Chemosensitization of Pancreatic Tumors via Inhibition of a DNA BER Enzyme, Ape1

通过抑制 DNA BER 酶 Ape1 实现胰腺肿瘤的化学增敏

• 批准号: 7254589
• 负责人: Melissa L Fishel
• 金额: $ 15.15万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254589
• 关键词: Alkylating Agents; Animal Model; Antisense Oligonucleotides; Apoptosis; Base Excision Repairs; Cancer Patient; Cancer cell line; Cells; Chemosensitization; Chemotherapy-Oncologic Procedure; Classification; Combined Modality Therapy; Cysteine; Cytotoxic agent; DNA; DNA Binding; DNA Damage; DNA Repair; DNA lesion; Data; Deoxyribonucleosides; Disease; Enzymes; Excision; Goals; Human; Investigation; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Molecular; Numbers; Oxidation-Reduction; Pancreas; Pathway interactions; Patients; Phase; Phosphodiesterase I; Pilot Projects; Play; Process; Proteins; Rate; Research; Resistance; Role; Signal Transduction; Site; System; TP53 gene; Therapeutic; Title; Transcription Factor AP-1; Treatment Protocols; Work; analog; cancer cell; chemotherapeutic agent; chemotherapy; clinical application; cytotoxicity; endonuclease; gemcitabine; improved; inhibitor/antagonist; methoxyamine; novel; pancreatic neoplasm; programs; repair enzyme; repaired; response; small molecule; temozolomide; transcription factor; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer is a deadly disease that is virtually never cured, therefore our long-term goal is to develop therapeutic regimens for pancreatic cancer patients that sensitize these chemo-resistant tumors to therapy and achieve prolonged patient response. This proposal will investigate to what extent impairing the ability of the pancreatic cancer cells to respond to DNA damage following therapy will result in an increase in response to treatment with DNA damaging agents. To increase the efficacy of chemotherapy in pancreatic cancer cells, we plan to inhibit a key protein in the DNA base excision repair (BER) pathway. The BER pathway including apurinic/apyrimidinic endonuclease/redox factor (Ape1/Ref-1 or Ape1) plays a major role in the repair of damage caused by chemotherapeutic agents. In addition to DNA repair activity, Ape1 also interacts with a number of transcription factors (Hif1-a, p53, AP1, NF?B, etc) to facilitate their DNA binding. Gemcitabine, a DNA chain terminator, is the foremost chemotherapeutic agent currently used to treat pancreatic cancer. Studies demonstrating a role for the 3' to 5' exonuclease activity of Ape1 in the excision of deoxyribonucleoside analogs from DNA provide rationale for combining Ape1 DNA repair inhibitors with gemcitabine treatment. In addition, a reduced level of Ape1 protein sensitized pancreatic cancer cells to gemcitabine. Furthermore, NF?B is known to be under redox control by Ape1, and Nf?B activity is a determinant of pancreatic cancer cells' response to gemcitabine. We have the ability to examine the endonuclease and the redox functions of Ape1 independently by using small molecules that block both of Ape1's functions. Therefore, our short term goal is to establish Ape1 as a target to sensitize pancreatic tumors to chemotherapy. Dismal response rates in pancreatic cancer necessitate better and novel therapies, therefore we propose the use of temozolomide (TMZ) in combination with Ape1 redox/DNA repair inhibitors. TMZ is an alkylating agent which creates DNA lesions that are repaired by the BER pathway. We have preliminary data demonstrating a dramatic enhancement of TMZ-induced cytotoxicity in combination with small molecule Ape1 inhibitor, methoxyamine (MX) in pancreatic cancer cell lines. TMZ is, therefore, an excellent candidate for combination therapy in pancreatic cancer involving Ape1 inhibitors in addition to gemcitabine. The overall hypothesis of the proposed work is that treatment of pancreatic cancer with gemcitabine and TMZ can be improved by blocking the activity of Ape1 and the repair of DNA lesions. In addition to the clinical application of enhanced sensitivity to chemotherapy (gemcitabine or TMZ) in the presence of Ape1 DNA repair or redox inhibitors, we will also gain a more thorough understanding of the mechanism of pancreatic cells' response to gemcitabine or TMZ and the role that Ape1 plays in that response. Pancreatic cancer is a deadly disease that is virtually never cured and known to be resistant to most chemotherapy regimens. We want to sensitize these chemo-resistant tumors to therapy and achieve prolonged patient response by inhibiting a protein involved in DNA repair and redox signaling, Ape1. This proposal will investigate to what extent impairing the ability of the pancreatic cancer cells to respond to DNA damage following chemotherapy will result in an increase in response to treatment with DNA damaging agents, gemcitabine and temozolomide.

