Pancreatic Cancer Management by Novel Gene Therapy & Dietary Agents

新型基因疗法治疗胰腺癌

• 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
• 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

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）代表了美国最致命和侵略性的人类恶性肿瘤之一，也是美国与癌症相关死亡的第四个最常见的原因，当疾病受到器官限制时，生存期为15％，在出现转移性疾病时仅限制4％。在约90％的PC中，K-RAS癌基因被突变。理解这种肿瘤发病机理的障碍是缺乏概括人类状况的合适的鼠模型。现在，通过使用靶向的Krasg12d表达在胰腺和Ink4a/arf缺乏症中的鼠模型的发展来减少这种障碍，以发展胰腺上皮内肿瘤（PANINS），这些肿瘤（PANINS）模仿人类疾病，迅速促进了侵入性的侵入性和转移性和转移性和转移性和转移性的癌症。该模型非常适合设计和测试这种普遍致命的人类恶性肿瘤的新型治疗/预防方法。我们以前克隆黑色素瘤分化相关的基因-7/白介素-24（MDA-7/IL-24），这是具有独特的癌症特异性细胞凋亡特性的IL-10相关细胞因子基因家族的新成员。最近的I/II期临床试验证实了其患有晚期癌和黑色素瘤的人类的安全性和功效。出乎意料的是，PC细胞中MDA-7/IL-24的异位表达在诱导凋亡中无效，因为K-ras诱导的“转化块”，该K-RAS诱导了MDA-7/IL-24 mRNA与多聚体的相关性。当抑制K-RAS表达或其下游MEK1/MEK2途径或应用活性氧（ROS）诱导剂时，MDA-7/IL-24 mRNA被转化为蛋白质并诱导凋亡。最近有趣的初步研究表明，饮食单苯乙烯，poH酒精（POH）促进了MDA-7/IL-24在PC细胞中的凋亡促进作用。这项研究提供了饮食剂与基因治疗之间在控制侵略性且目前无法治疗的癌症（例如PC）生长中存在协同相互作用的第一个例子。我们目前计划：i。分析AD.MDA-7和POH对一系列突变体和野生型K-RAS PC细胞的侵入性和转移的组合作用； ii。通过AD.MDA-7和POH阐明凋亡诱导的分子机制； III研究了MDA-7/IL-24和POH在抑制转基因PC动物模型中PC发育和进展中的功效。我们还正在开发胰腺中过表达MDA-7/IL-24的复合转基因小鼠，以直接确认原位生成的MDA-7/IL-24将与POH合作，以防止PC开发。我们提出的研究将为未来的努力提供重要的直接相关性信息，旨在将饮食化合物与新型癌症特异性细胞凋亡 - 诱导细胞因子进行有效结合，以进行化学预防和可能对PC进行治疗。公共卫生相关性：黑色素瘤分化相关的基因-7/interleukin-24（MDA-7/IL-24）是一种抑制性营养性肿瘤分子，仅在癌细胞中诱导细胞凋亡的独特特性。饮食单二烯，例如perillyly（POH）也表现出抗肿瘤特性。本提案描述了表达MDA-7/IL-24的饮食剂（POH）和基于腺病毒的基因疗法的组合方法，是胰腺癌最致命的肿瘤之一的化学预防和治疗方案。