Simultaneous attack of epithelial and stromal compartments in pancreatic cancer

描述（由申请人提供）：胰腺导管腺癌（PDA）是最致命的癌症之一，因为它的侵袭性生长和诊断通常是在已经发生转移的阶段做出的。由于对控制细胞增殖的生物学机制的不完全理解，或者这些机制的紊乱导致原发器官和转移部位的病理增殖，我们治疗PDA的能力受到限制。在我们最近对小鼠的研究中，我们发现了上皮和间质之间的信号反馈回路，这似乎是内胚层器官增殖活性的中央控制机制。这种增殖控制回路涉及上皮和间质之间的相互信号传导，在上皮中产生Hedgehog （Hh）信号，在间质中产生Wnt等信号。我们建议从遗传学和药理学上测试这种上皮/基质回路在PDA中的作用，特别是同时破坏上皮和基质间室中这种增殖控制回路的药物治疗的效果。该方法可作为PDA治疗的新模式。已知Hh信号通路在PDA的病理生理中起关键作用，因为肿瘤细胞表达Sonic hedgehog （Shh）信号蛋白；该信号激活胰腺间质中Hh通路反应，通过诱导间质细胞增殖，促进典型的PDA的促纤维形成反应。基质中对Hh的反应也增加了其他几种信号的产生，包括Wnt，这些信号似乎通过激活Wnt反应和刺激肿瘤细胞的增殖，在一个互惠的旁分泌循环中起作用。我们选择的内源性PDA小鼠模型忠实地再现了人类PDA的结缔组织增生反应和其他特征，在该模型中，肿瘤的发生是由致癌K-ras的上皮表达驱动的。我们将测试Hh通路拮抗剂与靶向上皮成分的药物联合使用，包括Wnt或致癌K-ras信号转导抑制剂。新开发的超声技术能够以毫米级的分辨率检测和测量体内胰腺肿瘤，从而简化了这种分析，从而减少了在药物治疗测试中测量存活的冗长研究的需要。我们的目标是通过：(i)建立一种策略的有效性，该策略采用靶向药物组合同时攻击PDA的上皮和基质成分；（ii）为FDA批准或处于临床试验后期的药物的早期临床试验的设计和实施提供具体的基础。此外，这项工作可能作为治疗其他内胚层器官恶性疾病的范例。

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.