SPORE in Pancreatic Cancer

描述(由申请人提供)：德克萨斯大学安德森分校胰腺癌分生孢子专注于将最近在分子生物学、细胞信号和DNA修复方面的观察转化为患者护理。这一申请勾勒出一项强有力的机构努力，以促进对人类胰腺癌病因学、生物学和治疗的研究，将基本研究成果转化为涉及胰腺癌患者的具体临床研究方案。为了实现这一目标，提出了五个项目：项目1-一个新的治疗基因p202，及其在胰腺癌治疗中的潜力寻求证明一种特定的新蛋白靶点，该靶点可用于胰腺癌，因为它能够抑制核因子-kappaB的活性。这一策略的成功开发将导致使用基因转移方法的直接治疗应用。项目2-环氧合酶-2在胰腺癌进展和治疗中的作用将探索环氧合酶-2在胰腺癌中过表达的机制。该项目将专门研究EGF-EGF受体相互作用控制胰腺癌细胞PLA2和COX2表达，以及COX-2调节重要细胞生存途径的假设。为了解决患者中的这一问题，建议进行一项题为“晚期胰腺癌患者对塞来昔布和OSL 774治疗反应的生物标志物评估”的临床试验。项目3-胰腺癌生物学和治疗中的NFkB信号通路探索了一系列抑制EGFR-Akt-NFKappaB信号通路的策略的生化效应和生物学后果。每一种测试的方法都与胰腺癌有潜在的临床相关性。为了临床评估EGFR抑制的影响，一项名为“抗表皮生长因子受体(EGFR)抗体西妥昔单抗与西妥昔单抗加吉西他滨在晚期胰腺癌患者中的II期随机试验”的临床试验被提出。项目4-转录因子Sp1对胰腺癌血管生成和转移的调节将验证Sp1表达和激活失控导致多个血管生成分子异常表达的假说，这些血管生成分子产生血管生成表型并维持肿瘤的生长和转移。项目5-DNA修复作为胰腺癌的风险因素测试了这样一个假设，即DNA修复能力是胰腺癌的风险因素，DNA修复和细胞周期基因的多态调节DNA修复能力的效率，从而增加个人患胰腺癌的风险或对治疗的反应。来自可切除胰腺癌患者的两项临床试验的数据将检验DNA修复对多种方式治疗后患者生存的影响。为支持这些努力，提议设立两个核心：核心--生物统计和信息管理将为通过孢子进行的所有项目和临床试验的设计和分析提供生物统计支助。核心组织采购和分配将促进获得胰腺癌和正常组织，并将其分配给所有孢子项目和合作者。该中心还将评估和分发从临床试验中获得的所有肿瘤活检和血液。我们相信，我们发展良好的项目将对胰腺癌的翻译研究产生重大和持续的影响，并确定新的研究机会，将对降低胰腺癌的发病率和死亡率产生影响。

DESCRIPTION (provided by applicant): The University of Texas M. D. Anderson SPORE in Pancreatic Cancer is focused on translating recent observations in molecular biology, cellular signaling, and DNA repair to patient care. This application outlines a strong institutional effort to foster research on the etiology, biology, and treatment of human pancreatic cancer that will translate basic research findings into concrete clinical research protocols involving pancreatic cancer patients. To accomplish this goal, five projects are proposed: Project 1 - A Novel Therapeutic Gene, p202, and its Potential in Pancreatic Cancer Therapy seeks to credential a specific new protein target that is applicable to pancreatic cancer because of its ability to inhibit the activity of NF-KappaB. The successful development of this strategy will lead to direct therapeutic application using a gene transfer approach. Project 2 - Role of COX-2 in Pancreatic Cancer Progression and Therapy will explore the mechanism of Cox-2 overexpression in pancreatic cancer. This project will specifically examine the hypothesis that EGF-EGF receptor interactions control PLA2 and COX2 expression in pancreatic cancer cells and that COX-2 regulates an important cell survival pathway. To address this issue in patients, a clinical trial entitled "Assessment of Biological Markers of Response to Treatment with Celecoxib and OSl 774 in Patients with Advanced Pancreatic Cancer" is proposed. Project 3 - NFkB Signaling Pathways in Pancreatic Cancer Biology & Therapy explores the biochemical effects and biologic consequences of a series of strategies to inhibit the EGFR - Akt - NFKappaB signaling pathway. Each approach tested has potential clinical relevance to pancreatic cancer. To clinically assess the impact of EGFR inhibition, a clinical trial entitled "Phase II Randomized Trial of Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Cetuximab vs. Cetuximab Plus Gemcitabine in Patients with Advanced Pancreatic Cancer" is proposed. Project 4 - Regulation of Pancreatic Cancer Angiogenesis and Metastasis by Transcription Factor Sp1 will examine the hypothesis that disregulated expression and activation of Sp1 is responsible for aberrant expression of multiple angiogenic molecules that generates the angiogenic phenotype and sustains tumor growth and metastasis. Project 5 - DNA Repair as a Risk Factor for Pancreatic Cancer tests the hypothesis that DNA repair capacity is a risk factor for pancreatic cancer, and that polymorphisms in DNA repair and cell cycle genes modulate the efficiency of DNA repair capacity thereby increasing individual risk of pancreatic cancer or response to therapy. Data from two clinical trials in patients with resectable pancreatic cancer will examine the effect of DNA repair on patient survival following multi-modality therapy. To support these efforts, two Cores are proposed: Core - Biostatistics and Information Management will provide biostatistical support for the design and analysis of all Projects and clinical trials conducted through the SPORE. Core - Tissue Procurement and Distribution will facilitate the acquisition and distribution of pancreatic cancer and normal tissue to all SPORE Projects and collaborators. This Core will also evaluate and distribute all tumor biopsies and blood obtained from the clinical trials. We believe that our well-developed program will provide a significant and sustained impact on pancreatic cancer translational research and identify new research opportunities that will have an impact in reducing pancreatic cancer incidence and mortality.