描述（由申请人提供）：胰腺癌是一种几乎永远无法治愈的致命疾病，因此我们的长期目标是为胰腺癌患者开发治疗方案，使这些化疗耐药肿瘤对治疗敏感并实现延长的患者反应。该提案将研究在多大程度上削弱胰腺癌细胞对治疗后DNA损伤的反应能力将导致对DNA损伤剂治疗的反应增加。为了提高化疗在胰腺癌细胞中的疗效，我们计划抑制DNA碱基切除修复（BER）途径中的一种关键蛋白。BER途径包括脱嘌呤/脱嘧啶核酸内切酶/氧化还原因子（Ape 1/Ref-1或Ape 1），其在由化疗剂引起的损伤的修复中起主要作用。除了DNA修复活性，Ape 1还与许多转录因子（Hif 1-a，p53，AP 1，NF？B等）以促进其DNA结合。吉西他滨是一种DNA链终止剂，是目前用于治疗胰腺癌的最重要的化疗药物。证明Ape 1的3'至5'外切核酸酶活性在从DNA切除脱氧核糖核苷类似物中的作用的研究为将Ape 1 DNA修复抑制剂与吉西他滨治疗组合提供了理论基础。此外，Ape 1蛋白水平降低可使胰腺癌细胞对吉西他滨敏感。此外，NF？B是已知的是由Ape 1氧化还原控制下，和Nf？B活性是胰腺癌细胞对吉西他滨反应的决定因素。我们有能力检查核酸内切酶和氧化还原功能的Ape 1独立使用小分子，阻止这两个Ape 1的功能。因此，我们的短期目标是建立Ape 1作为胰腺肿瘤对化疗敏感的靶点。胰腺癌的低反应率需要更好的新疗法，因此我们建议使用替莫唑胺（TMZ）联合Ape 1氧化还原/DNA修复抑制剂。TMZ是一种烷基化剂，其产生通过BER途径修复的DNA损伤。我们的初步数据表明，与小分子Ape 1抑制剂甲氧胺（MX）联合使用，TMZ诱导的细胞毒性在胰腺癌细胞系中显着增强。因此，TMZ是胰腺癌联合治疗的一个很好的候选药物，除了吉西他滨外，还包括Ape 1抑制剂。这项工作的总体假设是，通过阻断Ape 1的活性和DNA损伤的修复，可以改善吉西他滨和TMZ对胰腺癌的治疗。除了在Ape 1 DNA修复或氧化还原抑制剂存在下增强对化疗（吉西他滨或TMZ）的敏感性的临床应用外，我们还将更深入地了解胰腺细胞对吉西他滨或TMZ的反应机制以及Ape 1在该反应中所起的作用。胰腺癌是一种几乎无法治愈的致命疾病，并且已知对大多数化疗方案具有抗性。我们希望通过抑制参与DNA修复和氧化还原信号传导的蛋白Ape 1，使这些耐药肿瘤对治疗敏感，并延长患者的反应。该提案将研究在何种程度上削弱胰腺癌细胞对化疗后DNA损伤的反应能力将导致对DNA损伤剂吉西他滨和替莫唑胺治疗的反应增加。