Tumor-selective use of PARP inhibitors against NQO1+ nonsmall cell lung cancer

PARP 抑制剂针对 NQO1 非小细胞肺癌的肿瘤选择性使用

• 批准号: 10304927
• 负责人: Xiumei Huang
• 金额: $ 35.6万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304927
• 关键词: Affect; Antitumor Response; Apoptosis; Bystander Effect; Cancer cell line; Cell Death; Cells; Clinical; Clinical Trials; Consumption; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Single Strand Break; Development; Dose; Electrons; Enzymes; Goals; Grant; Human; Hydrogen Peroxide; In Vitro; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Methemoglobinemia; Mixed Neoplasm; NQO1 gene; Necrosis; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oncogenic; Oxidoreductase; Patients; Persons; Pharmaceutical Preparations; Phase; Poly(ADP-ribose) Polymerases; Polymerase; Population; Production; Quinones; Regimen; Reporting; Research; Resistance; Role; Site; Superoxides; Testing; Toxic effect; Xenograft Model; Xenograft procedure; antitumor effect; beta-Lapachone; cancer cell; cancer therapy; catalase; improved; in vivo; inhibitor; knock-down; lung cancer cell; mutant; neoplastic cell; novel; novel therapeutic intervention; overexpression; repaired; response; small hairpin RNA; synergism; targeted treatment; tumor

Our long-term goal is to develop novel antitumor therapies to treat recalcitrant non-small cell lung cancers (NSCLCs) by exploiting their unique over-expression of the two-electron, Phase II detoxifying enzyme, NAD(P)H:Quinone Oxidoreductase 1 (NQO1) in combination with inhibitors of poly(ADP-ribose) polymerase inhibitors. In NSCLC, NQO1 is elevated 5- to 200-fold above associated normal tissues, while catalase levels are expressed at extremely lower levels in NSCLCs than in associated normal lung (or all other normal) tissue. We showed that unique and novel NQO1 bioactivatable drugs, (e.g., ß- lapachone (ARQ761 in clinical trials), 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+ losses (Huang et al., Cancer Res, 2012). However, co-administration of a PARP inhibitor dramatically enhances the antitumor activities of these drugs (Huang et al., Cancer Cell, 2016). We have discovered a much more potent NQO1 bioactivatable drug, isobutyldeoxynyboquinone (IB-DNQ) that is significantly more synergistic with PARP inhibition that ß-lapachone. We hypothesize that IB-DNQ will be a significantly better drug alone than ARQ761 (ß- lapachone) and result in significantly greater synergistic, NQO1-dependent antitumor activity in combination with PARP inhibitors against NQO1+ NSCLC cells. We propose to complete three specific aims to test this hypothesis.: Aim 1: To define the mechanism of action of PARP inhibition + IB-DNQ synergistic cell death (Yrs 0-5); Aim 2: To define the role of IB-DNQ-induced H2O2-related bystander effect in simultaneous NQO1+ programmed necrosis vs NQO1- apoptosis in matched NSCLC cells (Yrs 0-5); and Aim 3: To define the tumor-selective, NQO1+-dependent antitumor effects of the PARP inhibition + IB-DNQ regimen vs IB-DNQ alone in orthotopic NSCLC xenografts (Yrs 0-5). The aims will be performed using genetically matched NQO1+ vs NQO1- NSCLC cell lines by si/shRNA knockdown of NQO1+ human cancer cell lines and/or forced NQO1 over-expression to match known levels in polymorphic NQO1- human NSCLCs. We will also examine genetically match PARP1 si/shRNA knockdown vs normal NSCLC cells in vitro and in vivo. We assembled an outstanding research team to explore the metabolic, bystander, and efficacy effects of PARP inhibition + IB-DNQ treatments in orthotopic NSCLC xenograft models in this 5-yr grant. Our results should lead to the development of a clinical trial using this combination in 5 years.

