Pancreatic Cancer ARTNet Center

摘要 胰腺癌患者显示出极差的预后，这至少部分是由于对化疗的不良反应。 目前的标准化疗。虽然胰腺肿瘤对 化疗，暴露于化疗导致获得性耐药性的发展。响应和 对化疗的抗性通过肿瘤细胞和伴随细胞中的信号传导和代谢改变来调节。 免疫和非免疫基质的变化。（a）理解信号反应的主要进展 （B）理解对信号传导和环境的代谢适应 （c）开发新的治疗组合，以改善对当前压力的长期反应 护理标准化疗，以及（d）协调NCI领导层的研究/翻译工作，将 在靶向/预防获得性治疗耐药性方面提供了无与伦比的进展。ARTNet中心 胰腺癌（ACPC）旨在通过一个综合研究主题来实现这些目标， 对肿瘤细胞中获得性耐药的代谢和信号传导介质的联合研究， 胰腺癌中的基质重塑将导致新的有效治疗以改善患者预后。 ACPC内部的研究将通过领导层、IAC、EAC、ARTNet网络的良好指导得到促进 NCI计划。该中心的总体目标是研究创新的假设驱动机制， 肿瘤细胞中的代谢和信号传导改变以及肿瘤间质代谢串扰， 胰腺导管腺癌（PDAC）的获得性治疗耐药性。我们假设我们独特的 领导团队，项目和核心领导者的杰出专业知识，独特的技术能力， ACPC的资源、作战设计和强有力的机构支持将推动变革性进展 在获得性治疗抵抗领域，将与其他ARTNet成员和NCI保持一致 计划的使命。为信号传导和代谢的机制方面提供了新的见解 机制，拟议的基础和翻译研究将最终推动新的发展 治疗组合，可以改变癌症治疗的临床过程。完成这项工作的方法是 具体目标：目标1。研究肿瘤界面获得性耐药的新机制- 基质代谢串扰，并检查所鉴定的靶点的临床前功效，以改善治疗效果。 对胰腺癌的反应。目标二。提供强大和创新的工具集和资源来进行调查 并验证了获得性耐药的机制。目标3。促进系统级机制 获得性耐药机制的理解。

Abstract Pancreatic cancer patients show an extremely poor prognosis, which is at least in part due to poor response to the current standard-of-care chemotherapies. While pancreatic tumors present an inadequate response to chemotherapy, exposure to chemotherapy leads to development of acquired resistance. The response and resistance to chemotherapies are modulated by signaling and metabolic alterations in tumor cells and companion changes in the immune and non-immune stroma. Major advances in (a) understanding signaling responses of cancer cells and stroma to therapy, (b) understanding metabolic adaptations to signaling and environmental stressors, (c) development of novel therapeutic combinations to improve long-term response to current standards-of-care chemotherapies, and (d) coordinating research/translation efforts by NCI leadership, will provide unparalleled advances in targeting/preventing acquired therapy resistance. The ARTNet Center for Pancreatic Cancer (ACPC) intends to achieve these objectives through an integrated research theme that combined investigations into the metabolic and signaling mediators of acquired resistance in tumor cells and stromal remodeling in pancreatic cancer will lead to novel effective therapies to improve the patient prognosis. Research within ACPC will be fostered through sound guidance from leadership, IAC, EAC, ARTNet network and NCI program. The overall goal of the Center is to study innovative hypothesis-driven mechanisms of metabolic and signaling alterations in tumor cells and tumor-stromal metabolic crosstalk that contribute to acquired therapy resistance in pancreatic ductal adenocarcinoma (PDAC). We hypothesize that our unique leadership team, outstanding expertise of project and core leaders, singular set of technological capabilities and resources, operational design, and strong institutional support of the ACPC will drive transformative advances in the acquired therapy resistance field that will be in alignment with the other ARTNet members and NCI’s mission for the program. Providing novel insights into the mechanistic aspects of the signaling and metabolic mechanisms, the proposed basic and translational studies will ultimately drive the development of novel therapeutic combinations that can change the clinical course of cancer therapy. This will be achieved through the following Specific Aims: Aim 1. Investigate novel mechanisms of acquired resistance at the interface of tumor- stromal metabolic cross talk and examine the preclinical efficacy of identified targets to improve the therapeutic response against pancreatic cancer. Aim 2. Provide robust and innovative toolsets and resources to investigate and validated mechanisms of acquired therapy resistance. Aim 3. Facilitate a systems-level mechanistic understanding of acquired therapy resistance mechanisms.