Pancreatic Cancer Management by Novel Gene Therapy & Dietary Agents

新型基因疗法治疗胰腺癌

基本信息

批准号：
7879988
负责人：
PAUL B FISHER
金额：
$ 31.02万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-25 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7879988
关键词：
Achievement Adenocarcinoma Cell Adenoviruses Adhesions Alleles Animal Model Animals Antibodies Antioxidants Apoptosis Appearance Cancer Etiology Cancer Model Carcinoma Cell Death Cessation of life Chemoprevention Chemopreventive Agent Clinic Clinical Trials Consumption Cytokine Gene Data Development Diet Disease Disseminated Malignant Neoplasm Ductal Ectopic Expression Effectiveness Engineering Event Exhibits Future Gene Family Gene Therapy Agent Generations Genes Growth Human Immune response In Situ In Vitro Induction of Apoptosis Interleukin-10 Interleukin-24 K-ras Gene K-ras Oncogene Knowledge Laboratories Lesion Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Mediating Messenger RNA Modality Modeling Molecular Molecular Target Molecular and Cellular Biology Monoterpenes Mus Mutate Mutation Nature Neoplasm Metastasis Neoplasms Normal Cell Organ Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic carcinoma Pathogenesis Pathway interactions Patients Phase Phosphotransferases Polyribosomes Premalignant Prevention Prevention therapy Preventive Process Property Proteins Radiation Reactive Oxygen Species Recording of previous events Regimen Reporting Resistance Safety Scientist Series Signal Pathway Signal Transduction Source Staging Testing Therapeutic Transgenic Animals Transgenic Mice Transgenic Organisms Translating Translational Research Translations Treatment Efficacy Treatment Protocols Tumor Suppressor Proteins Xenograft procedure angiogenesis base cancer cell cancer chemoprevention cancer therapy cell motility chemotherapy clinical efficacy combinatorial conventional therapy cytokine cytotoxic design effective therapy efficacy testing extracellular gene therapy human disease in vivo innovation insight killings melanoma member mouse development mouse model mutant neoplastic neoplastic cell novel novel therapeutics overexpression palliative pancreatic neoplasm perilla alcohol prenylation prevent promoter protocol development public health relevance ras Oncogene research study subtraction hybridization therapeutic gene tool tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PC) represents one of the most lethal and aggressive human malignancies and the fourth most common cause of cancer-related deaths in the US with 15% survival when the disease is organ confined, and only 4% when presenting with metastatic disease. In ~90% of PC, the K-ras oncogene is mutated. An obstacle to understanding the pathogenesis of this neoplasm has been the lack of suitable murine models that recapitulate the human condition. This impediment has now been diminished by the development of murine models that utilize a combination of targeted KrasG12D expression in the pancreas and Ink4a/Arf deficiency to develop pancreatic intraepithelial neoplasias (PanINs), which mimic the human disease, progressing rapidly to highly invasive and metastatic cancers. This model is ideally suited for designing and testing novel therapeutic/preventive approaches for this universally fatal human malignancy. We previously cloned melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a novel member of the IL-10-related cytokine gene family with unique cancer-specific apoptosis-inducing properties. Recent Phase I/II clinical trials confirm its safety and efficacy in humans with advanced carcinomas and melanomas. Unexpectedly, ectopic expression of mda-7/IL-24 in PC cells is ineffective in inducing apoptosis because of a 'translational block' induced by K- ras that delimits association of mda-7/IL-24 mRNA with polysomes. When K-ras expression or its downstream MEK1/MEK2 pathway is inhibited or a reactive oxygen species (ROS) inducer is applied, mda-7/IL-24 mRNA is converted into protein and apoptosis is induced. Recent intriguing preliminary studies show that a dietary monoterpene, perillyl alcohol (POH), facilitates the apoptosis-promoting effects of mda- 7/IL-24 in PC cells. This study provides a first example of a synergistic interaction between a dietary agent and gene therapy in controlling the growth of an aggressive and currently untreatable cancer, such as PC. We currently plan to: i. Analyze the combinatorial effects of Ad.mda-7 and POH on the invasiveness and metastasis of a series of mutant and wild type K-ras PC cells; ii. Elucidate the molecular mechanisms of apoptosis-induction by Ad.mda-7 and POH; iii study the efficacy of mda-7/IL-24 and POH in inhibiting PC development and progression in transgenic PC animal models. We also are developing a compound transgenic mouse overexpressing mda-7/IL-24 in the pancreas to directly confirm that in situ generated mda-7/IL-24 will cooperate with POH in preventing PC development. The studies we propose will provide important information of direct relevance for future efforts designed to translate into patients an effective combination of dietary compounds with a novel cancer-specific apoptosis- inducing cytokine for the chemoprevention and potentially therapy of PC. PUBLIC HEALTH RELEVANCE: Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a pleotrophic tumor suppressor molecule that exhibits the unique property of inducing apoptosis only in cancer cells. Dietary monoterpenes, such as perillyl alcohol (POH) also exhibit anti- tumor properties. The present proposal describes a combinatorial approach of a dietary agent (POH) and adenovirus-based gene therapy, expressing mda-7/IL-24, as chemopreventive and therapeutic regimens for one of the deadliest neoplasms, pancreatic cancer.

