Targets to Therapeutics in Pancreatic Cancer

描述(申请人提供)：胰腺癌现在是美国女性和男性死于癌症的第四大原因。迫切需要新的、创新的方法来预防和治疗胰腺癌。在亚利桑那大学亚利桑那癌症中心(AZCC)对胰腺癌和药物开发的兴趣和专业知识的坚实基础上，这项胰腺癌项目赠款(P01)申请满足了这一挑战性的需求。P01的中心主题和目标是加速针对胰腺癌新靶点的新治疗剂进入临床。这个P01的目标是在这个P01的每一年，我们将一个新的药物输送到胰腺癌患者的临床试验中，它达到了这个P01的一个项目中发现和验证的目标。 这个P01应用程序代表了修改后的应用程序，我们认为这是一种改进的、更有针对性的抗击疾病的努力。对每一项批评的答复都出现在申请的每一节的开头。 两年前，AZCC成立了悉尼鲑鱼胰腺癌团队(以AZCC的创始主任的名字命名，他死于这种疾病)。该团队已经建立了研究人员的基础设施(现有的和新的，在基础研究、转化研究和临床研究中)，建立了患者基础，开始了一系列临床试验，并创建了一个持续的论坛，用于交流新的研究倡议和发现。此外，这项申请的首席研究员冯·霍夫博士已经辞去亚利桑那州癌症中心主任一职，全身心地投入到这项工作中。我们对胰腺癌做出改变的方法侧重于开发创新的、可转化的方法来应对这种疾病。在这一基础工作的基础上，出现了P01应用程序，重点是胰腺癌。正如我们希望审查者看到的那样，我们的团队在确定胰腺癌的新靶点甚至新方法方面已经取得了实质性进展。这个P01应用程序侧重于正在进行的工作，并将该工作转化为将应用于患者的新疗法。 本P01包含三个转化研究项目，其共同目标是为胰腺癌患者开发新的治疗方法。这些相关项目包括：(1)胰腺癌耐缺氧的治疗；(2)消除具有特定突变/缺失模式的胰腺细胞的方法；以及(3)胰腺癌扩增基因的验证：改进吉西他滨疗法的新增敏靶点。每个项目都已经有了一些线索，每个项目的设计都是为了最大限度地发挥翻译潜力。正如在应用程序中将看到的，这些项目高度集成，因此我们每年最有可能将一种治疗方法带到诊所。这些项目得到了四个高度集成的共享服务(CORE)的支持：(1)胰腺癌生物样品储存库；(2)模式分析和计算生物学核心；(3)药物开发核心；以及(4)评估和管理核心。这些核心为项目提供材料、信息、开发和行政支持。由于我们有幸在亚利桑那州癌症中心(AZCC)拥有如此出色的共享服务，因此建议的P01中的核心旨在利用这些核心，因此对于此应用程序，我们只要求提供高于这些AZCC核心所能提供的服务的资源。此外，P01还包括内部和外部科学咨询委员会，以确保对科学和项目执行的最大投入。 P01的总体目标是每年P01向临床提供一种针对胰腺癌新靶点的新治疗剂。我们认为，随着胰腺癌的新方法集中在P01，这一努力有机会对疾病产生影响。

DESCRIPTION (provided by applicant): Pancreatic cancer is now the fourth leading cause of death from cancer in women and men in the United States. New, innovative approaches to the prevention and treatment of pancreatic cancer are sorely needed. This Program Project Grant (P01) application in pancreatic cancer takes up that challenging need, building on a strong foundation of interest and expertise in pancreatic cancer and in drug development at the Arizona Cancer Center (AZCC) at the University of Arizona. The central theme and goal of this P01 is to speed delivery into the clinic of new therapeutic agents against new targets in pancreatic cancer. The goal of this P01 is that in each year of this P01, we will deliver a new agent into clinical trials in patients with pancreatic cancer, which hits a target discovered and validated in one of the projects of this P01. This P01 application represents a revised application that we feel is an improved, more focused effort against the disease. Responses to each of the critiques are presented in the beginning of each section of the application. Two years ago, the AZCC formed the Sydney Salmon Pancreatic Cancer Team (named after the founding director of the AZCC who passed away from the disease). The team has built an infrastructure of investigators (established and new, in basic, translational, and clinical research), developed a patient base, begun a series of clinical trials, and created an ongoing forum for communicating new research initiatives and findings. In addition, Dr. .Von Hoff, the principal investigator for this application, has stepped down from the Directorship of the Arizona Cancer Center to devote full time to this effort. Our approach to make a difference against pancreatic cancer focuses on the development of innovative, translational ways to tackle the disease. Out of that groundwork effort comes this P01 application focusing on pancreatic cancer. As we hope the reviewers will see, our team has already made substantial progress in identifying new targets in and indeed new approaches to pancreatic cancer. This P01 application focuses that ongoing work and translates that work into new therapeutics that will be brought into patients. This P01 contains three translational research projects whose collective aims are to develop new therapeutics for patients with pancreatic cancer. These related Projects include: (1) Treatment of Hypoxia Resistance in Pancreatic Cancer; (2) Method to Eliminate Pancreatic Cells with Specific Patterns of Mutations/Deletions; and (3) Validation of Amplified Genes in Pancreatic Cancer: New sensitizing Targets for Improved Gemcitabine Therapy. Each project already has some leads and each project is designed to maximize translational potential. As will be seen in the application, the Projects are highly integrated so there is the highest probability we can bring that one therapeutic to the clinic each year. The projects are supported by four highly-integrated shared services (cores): (1) Pancreatic Cancer Biospecimens Repository; (2) Pattern Analysis and Computational Biology Core; (3) Drug Development Core; and (4) Evaluation and Administration Core. These cores provide material, informatic, development and administrative support for the projects. Since we are blessed by having such excellent shared services at the Arizona Cancer Center (AZCC), the cores in this proposed P01 are designed to utilize those cores and therefore for this application we are only asking for resources to provide the services that are over an above the services that can be provided by these AZCC cores. In addition, both internal and external scientific advisory boards are included in the P01 to assure maximum input into the science and into the execution of the Projects. The overall goal of this P01 is the delivery into the clinic one new therapeutic agent against a new target in pancreatic cancer each year of the P01. We feel this effort, with new approaches to pancreatic cancer, concentrated in a P01, has a chance to make an impact on the disease.