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的抗肿瘤疗法来治疗顽固的非小细胞肺癌 （NSCLCS）通过利用其对两电子II期解毒酶的独特过表达， NAD（P）H：喹酮氧化还原酶1（NQO1）与聚（ADP-核糖）抑制剂结合 聚合酶抑制剂。在NSCLC中，NQO1高于相关的正常组织5至200倍， 虽然过氧化氢酶的水平在NSCLC中的水平非常低于相关的正常肺 （或所有其他正常）组织。我们展示了独特而新颖的NQO1生物活化药物（例如，ß- lapachone（临床试验中的ARQ761）被NQO1“生物活化”，从而导致H2O2诱导的大量，，， 丙酰胺/肾上腺素（AP）位点和DNA单链单链介导的聚激活（ADP- 核糖基）聚合酶1（PARP1），会导致急剧的NAD+损失（Huang等，Cancer Res，2012）。 但是，PARP抑制剂的共同给药可显着增强这些抑制剂的抗肿瘤活性 药物（Huang等人，癌细胞，2016年）。我们发现了更有潜在的NQO1生物活化 药物，异丁氏脱氧基因酮（IB-DNQ），与PARP抑制更加协同相比 ß-拉帕孔。我们假设IB-DNQ仅比ARQ761（ß- lapachone），并在NQO1依赖性抗肿瘤活性中显着更大 与针对NQO1+ NSCLC细胞的PARP抑制剂组合。我们建议完成三个特定的 旨在检验此假设。：目标1：定义PARP抑制作用 + IB-DNQ的作用机理 协同细胞死亡（YRS 0-5）;目标2：定义IB-DNQ诱导的H2O2相关的作用 简单的NQO1+编程坏死与NQO1-匹配中的凋亡中的旁观者效应 NSCLC细胞（YRS 0-5）;和目标3：定义肿瘤选择性NQO1+依赖性抗肿瘤 PARP抑制作用 + IB-DNQ方案与IB-DNQ仅在原位NSCLC Xenographics中 （YRS 0-5）。目的将使用一般匹配的NQO1+ VS NQO1- NSCLC单元线执行 NQO1+人类癌细胞系和/或强制NQO1过表达的Si/ShRNA敲低以匹配 多态性NQO1-人NSCLC中已知水平。我们还将检查基因匹配PARP1 SI/SHRNA敲低与正常的NSCLC细胞在体外和体内。 我们组建了一个杰出的研究团队，以探索代谢，旁观者和有效的影响 PARP抑制作用 + IB-DNQ治疗在此5年赠款中原位NSCLC特征模型中的PARP抑制作用。我们的 结果应在5年内使用此组合导致临床试验的发展。

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