Chemoprevention of Pancreatic Cancer by EGCG

描述（由申请人提供）： 胰腺癌是美国癌症死亡的第四大原因。它是所有癌症中预后最差的，5年生存率<3%。胰腺癌通常被发现得太晚，手术是有帮助的，并且对目前的化疗和放射治疗具有高度抗性。目前，胰腺癌的唯一治愈性治疗是手术，但只有15%的患者在就诊时是手术的候选人，只有20%的接受治愈性手术的患者在5年后存活。因此，需要新的预防和治疗选择。该提议基于使用绿色茶多酚，表没食子儿茶素-3-没食子酸酯（EGCG），其对与肿瘤起始、促进和进展相关的多种细胞事件发挥显著的抑制作用。除了这些进展外，EGCG抑制胰腺癌细胞增殖和诱导凋亡的细胞内机制还不清楚。由于EGCG是无毒的，其作为癌症预防剂的世界范围内的兴趣已经增加。临床前评估EGCG抗胰腺癌的基本原理来自于我们的初步研究，这使我们假设EGCG将抑制ras依赖的PI 3 K/Akt和MAP激酶活性，并且这两种途径将在胰腺癌细胞中会聚以调节FOXO转录因子、细胞生长和凋亡。由于其通过调节FOXO转录因子诱导细胞周期停滞和凋亡的能力，EGCG将在抑制人胰腺癌细胞生长方面非常有效。本课题的具体目的是：（1）研究EGCG诱导胰腺癌细胞周期停滞和凋亡的分子机制，（2）研究口服EGCG对裸鼠移植的人胰腺癌细胞生长和消退的影响，（3）使用KrasG 12 D转基因小鼠模型研究EGCG对胰腺癌发生的体内疗效。这种转基因小鼠模型忠实地再现了人胰腺癌的组织学特征。 由于EGCG是无毒的，其作为癌症预防剂的世界范围内的兴趣已经增加。临床前评估EGCG抗胰腺癌的基本原理来自于我们的初步研究，这使我们假设EGCG将抑制ras依赖的PI 3 K/Akt和MAP激酶活性，并且这两种途径将在胰腺癌细胞中会聚以调节FOXO转录因子、细胞生长和凋亡。由于其通过调节FOXO转录因子诱导细胞周期停滞和凋亡的能力，EGCG将在抑制人胰腺癌细胞生长方面非常有效。本课题的具体目的是：（1）研究EGCG诱导胰腺癌细胞周期停滞和凋亡的分子机制，（2）研究口服EGCG对裸鼠移植的人胰腺癌细胞生长和消退的影响，（3）使用KrasG 12 D转基因小鼠模型研究EGCG对胰腺癌发生的体内疗效。这种转基因小鼠模型忠实地再现了人胰腺癌的组织学特征。本提案中概述的研究非常重要，因为它们将验证Kras转基因小鼠模型用于胰腺癌预防，并建立EGCG的临床潜力，可以延迟人类胰腺癌的发作和/或进展。

DESCRIPTION (provided by applicant): Pancreatic cancer ranks as the fourth leading cause of cancer mortality in the US. It has the worst prognosis of all cancers, with a 5-year survival rate of < 3%. Pancreatic cancer is often detected too late for surgery to be helpful and is highly resistant to current chemotherapy and radiation treatment. Currently, the only curative treatment for pancreatic cancer is surgery, but only 15% of patients are candidates for surgery at the time of presentation, and only 20% patients who undergo a curative operation are alive after 5 years. Therefore, new options for prevention and treatment are needed. This proposal is based on the use of green tea polyphenol, epigallocatechin-3-gallate (EGCG), which exerts significant inhibitory effects on diverse cellular events associated with tumor initiation, promotion and progression. Besides these advances, the intracellular mechanisms by which EGCG inhibits proliferation and induces apoptosis in pancreatic cancer cells are not well understood. Since EGCG is non-toxic, its worldwide interest as a cancer preventive agent has increased. Rationale for preclinical evaluation of EGCG against pancreatic cancer comes from our preliminary studies, which led us to hypothesize that EGCG will inhibit ras-dependent PI3K/Akt and MAP kinase activities, and these two pathways will converge to regulate FOXO transcription factors, cell growth and apoptosis in pancreatic cancer cells. EGCG will be highly effective in suppressing growth of human pancreatic cancer cells due to its ability to induce cell cycle arrest and apoptosis through regulation of FOXO transcription factors. The specific aims of the project are: (1) To examine the molecular mechanisms by which EGCG induces cell cycle arrest and apoptosis in pancreatic cancer cells, (2) To determine the effects of oral administration of EGCG on growth and regression of human pancreatic cancer cells implanted in nude mice, and (3) To determine in vivo efficacy of EGCG administration on pancreatic carcinogenesis using KrasG12D transgenic mouse model. This transgenic mouse model faithfully reproduces the histological features of human pancreatic cancer. Since EGCG is non-toxic, its worldwide interest as a cancer preventive agent has increased. Rationale for preclinical evaluation of EGCG against pancreatic cancer comes from our preliminary studies, which led us to hypothesize that EGCG will inhibit ras-dependent PI3K/Akt and MAP kinase activities, and these two pathways will converge to regulate FOXO transcription factors, cell growth and apoptosis in pancreatic cancer cells. EGCG will be highly effective in suppressing growth of human pancreatic cancer cells due to its ability to induce cell cycle arrest and apoptosis through regulation of FOXO transcription factors. The specific aims of the project are: (1) To examine the molecular mechanisms by which EGCG induces cell cycle arrest and apoptosis in pancreatic cancer cells, (2) To determine the effects of oral administration of EGCG on growth and regression of human pancreatic cancer cells implanted in nude mice, and (3) To determine in vivo efficacy of EGCG administration on pancreatic carcinogenesis using KrasG12D transgenic mouse model. This transgenic mouse model faithfully reproduces the histological features of human pancreatic cancer. Studies outlined in this proposal are highly significant because they will validate Kras transgenic mouse model for pancreatic cancer prevention and establish a clinical potential of EGCG that can delay the onset and/or progression of human pancreatic cancer.