描述（由申请人提供）：胰腺导管腺癌 (PC) 是最致命和最具侵袭性的人类恶性肿瘤之一，也是美国癌症相关死亡的第四大常见原因，当疾病仅限于器官时，其生存率为 15%，并且仅出现转移性疾病时为 4%。在约 90% 的 PC 中，K-ras 癌基因发生突变。了解这种肿瘤发病机制的一个障碍是缺乏能够概括人类状况的合适的小鼠模型。现在，这一障碍已通过小鼠模型的开发而得到消除，该小鼠模型利用胰腺中的靶向 KrasG12D 表达和 Ink4a/Arf 缺陷的组合来开发胰腺上皮内瘤变 (PanIN)，其模仿人类疾病，迅速进展为高度侵袭性和转移性癌症。该模型非常适合设计和测试针对这种普遍致命的人类恶性肿瘤的新型治疗/预防方法。我们之前克隆了黑色素瘤分化相关基因 7/IL-24 (mda-7/IL-24)，它是 IL-10 相关细胞因子基因家族的新成员，具有独特的癌症特异性细胞凋亡诱导特性。最近的 I/II 期临床试验证实了其对患有晚期癌症和黑色素瘤的人类的安全性和有效性。出乎意料的是，PC细胞中mda-7/IL-24的异位表达不能有效诱导细胞凋亡，因为K-ras诱导的“翻译阻断”限制了mda-7/IL-24 mRNA与多核糖体的关联。当 K-ras 表达或其下游 MEK1/MEK2 通路受到抑制或应用活性氧 (ROS) 诱导剂时，mda-7/IL-24 mRNA 转化为蛋白质并诱导细胞凋亡。最近有趣的初步研究表明，膳食单萜、紫苏醇 (POH) 可促进 PC 细胞中 mda-7/IL-24 的凋亡促进作用。这项研究提供了第一个例子，说明饮食制剂和基因疗法之间在控制侵袭性且目前无法治疗的癌症（例如 PC）的生长方面发挥协同作用。我们目前计划：分析Ad.mda-7和POH的组合对一系列突变型和野生型K-ras PC细胞侵袭和转移的影响；二.阐明Ad.mda-7和POH诱导细胞凋亡的分子机制； iii 在转基因 PC 动物模型中研究 mda-7/IL-24 和 POH 在抑制 PC 发育和进展方面的功效。我们还正在开发一种在胰腺中过表达 mda-7/IL-24 的复合转基因小鼠，以直接证实原位产生的 mda-7/IL-24 将与 POH 合作阻止 PC 的发展。我们提出的研究将为未来的努力提供直接相关的重要信息，这些努力旨在将膳食化合物与新型癌症特异性细胞凋亡诱导细胞因子的有效组合转化为患者，以用于 PC 的化学预防和潜在治疗。公共健康相关性：黑色素瘤分化相关基因 7/白细胞介素 24 (mda-7/IL-24) 是一种多效肿瘤抑制分子，具有仅在癌细胞中诱导细胞凋亡的独特特性。膳食单萜，例如紫苏醇（POH）也表现出抗肿瘤特性。目前的提案描述了一种饮食剂（POH）和基于腺病毒的基因疗法（表达 mda-7/IL-24）的组合方法，作为最致命的肿瘤之一胰腺癌的化学预防和治疗方案。