我们的长期目标是开发新型抗肿瘤疗法来治疗难治性非小细胞肺癌 (NSCLC) 通过利用其独特的双电子 II 期解毒酶过度表达， NAD(P)H：醌氧化还原酶 1 (NQO1) 与聚 (ADP-核糖) 抑制剂组合 聚合酶抑制剂。在 NSCLC 中，NQO1 比相关正常组织升高 5 至 200 倍， 而过氧化氢酶水平在非小细胞肺癌中的表达水平远低于相关的正常肺 （或所有其他正常）组织。我们展示了独特且新颖的 NQO1 生物可激活药物（例如 ß- 拉帕酮（临床试验中的 ARQ761）被 NQO1“生物激活”，导致大量 H2O2 诱导， 无嘧啶/无嘌呤 (AP) 位点和 DNA 单链断裂介导的聚 (ADP-) 过度激活 核糖基）聚合酶 1 (PARP1) 会导致 NAD+ 急剧损失（Huang 等人，Cancer Res，2012）。 然而，联合使用 PARP 抑制剂可显着增强这些药物的抗肿瘤活性。 药物（Huang 等人，Cancer Cell，2016）。我们发现了一种更有效的 NQO1 生物可激活物质 药物异丁基脱氧苯醌 (IB-DNQ) 与 PARP 抑制具有显着更强的协同作用 β-拉帕雄。我们假设 IB-DNQ 将是一种比 ARQ761 (ß- lapachone）并导致显着增强的协同、NQO1依赖性抗肿瘤活性 与 PARP 抑制剂联合对抗 NQO1+ NSCLC 细胞。我们建议完成三项具体工作 旨在检验这一假设。：目标 1：定义 PARP 抑制 + IB-DNQ 的作用机制 协同细胞死亡（0-5 年）；目标 2：明确 IB-DNQ 诱导的 H2O2 相关作用 匹配中同时 NQO1+ 程序性坏死与 NQO1- 凋亡的旁观者效应 NSCLC 细胞（0-5 年）；目标 3：定义肿瘤选择性、NQO1+ 依赖性抗肿瘤药物 PARP 抑制 + IB-DNQ 方案与单独 IB-DNQ 对原位 NSCLC 异种移植物的影响 （0-5 年级）。这些目标将使用基因匹配的 NQO1+ 与 NQO1- NSCLC 细胞系来实现 NQO1+人类癌细胞系的si/shRNA敲低和/或强制NQO1过度表达以匹配 多态性 NQO1- 人类 NSCLC 中的已知水平。我们还将检查 PARP1 的基因匹配 si/shRNA 敲低与正常 NSCLC 细胞的体外和体内比较。 我们组建了一支优秀的研究团队来探索代谢、旁观者和功效效应 在这项为期 5 年的资助中，对原位 NSCLC 异种移植模型进行 PARP 抑制 + IB-DNQ 治疗。我们的 结果应该会导致在 5 年内开发出使用这种组合的临床试验。

项目成果

Combined inhibition of Ref-1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co-culture models.

• DOI: 10.1111/jcmm.16132
• 发表时间: 2021-01
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Caston RA;Shah F;Starcher CL;Wireman R;Babb O;Grimard M;McGeown J;Armstrong L;Tong Y;Pili R;Rupert J;Zimmers TA;Elmi AN;Pollok KE;Motea EA;Kelley MR;Fishel ML
• 通讯作者: Fishel ML

Synergistic Effect of β-Lapachone and Aminooxyacetic Acid on Central Metabolism in Breast Cancer.

• DOI: 10.3390/nu14153020
• 发表时间: 2022-07-22
• 期刊: NUTRIENTS
• 影响因子: 5.9
• 作者: Chang, Mario C.;Mahar, Rohit;McLeod, Marc A.;Giacalone, Anthony G.;Huang, Xiumei;Boothman, David A.;Merritt, Matthew E.
• 通讯作者: Merritt, Matthew E.

Detecting Attomolar DNA-Damaging Anticancer Drug Activity in Cell Lysates with Electrochemical DNA Devices.

• DOI: 10.1021/acssensors.1c00365
• 发表时间: 2021-07-23
• 期刊: ACS sensors
• 影响因子: 8.9
• 作者: Wettasinghe AP;Singh N;Starcher CL;DiTusa CC;Ishak-Boushaki Z;Kahanda D;McMullen R;Motea EA;Slinker JD
• 通讯作者: Slinker JD