drugs,18,19 which then must be applied for at least 2 h for maximal DNA lesion formation, PARP hyperactivation and metabolic alterations7,8,12 that inhibit DSB repair and cause synergistic lethality of NQO1+ NSCLC cells. Three aims will be performed: Aim 1: To define DNA repair inhibitory effects (on homologous recombination (HR) and non- homologous end joining (NHEJ)) after IR + ß-lapachone. (Yrs 0-5). Premise: Nonlethal, low doses of IR or ß-lap can be used to cause DSBs and PARP hyperactivation that depletes NAD+/ATP levels and inhibits DSB repair (NHEJ and HR) to enhance efficacy against NSCLC. Aim 2: To define the inhibition of carbon metabolism (glycolytic and TCA cycle inhibition due to NAD+/ATP losses) after IR + ß-lapachone (Yrs 0-5). Premise: PARP hyperactivation causes dramatic NAD+/ATP losses that greatly suppress glycolysis (via GAPDH inhibition) and TCA cycling by LDH inhibition and other NAD(P)H-dependent pathways to maximize efficacy against NQO1+ NSCLC. Aim 3: To elucidate the most efficacious use of IR + NQO1 bioactivatable drug combination against NQO1+ NSCLCs. (Yrs 0-5). Premise: IR + NQO1 bioactivatable drugs will induce DSBs + DNA lesions that hyperactivate PARP, lead to dramatic NAD+/ATP losses, inhibit DSB repair, greatly suppress glycolysis and TCA cycle metabolism that induces tumor-selective programmed necrosis. An outstanding research team will explore the effects of IR + NQO1 bioactivatable drugs on DSB repair, metabolism and efficacy against NSCLC xenograft models, leading to a clinical trial in 3-5 years.