Simultaneous attack of epithelial and stromal compartments in pancreatic cancer

胰腺癌中上皮和间质室的同时攻击

• 批准号: 8242533
• 负责人: PHILIP A BEACHY
• 金额: $ 21.75万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242533
• 关键词: Affect; Biological; Bladder; Cell Proliferation; Clinical Trials; Connective Tissue; Desmoplastic; Diagnosis; Disease; Distant Metastasis; Drug Delivery Systems; Epithelial; Epithelium; Erinaceidae; FDA approved; Feedback; Functional disorder; Goals; Growth; Human; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Methods; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogenic; Organ; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Pharmaceutical Preparations; Play; Procedures; Production; Protocols documentation; Reporting; Resolution; Role; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Signaling Protein; Site; Staging; Stromal Cells; Stromal Neoplasm; Techniques; Technology; Testing; Ultrasonography; Work; Xenograft procedure; arm; assault; base; design; drug testing; effective therapy; gemcitabine; genetic manipulation; human disease; improved; in vivo; inhibitor/antagonist; millimeter; mouse model; neoplastic cell; pancreatic neoplasm; paracrine; research clinical testing; response; smoothened signaling pathway; therapy design; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of cancer because of its aggressive growth and because diagnosis typically is made at a stage by which metastasis has already occurred. We are limited in our ability to treat PDA by an incomplete understanding of the biological mechanisms that govern cell proliferation, or the derangements in these mechanisms that permit pathological proliferation within the primary organ and at metastatic sites. In our recent studies in the mouse we have discovered a signal feedback circuit between epithelium and stroma that appears to be a central control mechanism governing proliferative activity in endodermal organs. This proliferative control circuit involves reciprocal signaling between epithelium and stroma, with the Hedgehog (Hh) signal produced in the epithelium and Wnt and other signals in the stroma. We propose to test the role of this epithelial/stromal circuit genetically and pharmacologically in PDA and, in particular, the effects of drug treatments designed to simultaneously disrupt this proliferation control circuit in both the epithelial and stromal compartments. This approach may serve as a new model for therapy of PDA. The Hh signaling pathway is known to play a key role in the pathophysiology of PDA, as cells of the tumor express the Sonic hedgehog (Shh) signaling protein; this signal activates Hh pathway response in pancreatic stroma, contributing to the desmoplastic reaction typical of PDA by inducing proliferation of stromal cells. Response to Hh in the stroma also increases the production of several other signals, including Wnts, which appear to act in a reciprocal paracrine loop by activating Wnt response and stimulating proliferation of tumor cells. The desmoplastic reaction and other features of human PDA are faithfully recapitulated in the mouse model of endogenous PDA selected for our work, in which tumorigenesis is driven by epithelial expression of oncogenic K-ras. We will test Hh pathway antagonists in combination with agents that target the epithelial component, including Wnt or oncogenic K-ras signal transduction inhibitors. This analysis will be streamlined by the use of newly developed ultrasound techniques capable of detecting and measuring pancreatic tumors in vivo at millimeter resolution, thereby reducing the requirement for lengthy studies that measure survival in the testing of drug treatments. We aim to rapidly improve therapy for PDA by: (i) establishing the validity of a strategy that employs combinations of targeted agents to simultaneously attack epithelial and stromal components of PDA; and (ii) providing a concrete basis for design and implementation of early clinical trials with drugs that are FDA- approved or in advanced stages of clinical testing. In addition, this work may serve as a paradigm for treatment of malignant disease arising in other endodermal organs. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the most deadly of the major malignancies because it is usually diagnosed at an advanced stage and grows very aggressively. Our goal in this work is to develop more effective therapies by combining drugs that target signaling pathways that are abnormally active within the tumor.

描述（由申请人提供）：胰腺导管腺癌（PDA）是最致命的癌症形式之一，因为它具有侵袭性生长并且通常在已经发生转移的阶段进行诊断。由于对控制细胞增殖的生物机制的不完全理解，或者这些机制的紊乱导致原发器官内和转移部位的病理性增殖，我们治疗 PDA 的能力受到限制。在我们最近对小鼠的研究中，我们发现了上皮和基质之间的信号反馈电路，它似乎是控制内胚层器官增殖活动的中央控制机制。这种增殖控制回路涉及上皮和基质之间的相互信号传导，上皮中产生 Hedgehog (Hh) 信号，基质中产生 Wnt 和其他信号。我们建议从遗传学和药理学角度测试这种上皮/基质回路在 PDA 中的作用，特别是旨在同时破坏上皮和基质区室中这种增殖控制回路的药物治疗的效果。该方法可能成为治疗 PDA 的新模式。 众所周知，Hh 信号通路在 PDA 的病理生理学中发挥着关键作用，因为肿瘤细胞表达音刺猬 (Shh) 信号蛋白；该信号激活胰腺基质中的 Hh 通路反应，通过诱导基质细胞增殖，促进 PDA 典型的促纤维增生反应。基质中对 Hh 的反应也会增加其他几种信号的产生，包括 Wnt，它们似乎通过激活 Wnt 反应并刺激肿瘤细胞增殖，在相互旁分泌环中发挥作用。我们的工作选择的内源性 PDA 小鼠模型忠实地再现了人类 PDA 的促纤维增生反应和其他特征，其中肿瘤发生是由致癌 K-ras 的上皮表达驱动的。 我们将测试 Hh 通路拮抗剂与针对上皮成分的药物（包括 Wnt 或致癌 K-ras 信号转导抑制剂）的组合。通过使用能够以毫米分辨率检测和测量体内胰腺肿瘤的新开发的超声技术，该分析将得到简化，从而减少了在药物治疗测试中测量生存率的冗长研究的需要。我们的目标是通过以下方式快速改善 PDA 的治疗：(i) 确定采用靶向药物组合同时攻击 PDA 上皮和基质成分的策略的有效性； (ii) 为 FDA 批准或处于临床测试后期阶段的药物的早期临床试验的设计和实施提供具体基础。此外，这项工作可以作为治疗其他内胚层器官中发生的恶性疾病的范例。 公共健康相关性：胰腺癌是最致命的主要恶性肿瘤，因为它通常在晚期才被诊断出来，并且生长非常迅速。我们这项工作的目标是通过结合针对肿瘤内异常活跃的信号通路的药物来开发更有效的疗法。